Clinical trial NCT03512262
Conditions: Osteoporosis Osteoporosis, Age-Related Osteoporosis Localized to Spine Age Related Osteoporosis Osteoporosis Senile Osteoporosis of Vertebrae
Keywords: BA058 abaloparatide abaloparatide-SC osteoporosis male osteoporosis TYMLOS® fracture bone loss
Sponsor: Radius Health, Inc.
Start date: 2018-05-03; Completion date: 2021-09-08
Enrollment: 228 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A 12-month study to measure the efficacy and safety of abaloparatide in men with osteoporosis.

Detailed description:
The primary objective of this prospective controlled study is to evaluate the efficacy and the safety of abaloparatide 80 micrograms (mcg) per day administered subcutaneously (SC) compared to placebo in men with osteoporosis. Efficacy was primarily assessed by the change in bone mineral density (BMD) over 12 months.

Arms: arm 1: Participants self-administered daily doses of abaloparatide 80 mcg SC using a single-participant, multiple-use, prefilled injection pen that delivers 30 doses. Participants received a new injection pen every 30 days. arm 2: Participants self-administered daily doses of placebo SC using a single-participant, multiple-use, prefilled injection pen that delivers 30 doses. Participants received a new injection pen every 30 days.
Interventions: intervention 1: Abaloparatide intervention 2: Placebo
Intervention descriptions: intervention 1: Abaloparatide is a synthetic peptide that is a potent and selective activator of the parathyroid hormone 1 receptor signaling pathway. intervention 2: Abaloparatide-matched placebo.

Protocol documents:
Prot_000.pdf: 
Radius Health, Inc. (RADIUS) 
22 Boston Wharf Road, 7th Floor 
Boston, MA 02210 USA 
(617) 551-4000
Abaloparatide-SC 
CLINICAL STUDY PROTOCOL: BA058-05-019 
A Randomized, Double-blind, Placebo-controlled, Phase 3 Multicenter Study to Evaluate 
the Safety and Efficacy of Abaloparatide-SC for the Treatment of Men with Osteoporosis 
This study will be conducted according to the protocol and in compliance with Good Clinical Practice, the 
ethical principles stated in the Declaration of Helsinki, and other applicable regulatory requirements. 
Document Type: 
Clinical Study Protocol 
EudraCT Number:  
2017-004220-30  
IND Number: 
73,176 
Version Number: 
Amendment 6 (30 March 2021) 
Development Phase: 
3  
Study Site: 
Multicenter; international  
Protocol Version History 
Version Number 
Version Date 
Original 
12 October 2017 
Amendment 1 
09 January 2018 
Amendment 2 
30 October 2018 
Amendment 3 
06 June 2019 
Amendment 4 
10 December 2019 
Amendment 5 
02 October 2020 
Confidentiality Statement 
The information in this document contains trade secrets and/or commercial information that are privileged 
or confidential and may not be disclosed unless such disclosure is required by applicable law or 
regulations. In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them. These restrictions on 
disclosure will apply equally to all future information supplied to you which is indicated  
as privileged or confidential. 
NCT#: NCT03512262


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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP), as required by 
the International Council for Harmonisation of Technical Requirements of Pharmaceuticals for 
Human Use (ICH) GCP E6 (R2) guidance. 
In addition, I have read the clinical study protocol with the title of: A Randomized, Double-blind, 
Placebo-controlled, Phase 3 Multicenter Study to Evaluate the Safety and Efficacy of 
Abaloparatide-SC for the Treatment of Men with Osteoporosis, Amendment 6 dated 30 March 
2021, and agree to the following conditions: 
• To conduct this study in accordance with the design and provisions of this clinical 
study protocol. 
• To await Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approval for the protocol and informed consent (IC) before initiating enrollment into 
the study. If approval is suspended or terminated by the IRB/IEC the principal 
investigator will notify the Sponsor immediately. 
• To ensure that the requirements for obtaining IC are met and to obtain IC from 
subjects before their enrollment into the study. 
• To provide sufficient and accurate financial disclosure and update information if any 
relevant changes occur during the investigation and for 1 year following the 
completion of the study. 
• To collect and record data as required by this protocol into the case report form 
(CRF). 
• To maintain the confidentiality of all information received or developed in connection 
with this protocol. 
• To conduct this study in accordance with the ICH GCP guideline, the Declaration of 
Helsinki, and all applicable regulatory requirements. 
• To permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s) by providing direct access to source data/documents. 
• To maintain study documentation for the period of time required. 
• To report all adverse events (AEs) within the specified timeframe to Radius Health, 
Inc. (RADIUS) or their designee. 
• To report all serious AEs/incidents within 24 hours after becoming aware of the event 
to the Contract Research Organization and enter the data into the Electronic Data 
Capture system. 
• To adhere to the publication policy of RADIUS Health, Inc. for data collected during 
this study. 
 
 


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Signature of Principal Investigator 
 
 
 
 
 
Date 
Print Name 
 
Site Number 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .................................................................................................2 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................8 
PROTOCOL SYNOPSIS ..............................................................................................................12 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Background .................................................................................................................21 
1.1.1. 
Disease and Study Drug Background .........................................................................21 
1.1.2. 
Study Drug Development ...........................................................................................22 
1.1.2.1. 
Nonclinical Studies in Male Animals .........................................................................22 
1.1.2.2. 
Clinical Studies ...........................................................................................................23 
1.2. 
Study Rationale ...........................................................................................................25 
1.3. 
Dose Rationale ............................................................................................................25 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................31 
2.1. 
Primary Objective and Endpoint ................................................................................31 
2.2. 
Secondary Endpoints ..................................................................................................31 
3. 
STUDY DESIGN .......................................................................................................33 
3.1. 
Description of the Study Design .................................................................................33 
4. 
SELECTION OF STUDY POPULATION ................................................................34 
4.1. 
Inclusion Criteria ........................................................................................................34 
4.2. 
Exclusion Criteria .......................................................................................................35 
4.3. 
Participant Withdrawal or Termination ......................................................................37 
4.3.1. 
Reasons for Withdrawal or Termination ....................................................................37 
4.3.2. 
Handling of Participant Withdrawals or Terminations ...............................................38 
4.4. 
Concomitant Medications ...........................................................................................38 
4.5. 
Prohibited Medications ...............................................................................................39 
4.6. 
Premature Termination or Suspension of Study .........................................................39 
4.7. 
Temporary Suspension of Treatment ..........................................................................39 
4.7.1. 
Treatment Algorithm in Subjects Who Develop Hypercalcemia ...............................40 
4.7.2. 
Treatment Algorithm in Subjects Who Develop Hypercalciuria ...............................41 


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5. 
STUDY DRUG ADMINISTRATION AND MANAGEMENT ...............................43 
5.1. 
Study Medication ........................................................................................................43 
5.1.1. 
Abaloparatide-SC and Placebo ...................................................................................43 
5.1.2. 
Calcium and Vitamin D Supplements ........................................................................43 
5.2. 
Packaging, Labeling and Storage ...............................................................................43 
5.2.1. 
Packaging and Labeling ..............................................................................................43 
5.2.2. 
Storage ........................................................................................................................43 
5.3. 
Treatment Assignment ................................................................................................44 
5.4. 
Dosing and Administration .........................................................................................44 
5.5. 
Treatment Compliance ................................................................................................45 
5.6. 
Drug Accountability ...................................................................................................45 
5.7. 
Unblinding of Study Medication ................................................................................46 
5.7.1. 
Medical Emergency ....................................................................................................46 
6. 
STUDY PROCEDURES AND SCHEDULE ............................................................47 
6.1. 
Study Procedures ........................................................................................................47 
6.1.1. 
Study-Specific Procedures ..........................................................................................47 
6.2. 
Study Schedule ...........................................................................................................47 
6.2.1. 
Schedule of Assessments and Procedures ..................................................................47 
6.2.2. 
Informed Consent Process ..........................................................................................52 
6.2.3. 
Assigning Subject Numbers .......................................................................................52 
6.2.4. 
Subject and Disease Characteristics ...........................................................................52 
6.2.5. 
Screening Period (Visit 1) ..........................................................................................52 
6.2.6. 
Pretreatment Period (Visit 2) ......................................................................................53 
6.2.7. 
Treatment Period ........................................................................................................54 
6.2.8. 
Visit 3 (Day 1) ............................................................................................................54 
6.2.9. 
Visit 4 (Month 1) ........................................................................................................55 
6.2.10. 
Visit 5 (Month 3) ........................................................................................................55 
6.2.11. 
Visit 6 (Month 6) ........................................................................................................56 
6.2.12. 
Visit 7 (Month 9) ........................................................................................................57 
6.2.13. 
Visit 8 (Month 12)/Early Termination Visit ...............................................................57 
6.2.14. 
Visit 9/Safety Follow-up.............................................................................................58 
6.2.15. 
Unscheduled Visit .......................................................................................................58 


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6.3. 
Vital Signs and Physical Examinations ......................................................................58 
6.4. 
12-Lead Electrocardiogram ........................................................................................59 
6.5. 
Laboratory Evaluations ...............................................................................................59 
6.5.1. 
Clinical Laboratory Evaluations .................................................................................59 
6.5.2. 
Serum Markers of Bone Metabolism ..........................................................................60 
6.5.3. 
Immunogenicity Testing .............................................................................................61 
6.5.4. 
Pharmacokinetic Testing ............................................................................................61 
6.5.5. 
Specimen Preparation, Handling and Storage ............................................................61 
6.6. 
Imaging Procedures ....................................................................................................61 
6.6.1. 
Dual Energy X-ray Absorptiometry ...........................................................................61 
6.6.2. 
Quantitative Computed Tomography .........................................................................62 
6.6.3. 
Clinical and Radiologic Evaluation of Fractures ........................................................62 
6.7. 
Discontinuation from the Study ..................................................................................62 
6.7.1. 
Withdrawal of Consent ...............................................................................................63 
6.7.2. 
Early Study Termination .............................................................................................63 
7. 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
DOCUMENTATION .................................................................................................64 
7.1. 
Evaluation of Safety ...................................................................................................64 
7.1.1. 
Adverse Event .............................................................................................................64 
7.1.2. 
Serious Adverse Event ................................................................................................64 
7.1.3. 
Recording an Adverse Event ......................................................................................65 
7.1.3.1. 
Serious and Unanticipated Adverse Device Effects for Abaloparatide-SC ................67 
7.1.4. 
Serious Adverse Event Reporting ...............................................................................67 
7.1.5. 
Device Reporting ........................................................................................................68 
7.1.6. 
Follow-up of Adverse Events .....................................................................................68 
7.1.7. 
Abuse, Misuse, Overdose, or Medication Error .........................................................68 
7.1.8. 
Pregnancy ...................................................................................................................68 
7.1.9. 
Regulatory Agency, Institutional Review Board, Ethics Committee and Site 
Reporting ....................................................................................................................69 
7.2. 
Study Completion and Post-Study Treatment ............................................................69 
7.3. 
Lost to Follow-up .......................................................................................................69 
8. 
STATISTICAL CONSIDERATIONS .......................................................................70 
8.1. 
Statistical and Analytical Plans ..................................................................................70 


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8.2. 
Statistical Hypotheses .................................................................................................70 
8.3. 
Analysis Datasets ........................................................................................................70 
8.3.1. 
Populations for Analysis .............................................................................................70 
8.4. 
Description of Statistical Methods ..............................................................................70 
8.4.1. 
General Approach .......................................................................................................70 
8.4.2. 
Analysis of the Primary Efficacy Endpoint(s) ............................................................70 
8.4.3. 
Analysis of Secondary Endpoint(s) ............................................................................71 
8.4.4. 
Pharmacokinetic Analyses ..........................................................................................73 
8.4.5. 
Safety Analyses ..........................................................................................................73 
8.4.6. 
Adherence and Retention Analyses ............................................................................74 
8.4.7. 
Baseline Descriptive Statistics ....................................................................................74 
8.4.8. 
Interim Analyses .........................................................................................................75 
8.4.9. 
Additional Subgroup Analyses ...................................................................................75 
8.4.10. 
Multiple Comparison/Multiplicity ..............................................................................75 
8.4.11. 
Tabulation of Individual Response Data ....................................................................75 
8.4.12. 
Exploratory Analyses ..................................................................................................75 
8.5. 
Sample Size Calculation .............................................................................................75 
8.6. 
Measures to Minimize Bias ........................................................................................75 
8.7. 
Enrollment/Randomization/Masking Procedures .......................................................75 
9. 
ADMINISTRATIVE REQUIREMENTS ..................................................................76 
9.1. 
Ethical Considerations ................................................................................................76 
9.2. 
Subject Information and Informed Consent ...............................................................76 
9.3. 
Investigator Compliance .............................................................................................76 
9.4. 
Access to Records .......................................................................................................76 
9.5. 
Subject and Data Confidentiality ................................................................................77 
9.6. 
Research Use of Stored Human Samples, Specimens, or Data ..................................77 
9.7. 
Data Quality Assurance ..............................................................................................77 
9.8. 
Monitoring ..................................................................................................................78 
9.9. 
Data Collection and Management Responsibilities ....................................................78 
9.10. 
Study Records Retention ............................................................................................79 
9.11. 
Publication and Data Sharing Policy ..........................................................................79 
10. 
LITERATURE REFERENCES..................................................................................80 


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LIST OF TABLES 
Table 1: 
Summary of PK Data in Subjects Treated with Abaloparatide-SC 80 µg 
(Pooled Data#) .............................................................................................................26 
Table 2: 
Pooled Treatment-Emergent Adverse Events – Differences Between Male 
and Female Subjects in Phase 1 Studies (BA05805-010, BA05805-010, 
BA05805-011, BA05805-012, and BA05805-014) * .................................................29 
Table 3: 
Schedule of Assessments and Procedures ..................................................................48 
Table 4: 
Schedule for Pharmacokinetic Sample Collections ....................................................51 
Table 5: 
Clinical Laboratory Tests ...........................................................................................60 
 
LIST OF FIGURES 
Figure 1: 
L4 Vertebral Body BMD after 4 Weeks of Treatment in Male Rats ..........................23 
Figure 2: 
PK Concentration over Time in Subjects Treated with Abaloparatide-SC 
80 µg (Pooled Data#) ..................................................................................................27 
Figure 3: 
Study BA058-05-012 – Mean (95% CI) Change from Baseline in Serum 
Calcium over Time by Gender for Abaloparatide 80 µg Treatment (Safety 
Population) ..................................................................................................................28 
Figure 4: 
Study BA058-05-019 Design .....................................................................................33 
Figure 5: 
Treatment Algorithm in Subjects Who Develop Hypercalcemia ...............................42 
 


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LIST OF ABBREVIATIONS 
Abbreviation  
Term 
aBMD 
 
Areal bone mineral density 
AE 
 
Adverse event 
AFF 
 
Atypical femoral fracture 
ALT 
 
Alanine aminotransferase  
ANCOVA 
 
Analysis of covariance 
ANOVA 
 
Analysis of variance 
AST 
 
Aspartate aminotransferase  
AUC 
 
Area under the plasma concentration-time curve 
AUC0–∞ 
 
Area under the plasma concentration-time curve from time zero 
to infinity 
AUClast  
 
Area under the plasma concentration-time curve from time zero 
to the time of the last quantifiable concentration 
BMD  
 
Bone mineral density 
BMI 
 
Body mass index  
BP 
 
Blood pressure 
bpm 
 
Beats per minute 
BSAP 
 
Bone-specific alkaline phosphatase 
BUN 
 
Blood urea nitrogen  
BVF 
 
Bone volume fraction 
cAMP 
 
Cyclic adenosine monophosphate 
Cmax 
 
Maximum plasma concentration 
COVID-19 
 
Coronavirus disease 2019 
CPK 
 
Creatine phosphokinase  
CRF 
 
Case report form 
CRO 
 
Contract research organization 
DXA 
 
Dual energy X-ray absorptiometry  
ECG 
 
Electrocardiogram 
eCRF 
 
Electronic case report form 
EDC 
 
Electronic data capture 
EU 
 
European Union 
FDA 
 
Food and Drug Administration 
FRAX 
 
Fracture Risk Assessment  
GCP 
 
Good clinical practice 
GGT 
 
Gamma-glutamyl transpeptidase  
GLP  
 
Good laboratory practice 
Gmean 
 
Geometric mean 
GMP  
 
Good manufacturing practice 
HIPAA 
 
Health Insurance Portability and Accountability Act 


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Abbreviation  
Term 
HIV 
 
Human immunodeficiency virus 
IB 
 
Investigator's Brochure 
IC 
 
Informed consent 
ICF 
 
Informed consent form 
ICH 
 
International Council for Harmonisation 
IEC 
 
Independent Ethics Committee 
IRB 
 
Institutional Review Board 
IRT 
 
Interactive response technology 
ITT 
 
Intention-to-treat 
IUD 
 
Intrauterine device 
IV 
 
Intravenous 
LDH 
 
Lactate dehydrogenase  
LLN 
 
Lower limit of normal 
LOCF 
 
Last observation carried forward 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
mmHg 
 
Millimeter of mercury 
MMRM 
 
Mixed Model for Repeated Measures 
ONJ 
 
Osteonecrosis of the jaw 
ORX 
 
Orchidectomized 
PI 
 
Principal Investigator 
PK 
 
Pharmacokinetic(s) 
PMM 
 
Pattern-mixture model 
PP 
 
Per-Protocol 
PT 
 
Prothrombin time 
PTH  
 
Parathyroid hormone 
PTHR1 
 
Parathyroid hormone related protein type 1 receptor 
PTHrP  
 
Parathyroid hormone related peptide 
PTT 
 
Partial thromboplastin time  
Q1, Q3 
 
Interquartile range 
QA 
 
Quality assurance 
QCT 
 
Quantitative computed tomography 
QT  
 
Total depolarization and repolarization time 
QTc  
 
Total depolarization and repolarization time corrected with heart 
rate 
R0 
 
Non-G protein-coupled 
RANK 
 
Receptor activator of nuclear factor kappa-B 
RBC  
 
Red blood cell 
RG 
 
G protein-coupled 
rhPTH 
 
Recombinant human parathyroid hormone 


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Abbreviation  
Term 
SAE 
 
Serious adverse event 
SAP 
 
Statistical Analysis Plan 
SC 
 
Subcutaneous 
s-CTX 
 
Serum carboxy-terminal cross-linking telopeptide of type I 
collagen 
SD 
 
Standard deviation 
SHBG 
 
Sex hormone binding globulin 
sMTS 
 
Solid microstructured transdermal system 
SOC 
 
System organ class 
SOP 
 
Standard operating procedure 
s-PINP 
 
Serum procollagen type I N-terminal propeptide 
SUSAR 
 
Suspected unexpected serious adverse reaction 
t1/2 
 
Apparent terminal phase half-life 
TEAEs 
 
Treatment-emergent adverse events 
tmax  
 
Time to reach maximum plasma concentration following drug 
administration 
TSH 
 
Thyroid stimulating hormone 
UADE 
 
Unanticipated adverse device effect 
ULN 
 
Upper limit of normal 
US 
 
United States 
vBMD 
 
Volumetric bone mineral density 
WHO 
 
World Health Organization 
 


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PROTOCOL SYNOPSIS 
Title: A Randomized, Double-blind, Placebo-controlled, Phase 3 Multicenter Study to Evaluate 
the Safety and Efficacy of Abaloparatide-SC for the Treatment of Men with Osteoporosis 
Protocol Number: BA058-05-019 
Test Drug: Abaloparatide 80 µg for subcutaneous injection 
Study Objectives and Endpoints 
Objective: The primary objective of this prospective controlled study is to evaluate the efficacy 
and the safety of abaloparatide-subcutaneous (SC) 80 µg per day compared to placebo in men 
with osteoporosis. 
Endpoints 
The primary efficacy endpoint is the percent change from baseline in lumbar spine bone mineral 
density (BMD) at 12 months. 
The key secondary efficacy endpoints are: 
• Percent change from baseline in total hip BMD at 12 months 
• Percent change from baseline in femoral neck BMD at 12 months 
Additional secondary efficacy endpoints are: 
• Percent change from baseline in: 
− Lumbar spine BMD at 3 and 6 months 
− Total hip BMD at 3 and 6 months 
− Femoral neck BMD at 3 and 6 months 
− Ultra-distal radius BMD at 3, 6, and 12 months 
− Distal one-third radius BMD at 3, 6, and 12 months 
• Log ratio of post-baseline over baseline in: 
− Serum procollagen type I N-terminal propeptide (s-PINP) at 1, 3, 6, and 12 
months 
− Serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX) at 1, 
3, 6, and 12 months 
• Proportion of subjects experiencing BMD gains from baseline of > 0%, > 3%, and 
> 6% at the lumbar spine, femoral neck, and total hip at 3, 6, and 12 months 
• Incidence of new clinical fractures at 12 months 
• Proportion of subjects converting from the categories of osteoporosis to osteopenia or 
to normal at 12 months, where: 
− Osteoporosis is defined as lumbar spine or total hip BMD T-score ≤ -2.5.  


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− Osteopenia is defined as one of the following: 
o 
Lumbar spine > -2.5 and total hip BMD T-score > -2.5 and < -1.0  
o 
Lumbar spine > -2.5 and < -1.0 and total hip BMD T-score > -2.5 
− Normal is defined as lumbar spine and total hip BMD T-score ≥ -1.0. 
• The percent change in total hip and femoral neck volumetric BMD (vBMD) as 
measured by quantitative CT (QCT) from baseline to 12 months. QCT will be 
performed in a subset of subjects at a selected number of study sites. 
For those subjects who consent to pharmacokinetic (PK) sample collection, the PK endpoints 
are: 
• The plasma concentration of abaloparatide based on sparse PK sampling at the 
following visits: 
− Month 6: postdose PK samples collected 45 minutes (±15 minutes) and 2.5 hours 
(±0.5 hour) after abaloparatide-SC injection 
− Month 9: postdose PK samples collected 20 minutes (±10 minutes) and 4 hours 
(±0.5 hour) after abaloparatide-SC injection 
− Month 12: a predose sample and a postdose sample collected 1.5 hours 
(±0.5 hour) after abaloparatide-SC injection 
The safety endpoints are: 
• Overall safety and tolerability of abaloparatide-SC in men with osteoporosis as 
assessed by adverse events (AE), vital signs, electrocardiograms (ECGs), laboratory 
tests of chemistry and hematology, urinalyses, local tolerance, and presence of 
antibodies 
Subgroup analyses (e.g., age, geography, Fracture Risk Assessment, FRAX [if applicable], prior 
fracture, and baseline BMD, s-PINP, testosterone, and estradiol levels) may be performed and 
will be described in the Statistical Analysis Plan. 
Study Population 
Men aged 40 to 85 years with primary osteoporosis or osteoporosis associated with 
hypogonadism. 
Inclusion Criteria 
1. The subject is a healthy ambulatory male from 40 to 85 years of age (inclusive) with 
primary osteoporosis or osteoporosis associated with hypogonadism. 
2. The subject has a BMD T-score (based on the male reference range as assessed by the 
central imaging vendor) of: 
a. ≤ -2.5 at the lumbar spine (L1–L4) or hip (femoral neck or total hip) by dual energy 
X-ray absorptiometry (DXA); or 


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b. ≤ -1.5 and with radiologic evidence of vertebral fracture or a documented (radiograph 
films or report) history of low-trauma nonvertebral fracture sustained in the past 5 
years. 
c. Men older than 65 years may be enrolled if they have a BMD T-score ≤ -2.0 even if 
they do not meet the fracture criteria. 
3. The subject is in good general health as determined by medical history and physical 
examination (including vital signs) and is without evidence of a clinically significant 
abnormality in the opinion of the Investigator, or none for which there is a reasonable 
chance of interfering with the subject’s health and/or medical treatment during the study. 
The subject has a body mass index (BMI) of 18.5 to 33, inclusive. The BMI is derived 
from the subject’s height and weight. In the case where a subject’s height cannot be 
adequately assessed (e.g., due to vertebral compression fractures or scoliosis), the subject’s 
historical height (as documented in the subject’s medical record) will be used to derive the 
BMI.  
4. Hypogonadal subjects whose doses of androgens have been stable for at least 12 months 
before randomization are eligible and may continue therapy during the study. 
5. The subject has serum calcium (albumin-corrected), parathyroid hormone (PTH), serum 
phosphorus and alkaline phosphatase, and thyroid stimulating hormone (TSH) values all 
within the normal range during the Screening Period. Any subject with an elevated 
alkaline phosphatase value and who meets all other entry criteria must have a normal 
bone-specific alkaline phosphatase to be enrolled. Any subject with a TSH value outside 
of the normal range must have central laboratory reported T3 and free T4 values within 
the normal ranges to be enrolled. 
6. The subject has serum 25-hydroxyvitamin D values ≥ 20 ng/mL and within the normal 
range. Subjects with serum 25-hydroxyvitamin D levels < 20 ng/ml may be treated with 
vitamin D and retested once during the Screening Period. 
7. The subject’s systolic blood pressure is ≥ 100 and ≤ 155 mmHg, diastolic blood pressure 
is ≥ 40 and ≤ 95 mmHg, and heart rate is ≥ 45 and ≤ 100 bpm (taken sitting or supine). 
Any recorded values outside of these ranges and assessed by the Investigator to be not 
clinically significant must be reviewed with the Medical Monitor and Sponsor for 
approval prior to enrollment. 
8. The subject has no clinically significant abnormality of serum hemoglobin, hematocrit, 
white blood cells and platelets, or usual serum biochemistry: electrolytes, renal function, 
liver function and serum proteins that might be expected to interfere with the subject’s 
health and/or medical treatment during the study. 
9. In subjects who have partners of childbearing potential, the subject and his partner should 
abstain from sexual intercourse, or use highly effective contraceptive measures (e.g., oral 
contraceptive and condom, intrauterine device [IUD] and condom, or diaphragm with 
spermicide and condoms; other forms of contraception must be approved by the Medical 
Monitor) when engaging in sexual intercourse throughout the study, and for at least 90 
days after the last dose of abaloparatide. 
10. The subject has read, understood, and signed the written informed consent form. 


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Exclusion Criteria 
General exclusion criteria: 
1. Presence of abnormalities of the lumbar spine that would prohibit assessment of spinal 
BMD, defined as having at least 2 radiologically evaluable vertebrae within L1–L4 as 
assessed by the central imaging reader. 
Anatomically abnormal vertebrae are excluded if: 
• They are clearly abnormal and non-assessable within the resolution of the system; or 
• There is a more than 1.0 T-score difference between the vertebra in question and 
adjacent vertebrae. 
2. A BMD T-score of ≤ -3.5 at the total hip, femoral neck or lumbar spine based upon the 
male reference range. 
3. Unevaluable hip BMD or subjects who have undergone bilateral hip replacement 
(unilateral hip replacement is acceptable). 
4. Fragility fracture within the past 12 months. 
5. History of severe vertebral fracture or > 2 moderate vertebral fractures. 
6. History of bone disorders (e.g., Paget’s disease) other than osteoporosis. 
7. Subjects with clinical signs of hypogonadism present at screening who plan to initiate 
testosterone replacement. 
8. History of prior external beam or implant radiation therapy involving the skeleton, other 
than radioiodine. 
9. History of chronic or recurrent renal, hepatic, pulmonary, allergic, cardiovascular, 
gastrointestinal, endocrine, central nervous system, hematologic or metabolic diseases, or 
immunologic, emotional and/or psychiatric disturbances to a degree that would interfere 
with the interpretation of study data or compromise the safety of the subject. 
10. History of Cushing’s disease, growth hormone deficiency or excess, hyperthyroidism, 
hypo- or hyperparathyroidism or malabsorptive syndromes within the past year. 
11. History of significantly impaired renal function (serum creatinine > 177 μmol/L or 
> 2.0 mg/dL). If the serum creatinine is > 1.5 and ≤ 2.0 mg/dL, the calculated creatinine 
clearance (Cockcroft-Gault) must be ≥ 37 mL/min. 
12. History of any cancer within the past 5 years (other than basal cell or squamous cancer of 
the skin). 
13. History of osteosarcoma at any time. 
14. Subjects with hereditary disorders predisposing to osteosarcoma. 
15. History of nephrolithiasis or urolithiasis within the past 5 years. 
16. Subjects known to be positive for Hepatitis B, Hepatitis C, human immunodeficiency 
virus (HIV)-1 or HIV-2. Testing is not required in the absence of clinical signs and 
symptoms suggestive of HIV infection or acute or chronic hepatitis. 


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Medication-related exclusion criteria: 
17. Known history of hypersensitivity to any of the test materials or related compounds. 
18. Prior treatment with PTH- or parathyroid hormone related protein (PTHrP)-derived 
drugs, or bone anabolic drugs including abaloparatide, teriparatide, or PTH(1-84). 
19. Prior treatment with intravenous (IV) bisphosphonates at any time or oral 
bisphosphonates within the past 3 years. Subjects who had received a short course of oral 
bisphosphonate therapy (3 months or less) may be enrolled as long as the treatment 
occurred 6 or more months prior to enrollment. 
20. Treatment with fluoride or strontium in the past 5 years or prior treatment with gallium 
nitrate or other bone-acting investigational agents at any time. Limited use of gallium 
citrate/nitrate for diagnostic purposes (i.e., a gallium scan) is not exclusionary. 
21. Prior treatment with calcitonin or tibolone in the past 6 months. 
22. Prior treatment with denosumab within the past 18 months. 
23. Treatment with anticonvulsants that affect vitamin D metabolism (phenobarbital, 
phenytoin, carbamazepine, or primidone) or with chronic heparin within the 6 months 
prior to the Screening Period. 
24. Treatment with anabolic steroids or calcineurin inhibitors (cyclosporin, tacrolimus) 
within the past 90 days.  
25. Daily treatment with oral, intranasal, or inhaled corticosteroids within the 12 months 
prior to the Screening Period. Occasional use of all corticosteroids (for seasonal allergies 
or asthma) is not exclusionary. 
26. Exposure to an investigational drug within the 12 months prior to the Screening Period. 
Lifestyle-related exclusion criteria: 
27. Abnormal nutritional status (as assessed by the Investigator), vitamin D intake of 
≥ 4,000 IU/day or vitamin A intake of ≥ 10,000 IU/day. Short term use of high doses of 
vitamin D to increase endogenous vitamin D levels for study entry is not exclusionary. 
28. Subject is known to consume > 2 alcoholic drinks per day, to use illegal drugs, or to 
abuse tobacco or marijuana (medicinally or recreationally where legal) within 12 months 
of the Screening Period. The Investigator must determine and document use vs. abuse of 
tobacco or marijuana. 
Design and Methodology 
Number of Subjects 
Approximately 225 men will be enrolled into the study. 
Design 
This is a randomized, double-blind, placebo-controlled, Phase 3, multicenter study enrolling 
approximately 225 subjects at approximately 40 study sites designed to evaluate the efficacy and 
safety of abaloparatide-SC 80 µg per day for the treatment of osteoporosis in men. The study will 
consist of a Screening Period (up to 2 months), a Pretreatment Period (1 week), and a Treatment 


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Period (12 months) with a final visit 1 month after the last dose of study medication (Follow-up 
Visit). Eligible subjects will be randomized, on a 2:1 basis, to receive either abaloparatide-SC 
80 µg per day or matched-SC placebo injections for 12 months to determine the effect of 
abaloparatide on lumbar spine BMD and other bone health-related endpoints. Both groups of 
subjects will undergo protocol-specified procedures (Schedule of Assessments and Procedures, 
Table 3) including BMD and fracture assessments. The study design is presented in the figure 
below. 
Protocol BA058-05-019 Study Design 
 
Study Visits 
All subjects will have clinic visits for study-related procedures at Day 1, Month 1, Month 3, 
Month 6, Month 9, and Month 12, with a Follow-up Visit 1 month after the last dose of study 
medication. For the purposes of this study 1 month is equal to 30 days. 
Treatments Administered 
Eligible subjects will be randomly allocated, using a 2:1 randomization ratio using a permuted 
block randomization on Day 1 to receive treatment with either blinded abaloparatide-SC 80 µg 
per day or daily abaloparatide-SC placebo injections, respectively. Treatment will be blinded to 
subjects, Investigators, and the Sponsor throughout the study unless unblinding is necessary for 
subject treatment in the case of medical emergency, and with exception of Sponsor 
pharmacovigilance and/or regulatory personnel as needed for suspected unexpected serious 
adverse reaction (SUSAR) reporting purposes. All subjects will be provided calcium and vitamin 
D to ensure that their daily intake is in the range of calcium 500–1000 mg/day and vitamin D 
400-800 IU/day, or a dose determined by the Investigator and agreed by the Sponsor Medical 
Monitor, according to the subject’s need. 
Procedures and Assessments 
Refer to the Schedule of Events for full details about the procedures and assessments required at 
each study visit. 


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During the Screening Period, informed consent will be obtained, eligibility for study entry 
assessed, and screening evaluations performed, including baseline lumbar and thoracic spine 
radiographs, BMD assessments by DXA, serum total testosterone, sex hormone binding 
globulin, and baseline laboratory tests. 
• Subjects whose laboratory tests do not fall within the specified ranges as detailed in 
the inclusion/exclusion criteria may have the samples redrawn and the tests repeated 
once during the Screening Period. If upon retesting, the values fall within the 
inclusion/exclusion criteria, the subject may enter the study. 
• Subjects who do not meet the vitamin D entry criterion (their 25-hydroxyvitamin D is 
less than 20 ng/ml) may receive vitamin D supplementation and be retested once 
during the Screening Period as may subjects with minor elevations of PTH. All 
subjects enrolled following retesting must have safety labs within 30 days of 
randomization (Day 1). 
Following these evaluations, eligible subjects will enter the Pretreatment Period of the study and 
will be given daily calcium and vitamin D supplements, which will continue until the end of the 
Treatment Period. Subjects will also receive training in the use of the injector pen for self-
administration. 
At Day 1, the subject will have baseline assessments including bone turnover markers, 
immunogenicity testing, DXA of the wrist, and QCT measurement at the hip (at a subset of 
sites).  
During the Treatment Period, subjects will self-administer a single subcutaneous dose of the 
randomly assigned study medication once a day. Subjects will have clinic visits for study-related 
protocol procedures at Day 1, Month 1, Month 3, Month 6, Month 9, and Month 12. Study 
procedures will include the measurement of BMD by DXA and collection of serum samples to 
assess markers of bone turnover. At each visit, clinical fractures will also be assessed. Serum 
samples for evaluation of calcium after study drug administration and immunogenicity testing 
will be drawn at specified visits during the Treatment Period.  
Statistical Considerations 
The primary population for efficacy analyses will be the Intention-to-Treat (ITT) Population, 
defined as all subjects randomized into this study. The primary population for safety analyses 
will be the Safety Population, defined as all subjects who received at least one dose of study 
medication. The Per-Protocol Population will include all ITT subjects who did not have any 
significant protocol deviations and will be used for supportive analyses. 
Sample Size 
A study sample size of 225 subjects (150 in the abaloparatide-SC group and 75 in the placebo 
group) will provide at least 99% power to detect a mean difference of 6.5% in the percentage 
change from baseline in lumbar spine BMD at 12 months between the abaloparatide-SC and the 
placebo groups at a 2-sided alpha of 0.01, assuming a standard deviation (SD) of 6.0% and a 
drop-out rate of 10%. 
For the key secondary endpoints, this total sample size of 225 subjects will have 96% power to 
detect a 2.2% mean difference (SD = 3.5%) of percent change in total hip BMD at 12 months 


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and 80% power to detect a 2.0% mean difference (SD = 4.1%) of percent change in femoral neck 
BMD at 12 months. 
Baseline Comparisons 
Baseline characteristics, medical history, physical examination, vital signs, and ECGs will be 
summarized using standard descriptive statistics by treatment group. 
Efficacy Analysis 
The primary and key secondary efficacy endpoints will be analyzed using a fixed-sequence 
testing procedure to control the family-wise error rate for any joint distribution of hypothesis test 
statistics. To claim statistical significance at the 2-sided level of 1%, the following 3 fixed-
sequence tests will be performed in sequential order. At any step of the sequential testing, if the 
treatment difference is not statistically significant at the 1% level then all the subsequent 
comparisons following the fixed sequence cannot be claimed statistically significant. 
1. Percent change from baseline in BMD at the lumbar spine at 12 months 
2. Percent change from baseline in BMD at the total hip at 12 months 
3. Percent change from baseline in BMD at the femoral neck at 12 months 
P-values for treatment comparisons of all other efficacy endpoints will be generated to support 
the study findings without any adjustments for multiplicity. 
For the analysis of BMD data, the primary analysis will be based on a pattern-mixture model 
(PMM) analysis with multiple imputation using the wash-out imputation method. This method 
uses sequential regression and wash-out imputation methodology to impute missing values after 
a subject’s discontinuation from the study. The missing primary endpoint values for subjects in 
the abaloparatide-SC group will be imputed with the observed baseline and data from the 
placebo group; no intermediate values from the abaloparatide-SC group will be used in the 
imputation for the abaloparatide-SC group. For subjects in the placebo group, intermediate 
observed values from the completers in the placebo group will be used while imputing missing 
values during the 12-month Treatment Period. The PROC MI methodology for imputation of 
monotone missing data patterns will be used to impute the outcome variables at consecutive 
visits in a sequential (chain) manner. Each of these imputed datasets will be analyzed using 
analysis of covariance (ANCOVA) with treatment and DXA instrument manufacturer as fixed 
effects and the baseline lumbar spine BMD as a covariate. Results from all imputed datasets will 
be combined using PROC MIANALYZE for overall statistical inference. The statistical tests will 
be 2-sided comparing abaloparatide-SC to placebo; 99% CIs will be presented together with the 
estimated p-values. 
Analysis of bone turnover markers, s-PINP and s-CTX, will be based on the ratio of the post-
baseline value relative to the baseline value at each visit. The transformation of the loge ratio of 
post-baseline versus baseline value will be used to normalize the distributions of the s-PINP and 
s-CTX parameters. The analysis comparing abaloparatide-SC with placebo will use a PMM 
analysis with multiple imputation using the wash-out imputation method, as described for BMD. 
Safety Analysis 
Safety analysis will be analyzed descriptively and will include the following parameters: 


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• Treatment-emergent AEs (TEAEs) 
• Changes in vital signs (including orthostatic blood pressure [BP]), ECGs, and 
laboratory (hematology, serum chemistry, and urinalysis) tests 
• Investigator and subject assessment of local tolerance 
• Presence of antibodies 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Safety 
Recent health status will be obtained, the diary reviewed, and AEs collected at each visit and 
vital signs will be performed at each clinic visit. Laboratory assessments of chemistry and 
hematology, and urinalyses will be obtained at screening, and at Month 1, Month 6, and 
Month 12. A final visit will take place 1 month after the last dose of study medication. 
Any subject who demonstrates decreases in BMD ≥ 7% from baseline of this study at the lumbar 
spine or total hip will have the assessment repeated and, if confirmed, will be notified by the 
Investigator, and be withdrawn from the study. Subjects sustaining a radiologically confirmed 
incident vertebral or nonvertebral fragility fracture will be informed of the finding and will be 
counseled as to treatment options and may discontinue or choose to remain on the study. Should 
a subject who experiences an incident clinical vertebral or nonvertebral fragility fracture choose 
to remain in the study, he will be asked to sign an additional informed consent form explaining 
the potential risks and benefits of remaining in the study. 
Duration of Subject Participation: 
Participation will be up to 16 months (12 months total treatment duration). 


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1. 
INTRODUCTION 
1.1. 
Background 
Human parathyroid hormone (PTH) is a naturally occurring 84 amino acid hormone and is 
primarily a regulator of calcium homeostasis (Mannstadt et al, 1999). PTH acts directly on bone 
to increase calcium resorption, on the gastrointestinal system to increase calcium absorption, and 
on the kidney to increase calcium reabsorption and 1,25-dihydroxyvitamin D production. In turn, 
PTH levels are tightly regulated by calcium and vitamin D levels. When given intermittently at 
low doses, PTH has a well-documented anabolic effect on bone, and can increase bone mineral 
density (BMD) in a number of intact animal models and in osteoporotic subjects (Dempster et al, 
1993). 
Abaloparatide (marketed as TYMLOS® in the United States [US]) is a novel, synthetic, 34 amino 
acid peptide designed to be a potent and selective activator of the PTH/PTH-related protein 
(PTHrP) type 1 receptor (PTHR1) signaling pathway with 41% homology to PTH[1–34]) and 
76% homology to human PTHrP[1–34]. Abaloparatide is differentiated from PTH and PTHrP 
ligands based on its high affinity and > 1,000-fold greater selectivity for the G protein-coupled 
(RG) vs the non-G protein-coupled (R0) conformation of PTHR1 (Hattersley et al, 2016). 
Differential PTHR1-RG binding with abaloparatide results in potent and transient intracellular 
cyclic adenosine monophosphate (cAMP) signaling. In nonclinical studies, the transient PTHR1 
activation with abaloparatide strongly favors bone anabolism with a limited effect on bone 
resorption (Makino et al, 2015). Thus, abaloparatide was developed with the expectation that it 
would be effective at increasing BMD and reducing fracture in individuals with osteoporosis, but 
with a limited effect on bone resorption and a reduced risk of hypercalcemia. 
1.1.1. 
Disease and Study Drug Background 
Osteoporosis is a systemic skeletal disease characterized by low bone mass and 
microarchitectural deterioration of bone tissue that leads to enhanced fragility and increased risk 
of fractures (Rizzoli et al, 2001). This disease is characterized by low BMD and fractures. The 
fractures associated with the greatest morbidity and mortality, as well as economic burden to 
society, together make up the clinically significant and medically relevant group termed major 
osteoporotic fractures. In the US, there are an estimated 2 million osteoporotic fractures annually 
(Litwic et al, 2014). The number of osteoporotic fractures is projected to increase in both men 
and women by more than 3-fold over the next 50 years as a result of the aging population (WHO 
2007). 
Although osteoporosis predominantly affects postmenopausal women, approximately 20% of 
men over the age of 50 years will sustain an osteoporotic-related fracture in their lifetime. In 
2005, the total cost of treatment and rehabilitation for fractures in men in the US was $4.1 billion 
and this is projected to rise to $6.8 billion in 2025 (IOF 2014). Most men experience bone loss 
with aging and low BMD is frequent in older men and a risk factor for fracture. Many different 
risk factors may contribute to bone loss and fracture risk in men, including most importantly 
hypogonadism, glucocorticoids, and excessive alcohol use (Ebeling 2008). Additionally, some 
men develop osteoporosis without apparent cause, so-called idiopathic osteoporosis (Khosla 
2008).  


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Bone remodeling occurs through the action of osteoclasts, which are involved in the resorption 
of bone followed by the formation of new bone by osteoblasts. In addition to continued use of 
calcium and vitamin D, the current therapeutic approach to the treatment of osteoporosis through 
inhibition of bone resorption includes agents such as bisphosphonates (Rosen 2005) or 
monoclonal antibody denosumab, that inhibits the action of osteoclasts by binding to receptor 
activator of nuclear factor kappa-B (RANK) ligand. An alternative approach has been to tip the 
balance between osteoblastic bone formation and osteoclastic resorption through the use of 
parathyroid hormone receptor modulation using teriparatide (rhPTH[1–34]). 
Until recently, teriparatide has been the only approved osteoporosis treatment in which the major 
mode of action is stimulation of bone formation (anabolic) rather than suppression of bone 
resorption. The efficacy of teriparatide has important limitations related to its delayed and 
modest effects on increasing BMD at the total hip and femoral neck, and on decreasing BMD at 
the distal one-third radius. The increase in cortical porosity that can occur may result in 
maladaptive effects on cortical bone microarchitecture (Bilezikian 2007). Abaloparatide has been 
evaluated in a number of nonclinical and clinical studies for its potential as a novel treatment for 
osteoporosis. Based on the biology of the PTH1 receptor signaling pathway, abaloparatide is 
designed to have less resorptive and hypercalcemic effects than PTH, resulting in a greater net 
anabolic effect. Abaloparatide has recently been approved in the US for the treatment of women 
with postmenopausal osteoporosis at high fracture risk. In addition to their role in the 
management of postmenopausal osteoporosis, bisphosphonates, denosumab, and teriparatide 
have also been approved for the treatment of osteoporosis in men or to increase bone mass in 
men with osteoporosis. 
1.1.2. 
Study Drug Development 
1.1.2.1. 
Nonclinical Studies in Male Animals 
Abaloparatide was tested in a non-Good Laboratory Practice (GLP) pharmacology study 
(16RADL120) using a male rat castration (orchidectomized [ORX]) model of osteoporosis. Male 
rats underwent ORX or sham surgery at approximately 3 months of age and following a 4-week 
bone depletion period. Treatment was then initiated with either abaloparatide (20 μg/kg/d, n = 8) 
or vehicle (n = 8) once daily for an additional 4-weeks. After 8 weeks of androgen deficiency, 
the ORX group had 13% lower L4 BMD and 17% lower trabecular bone volume fraction (BVF), 
compared with sham controls. After 4 weeks of treatment, the abaloparatide treated group had a 
17% greater L4 BMD, 50% greater BVF, and 33% greater trabecular thickness compared with 
ORX controls (all p < 0.0001), Figure 1. Trabecular bone pattern factor was 39% lower 
compared with ORX controls (p < 0.05), suggesting a more organized and better-connected 
trabecular architecture. The abaloparatide group also had 24% greater BVF and 29% greater 
trabecular thickness, compared with sham controls (both p < 0.01). These data demonstrate that 
abaloparatide reversed vertebral BMD loss and restored trabecular microarchitectural 
deterioration in ORX rats by increasing trabecular bone volume and thickness. 


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Figure 1: 
L4 Vertebral Body BMD after 4 Weeks of Treatment in Male Rats 
 
Two rodent GLP nonclinical studies were completed evaluating abaloparatide effects on male 
reproduction following repeated subcutaneous administration. A 4-week repeat-dose toxicology 
study with male fertility assessment (BA058-114) and a definitive male fertility study with an 
early embryonic development component (SBL062-288) were performed. In both studies, 
Abaloparatide failed to produce adverse effects in male fertility indices, fecundity, early 
embryonic development, and spermatogenesis at exposures up to 128-fold human exposure 
(animal: human exposure multiple) based on a human area under the concentration-time curve 
(AUC) of 1546 pg*hr/mL from Study BA058-05-001B and AUC from the rat 28-day repeat-
dose toxicology Study BA058-114. 
Abaloparatide was tested in repeat-dose toxicity studies in male rats up to 70 μg/kg for up to 
26 weeks (BA058-114, BA058-115 and 7801-124), and in male monkeys at 10 μg/kg for up to 
39 weeks (BA058-119 and 7801-125). The conclusions from the repeat-dose toxicity studies 
were consistent with a primary pharmacology of abaloparatide associated with a new bone 
formation in male animals. There were no significant differences in safety, tolerability or 
histopathological findings between male and female animals noted in these studies. These 
nonclinical results are consistent with abaloparatide having positive bone anabolic effect in male 
animals. 
1.1.2.2. 
Clinical Studies 
There are 19 completed and ongoing clinical studies which comprise the abaloparatide-
subcutaneous (SC) and abaloparatide-solid microstructured transdermal system (sMTS) clinical 
development program. The abaloparatide-SC clinical trial program consists of 11 clinical trials, 
including a large pivotal Phase 3 study (BA058-05-003) followed by an open-label extension 
(Study BA058-05-005) and Phase 2 studies in postmenopausal women with osteoporosis 
(abaloparatide-SC Studies BA058-05-002 and BA058-05-002 extension as well as 
BA058-05-007, an abaloparatide-sMTS study in which abaloparatide-SC at a dose of 80 µg was 
0.44
0.46
0.48
0.5
0.52
0.54
0.56
0.58
SHAM
ORX
ORX + ABL
gHA/cc
Day 28


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used as the active comparator) and Phase 1 studies in healthy postmenopausal women, healthy 
male and female subjects, and subjects with renal impairment. 
In the pivotal Phase 3 study (BA058-05-003, the ACTIVE trial), 2,463 postmenopausal women 
were randomized to receive daily 80 µg abaloparatide-SC (n = 824), placebo (n = 821), or 
teriparatide 20 µg (n = 818) (rhPTH 1-34) for 18 months. In this trial, abaloparatide-SC and 
teriparatide significantly reduced the risk of new morphometric vertebral fractures, by 86% and 
80%, respectively, compared to placebo. Abaloparatide-SC significantly reduced nonvertebral, 
major osteoporotic and clinical fractures compared to placebo. Compared to teriparatide, 
abaloparatide significantly reduced major osteoporotic fractures. The Kaplan-Meier plots 
indicate an early and sustained fracture risk reduction of nonvertebral, major osteoporotic and 
clinical fractures with abaloparatide-SC treatment. Abaloparatide-SC has an acceptable safety 
profile, and consistent with reduced abaloparatide-SC-mediated calcium mobilization, the rates 
of hypercalcemia were lower in the abaloparatide-SC group compared to the teriparatide group. 
In the ACTIVExtend trial (BA058-05-005), subjects who were in the abaloparatide-SC or 
placebo arms were transitioned to oral alendronate 70 mg weekly. Subjects who received 
18 months of abaloparatide-SC followed by 6 months of alendronate experienced no new 
morphometric vertebral fractures from Study 005 baseline and continued to have statistically 
significant reductions in nonvertebral, major osteoporotic, and clinical fractures when compared 
to subjects who previously received 18 months of placebo followed by 6 months of alendronate. 
These results validate the osteoporosis treatment paradigm of build (with an anabolic agent), and 
then maintain and consolidate gains (with an antiresorptive agent). 
Abaloparatide-SC demonstrated an increase in BMD at the lumbar spine, total hip, femoral neck, 
and ultra-distal radius in osteoporosis subjects, consistent with the fracture risk reduction. The 
results from the ACTIVE trial and the first 6 months of the ACTIVExtend trial, together with the 
entire data set from the abaloparatide-SC development program, support the safety and efficacy 
of abaloparatide-SC for the reduction of fractures in postmenopausal women with osteoporosis. 
At the 43-month timepoint, the previous abaloparatide-SC treated subjects, who received up to 
2 years of treatment with alendronate, had a significant 84% relative risk reduction (p < 0.0001) in 
the incidence of new vertebral fractures compared with women who received placebo followed by 
alendronate for up to 2 years. They also demonstrated a 39% risk reduction in nonvertebral 
fractures (p = 0.038), a 34% risk reduction in clinical fractures (p = 0.045) and a 50% risk 
reduction in major osteoporotic fractures (p = 0.011) compared with women who received placebo 
followed by alendronate. 
The adverse events (AEs) were comparable between abaloparatide-SC treated subjects and the 
previous placebo group. The incidences of cardiovascular AEs including serious adverse events 
(SAEs) were similar between groups. There have been no cases of osteonecrosis of the jaw (ONJ) 
or atypical femoral fracture (AFF) in the entire abaloparatide-SC development program. 
Overall, the clinical results of abaloparatide-SC-mediated early vertebral and nonvertebral 
fracture risk reduction and increases in BMD are consistent with the known anabolic mechanism 
of action, changes in bone turnover markers and nonclinical results. 
For the most up-to-date information on clinical studies with abaloparatide, refer to the 
abaloparatide Investigator’s Brochure (IB).  


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1.2. 
Study Rationale 
As noted above, abaloparatide-SC recently became the second bone anabolic agent to be 
approved for the treatment of postmenopausal osteoporosis. While other agents from both 
anabolic and antiresorptive classes of anti-osteoporosis therapies have also been approved for the 
treatment of osteoporosis in men, the safety and efficacy of abaloparatide has yet to be 
demonstrated in osteoporotic men. However, given the existence of an enhanced therapeutic 
response to abaloparatide-SC in postmenopausal women at high risk of fracture, as well as the 
substantive morbidity and mortality burden associated with osteoporotic fractures, confirmation 
of a similarly robust effect of abaloparatide-SC in men is indeed a clinical priority. The present 
study seeks to provide that confirmation, in order for abaloparatide-SC to be made available to 
men with osteoporosis and whose clinical need remains unmet by currently available therapies. 
1.3. 
Dose Rationale 
The approved dose of abaloparatide-SC in the US for the treatment of postmenopausal women at 
a risk for fracture is 80 µg per day, this is also the proposed dose in the European Union (EU). 
While the long-term treatment of men with abaloparatide-SC has not been evaluated, Phase 1 
studies have been conducted to evaluate pharmacokinetics following a single administration of 
abaloparatide-SC, at a dose of 80 µg in both male and female subjects, the proposed dose 
selected for the present study. 
To provide a comparison of pharmacokinetics (PK) and safety for male and female subjects, the 
data from 3 recent Phase 1 clinical trials were pooled (BA058-05-010 was a 
bioavailability/maximum tolerated dose study, BA058-05-011 was a study in subjects with 
varying degrees of renal disease, BA058-05-012 was a study to determine the effects of 
abaloparatide-SC on total depolarization and repolarization time / total depolarization and 
repolarization time corrected with heart rate (QT/QTc) and BA058-05-014 was a study done to 
provide initial evaluation of the bioequivalence of abaloparatide administered subcutaneously 
from 2 similar pen injectors to healthy male and female subjects). Summary PK data are 
presented in Table 1. The 90% CIs for the ratio of AUC and for the ratio of maximum serum 
concentration (Cmax) between males and females were generated based on an analysis of variance 
(ANOVA) model with sex as fixed effect. Maximal time (tmax) values were compared using a t-
test. These results show that there were no differences in the systemic exposure of abaloparatide-
SC between male and female subjects following a single administration of abaloparatide-SC at a 
dose of 80 µg. 


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Table 1: 
Summary of PK Data in Subjects Treated with Abaloparatide-SC 80 µg 
(Pooled Data#) 
Parameters (Unit) 
Statistics 
Female 
Male 
AUClast (pg*h/mL) 
n 
 64 
 92 
Mean (SD) 
664.49 (349.232) 670.41 (345.728) 
Median 
618.50 
567.53 
Q1, Q3 
469.68, 743.95 
390.45, 926.21 
Min, Max 
128.0, 2288.3 
156.9, 1832.0 
MSE 
43.654 
36.045 
Gmean 
591.28 
588.07 
Ratio of Male/Female (90% CI) [1] 
0.9946 (0.8664, 1.1417) 
Ratio of Male/Female (90% CI) [2] 
1.0049 (0.8781, 1.1501) 
AUC0–∞ (pg*h/mL) 
n 
 61 
 88 
Mean (SD) 
703.39 (359.555) 724.75 (363.382) 
Median 
644.00 
618.39 
Q1, Q3 
505.33, 775.74 
428.35, 980.34 
Min, Max 
194.0, 2325.4 
176.2, 1923.0 
MSE 
46.036 
38.737 
Gmean 
632.53 
641.28 
Ratio of Male/Female (90% CI) [1] 
1.0138 (0.8861, 1.1600) 
Ratio of Male/Female (90% CI) [2] 
1.0323 (0.9056, 1.1768) 
Cmax (pg/mL) 
n 
 64 
 92 
Mean (SD) 
524.69 (168.997) 467.17 (152.786) 
Median 
507.00 
455.00 
Q1, Q3 
416.00, 618.00 
366.00, 545.00 
Min, Max 
198.0, 1140.0 
214.0, 928.0 
MSE 
21.125 
15.929 
Gmean 
498.86 
443.77 
Ratio of Male/Female (90% CI) [1] 
0.8896 (0.8153, 0.9706) 
Ratio of Male/Female (90% CI) [2] 
0.8943 (0.8195, 0.9758) 
tmax (h) 
n 
 64 
 92 
Mean (SD) 
0.40 (0.191) 
0.42 (0.177) 
Median 
0.33 
0.33 
Q1, Q3 
0.25, 0.50 
0.25, 0.50 
Min, Max 
0.3, 1.1 
0.3, 1.1 
MSE 
0.024 
0.018 
Gmean 
0.36 
0.39 
P-value [3] 
0.4177 
t½ (h) 
n 
 62 
 89 
Mean (SD) 
1.26 (2.270) 
1.07 (0.565) 
Median 
0.96 
0.95 
Q1, Q3 
0.77, 1.11 
0.67, 1.30 
Min, Max 
0.5, 18.7 
0.4, 3.2 
MSE 
0.288 
0.060 
Gmean 
0.97 
0.96 
# The data include studies BA058-05-010, BA058-05-011, BA058-05-012, and BA058-05-014. Ten female subjects 
and 17 male subjects in Study BA058-05-014 received 2 doses of abaloparatide-SC; both PK profiles are included in 
the summary table. 
[1] Ratio is based on ANOVA model with sex as fixed effect. 


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[2] Ratio is based on ANOVA model with sex and study as fixed effects. 
[3] P-value is based on T-test 
AUC0–∞ = area under the plasma concentration-time curve from time zero to infinity; AUClast = area under the plasma 
concentration-time curve from time zero to the time of the last quantifiable concentration; Cmax = maximum plasma 
concentration; Gmean = geometric mean; MSE = standard error of the mean;.Q1, Q3 = interquartile range; SD = 
standard deviation; t1/2 = apparent terminal phase half-life; tmax = time to reach maximum plasma concentration 
following drug administration. 
Postdose BQL values were set to half the LLOQ for computation of mean postdose concentration values. 
 
There were also no apparent differences in abaloparatide clearance (Figure 2). 
 
Figure 2: 
PK Concentration over Time in Subjects Treated with Abaloparatide-SC 
80 µg (Pooled Data#) 
 
# The data include studies BA058-05-010, BA058-05-011, BA058-05-012, and BA058-05-014. 
Abaloparatide Concentration Mean (+/- SE) (pg/mL)
0
50
100
150
200
250
300
350
400
450
500
550
Time Point (Hour)
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Female
Male


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Figure 3: 
Study BA058-05-012 – Mean (95% CI) Change from Baseline in Serum 
Calcium over Time by Gender for Abaloparatide 80 µg Treatment (Safety 
Population) 
 
In the clinical trial of women with postmenopausal osteoporosis (BA058-05-003), 
abaloparatide-SC caused increases in serum calcium concentrations, evident at 4-hours post 
administration. Serum calcium concentrations were assessed in both male and female subjects in 
Study BA058-05-012. In this study, male and female subjects were dosed with a single injection 
of 80 µg of abaloparatide-SC. Serum calcium levels were measured at baseline, and at 2, 4, and 
8 hours postdose. Although the levels across time were slightly higher in males than in females 
(Figure 3), the temporal pattern of change in serum calcium concentration was similar, with the 
maximal concentrations observed approximately 4 hours after dosing. 


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Table 2: 
Pooled Treatment-Emergent Adverse Events – Differences Between Male 
and Female Subjects in Phase 1 Studies (BA05805-010, BA05805-010, 
BA05805-011, BA05805-012, and BA05805-014) * 
System Organ Class 
  Preferred Term 
Female 
(N = 54) 
n (%) 
Male 
(N = 77) 
n (%) 
At Least one TEAE 
25 (46.3) 
16 (20.8) 
 
Cardiac disorders 
2 (3.7) 
1 (1.3) 
  Bundle branch block left 
1 (1.9) 
0 
  Palpitations 
1 (1.9) 
0 
  Postural orthostatic tachycardia syndrome 
0 
1 (1.3) 
 
Gastrointestinal disorders 
4 (7.4) 
4 (5.2) 
  Nausea 
3 (5.6) 
4 (5.2) 
  Abdominal distension 
1 (1.9) 
0 
  Abdominal pain 
1 (1.9) 
0 
  Diarrhoea 
1 (1.9) 
0 
  Vomiting 
0 
1 (1.3) 
 
General disorders and administration site conditions 
9 (16.7) 
4 (5.2) 
  Injection site erythema 
8 (14.8) 
3 (3.9) 
  Injection site pruritus 
5 (9.3) 
0 
  Application site erythema 
1 (1.9) 
0 
  Chills 
0 
1 (1.3) 
  Injection site haemorrhage 
0 
1 (1.3) 
 
Infections and infestations 
1 (1.9) 
0 
  Viral upper respiratory tract infection 
1 (1.9) 
0 
 
Investigations 
1 (1.9) 
0 
  Blood pressure increased 
1 (1.9) 
0 
 
Metabolism and nutrition disorders 
1 (1.9) 
1 (1.3) 
  Decreased appetite 
1 (1.9) 
1 (1.3) 
 
Musculoskeletal and connective tissue disorders 
1 (1.9) 
1 (1.3) 
  Musculoskeletal pain 
1 (1.9) 
0 
  Myalgia 
0 
1 (1.3) 
 
 
 
Nervous system disorders 
13 (24.1) 
10 (13.0) 
  Headache 
11 (20.4) 
7 (9.1) 
  Dizziness postural 
2 (3.7) 
2 (2.6) 
  Dizziness 
1 (1.9) 
2 (2.6) 
  Paraesthesia 
0 
1 (1.3) 
  Somnolence 
0 
1 (1.3) 


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System Organ Class 
  Preferred Term 
Female 
(N = 54) 
n (%) 
Male 
(N = 77) 
n (%) 
Respiratory, thoracic and mediastinal disorders 
2 (3.7) 
1 (1.3) 
  Dyspnoea 
1 (1.9) 
0 
  Oropharyngeal pain 
1 (1.9) 
0 
  Nasal congestion 
0 
1 (1.3) 
  Productive cough 
0 
1 (1.3) 
 
 
 
Skin and subcutaneous tissue disorders 
1 (1.9) 
0 
  Erythema 
1 (1.9) 
0 
 
 
 
Vascular disorders 
1 (1.9) 
0 
  Orthostatic hypotension 
1 (1.9) 
0 
Each subject was counted once for the same system organ class and the same preferred term. 
Preferred terms were sorted by descending order of counts by female and male. 
TEAE = treatment-emergent adverse event 
 
Abaloparatide has been studied in the male population, and differences in treatment-emergent 
adverse events (TEAEs) were observed between males and females (Table 2). In pooled data 
across 4 Phase 1 studies (BA05805- 010, BA05805-011, BA05805-012, and BA05805-014), 25 
of 54 females (46.3%) and 16 of 77 males (20.8%) experienced at least one TEAE. 
Based on these results, which demonstrated no apparent difference in the systemic exposure of 
abaloparatide-SC between males and females across 4 different Phase 1 clinical trials, together 
with Phase 3 safety and efficacy data showing significant increases in BMD in osteoporotic 
women following 6, 12, and 18 months of treatment with abaloparatide-SC, the 80-µg dose is 
therefore an appropriate dose for the treatment of men with osteoporosis. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Primary Objective and Endpoint 
The primary objective of this prospective controlled study is to evaluate the efficacy and the 
safety of abaloparatide-SC 80 µg per day compared to placebo in men with osteoporosis. The 
primary efficacy endpoint is the percent change from baseline in lumbar spine BMD at 
12 months. 
2.2. 
Secondary Endpoints 
The key secondary efficacy endpoints are: 
• Percent change from baseline in total hip BMD at 12 months 
• Percent change from baseline in femoral neck BMD at 12 months 
Additional secondary efficacy endpoints are: 
• Percent change in baseline in: 
− Lumbar spine BMD at 3 and 6 months 
− Total hip BMD at 3 and 6 months  
− Femoral neck BMD at 3 and 6 months 
− Ultra-distal radius BMD at 3, 6, and 12 months 
− Distal one-third radius BMD at 3, 6, and 12 months 
• Log ratio of post-baseline over baseline in: 
− Serum procollagen type I N-terminal propeptide (s-PINP) at 1, 3, 6, and 
12 months 
− Serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX) at 1, 
3, 6, and 12 months 
• Proportion of subjects experiencing BMD gains from baseline of > 0%, > 3%, and 
> 6% at the lumbar spine, femoral neck, and total hip at 3, 6, and 12 months 
• Incidence of new clinical fractures at 12 months 
• Proportion of subjects converting from the categories of osteoporosis to osteopenia or 
to normal at 12 months, where: 
− Osteoporosis is defined as lumbar spine or total hip BMD T-score ≤ -2.5.  
− Osteopenia is defined as as one of the following: 
o Lumbar spine > -2.5 and total hip BMD T-score > -2.5 and < -1.0  
o Lumbar spine > -2.5 and < -1.0 and total hip BMD T-score > -2.5  
− Normal is defined as lumbar spine and total hip BMD T-score ≥ -1.0.  


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• The percent change in total hip and femoral neck volumetric BMD as measured by 
quantitative CT (QCT) from baseline to 12 months QCT will be performed in a subset 
of subjects in a selected number of study sites. 
For those subjects who consent to PK sample collection, the PK endpoints are: 
• The plasma concentration of abaloparatide based on sparse PK sampling at the 
following visits: 
− Month 6: postdose PK samples collected 45 minutes (±15 minutes) and 2.5 hours 
(±0.5 hour) after abaloparatide-SC injection 
− Month 9: postdose PK samples collected 20 minutes (±10 minutes) and 4 hours 
(±0.5 hour) after abaloparatide-SC injection 
− Month 12: a predose sample and a postdose sample collected 1.5 hours 
(±0.5 hour) after abaloparatide-SC injection 
The safety endpoints are: 
• Overall safety and tolerability of abaloparatide-SC in men with osteoporosis as 
assessed by AEs, vital signs, electrocardiograms (ECGs), laboratory tests of 
chemistry and hematology, urinalysis, local tolerance, and presence of antibodies 
Subgroup analysis (e.g., age, geography, FRAX (if applicable), prior fracture, and baseline 
BMD, s-PINP, testosterone and estradiol levels) may be performed and will be described in the 
Statistical Analysis Plan (SAP). 


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3. 
STUDY DESIGN 
3.1. 
Description of the Study Design 
This is a randomized, double-blind, placebo-controlled, Phase 3, multicenter study enrolling 
approximately 225 subjects at approximately 40 study sites designed to evaluate the efficacy and 
safety of abaloparatide-SC 80 µg per day for the treatment of osteoporosis in men. The study will 
consist of a Screening Period (up to 2 months), a Pretreatment Period (1 week), and a Treatment 
Period (12 months) with a Follow-up Visit 1 month after the last dose of study medication.  
During the Screening Period, informed consent will be obtained, eligibility for study entry 
assessed, and screening evaluations performed. Subjects who are eligible for the study, on the 
basis of screening evaluations, will enter the Pretreatment Period of the study and will have 
additional baseline assessments.  
Subjects who remain eligible for study participation will be randomly allocated, using a 
2:1 randomization ratio on Day 1 to receive treatment with either blinded abaloparatide-SC 
80 µg per day or daily placebo injections, respectively. Treatment will be blinded to subjects and 
Investigators throughout the study except in a medical emergency where the identity of study 
medication is necessary to appropriately treat the subject (Section 5.7). The Sponsor 
pharmacovigilance/regulatory personnel may also be unblinded for suspected unexpected serious 
adverse reaction (SUSAR) reporting purposes.  
All subjects will receive calcium 500–1000 mg/day and vitamin D 400–800 IU/day, or a dose 
determined by the Investigator and agreed by the Sponsor Medical Monitor, according to the 
subject’s need. 
The study design is presented in Figure 4, below. All subjects will undergo safety, BMD, bone 
marker, and fracture assessments at regular intervals, according to the Schedule of Assessments 
and Procedures (Table 3). Subjects will be asked if they are willing to provide PK samples to 
evaluate the amount of abaloparatide in the plasma at various timepoints. Those subjects who 
consent to this sparse PK sampling will have samples collected at Months 6, 9, and 12 as shown 
in Table 4. 
Figure 4: 
Study BA058-05-019 Design 
 


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4. 
SELECTION OF STUDY POPULATION 
To participate in this study, a subject must meet all of the inclusion criteria listed in Section 4.1 
and none of the exclusion criteria listed in Section 4.2. Subjects who were screened and excluded 
from this study will be recorded in the electronic case report form (eCRF), as well as the reason 
why they were screen failures. 
4.1. 
Inclusion Criteria 
1. The subject is a healthy ambulatory male from 40 to 85 years of age (inclusive) with 
primary osteoporosis or osteoporosis associated with hypogonadism. 
2. The subject has a BMD T-score (based on the male reference range as assessed by the 
central imaging vendor) of: 
a. ≤ -2.5 at the lumbar spine (L1–L4) or hip (femoral neck or total hip) by dual energy 
X-ray absorptiometry (DXA); or 
b. ≤ -1.5 and with radiologic evidence of vertebral fracture or a documented history of 
low-trauma nonvertebral fracture sustained in the past 5 years.  
c. Men older than 65 years may be enrolled if they have a BMD T-score ≤ -2.0 even if 
they do not meet the fracture criteria. 
3. The subject is in good general health as determined by medical history and physical 
examination (including vital signs) and is without evidence of a clinically significant 
abnormality in the opinion of the Investigator, or none for which there is a reasonable 
chance of interfering with the subject’s health and/or medical treatment during the study. 
The subject has a body mass index (BMI) of 18.5 to 33, inclusive. The BMI is derived 
from the subject’s height and weight. In the case where a subject’s height cannot be 
adequately assessed (e.g., due to vertebral compression fractures or scoliosis), the subject’s 
historical height (as documented in the subject’s medical record) will be used to derive the 
BMI. 
4. Hypogonadal subjects whose doses of androgens have been stable for at least 12 months 
before randomization are eligible and may continue therapy during the study. 
5. The subject has serum calcium (albumin-corrected), PTH, serum phosphorus and alkaline 
phosphatase, and thyroid stimulating hormone (TSH) values all within the normal range 
during the Screening Period. Any subject with an elevated alkaline phosphatase value and 
who meets all other entry criteria must have a normal bone-specific alkaline phosphatase 
to be enrolled. Any subject with a TSH value outside of the normal range must have 
central laboratory reported T3 and free T4 values within the normal ranges to be enrolled. 
6. The subject has serum 25-hydroxyvitamin D values ≥ 20 ng/mL and within normal range. 
Subjects with serum 25-hydroxyvitamin D levels < 20 ng/ml may be treated with vitamin 
D and retested once during the Screening Period. 
7. The subject’s systolic blood pressure is ≥ 100 and ≤ 155 mmHg, diastolic blood pressure 
is ≥ 40 and ≤ 95 mmHg, and heart rate is ≥ 45 and ≤ 100 bpm (taken sitting or supine). 
Any recorded values outside of these ranges and assessed by the Investigator to be not 


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clinically significant must be reviewed with the Sponsor Medical Monitor for approval 
prior to enrollment. 
8. The subject has no clinically significant abnormality of serum hemoglobin, hematocrit, 
white blood cells, and platelets, or usual serum biochemistry: electrolytes, renal function, 
liver function and serum proteins that might be expected to interfere with the subject’s 
health and/or medical treatment during the study. 
9. In subjects who have partners of childbearing potential, the subject and his partner should 
abstain from sexual intercourse, or use highly effective contraceptive measures (e.g., oral 
contraceptive and condom, intrauterine device [IUD] and condom, or diaphragm with 
spermicide and condoms; other forms of contraception must be approved by the Medical 
Monitor) when engaging in sexual intercourse throughout the study, and for at least 90 
days after the last dose of abaloparatide.  
10. The subject has read, understood, and signed the written informed consent form (ICF). 
4.2. 
Exclusion Criteria 
General exclusion criteria: 
1. Presence of abnormalities of the lumbar spine that would prohibit assessment of spinal 
BMD, defined as having at least 2 radiologically evaluable vertebrae within L1–L4 as 
assessed by the central imaging vendor. 
Anatomically abnormal vertebrae are excluded if: 
• They are clearly abnormal and non-assessable within the resolution of the system; or 
• There is a more than 1.0 T-score difference between the vertebra in question and 
adjacent vertebrae. 
2. A BMD T-score of ≤ -3.5 at the total hip, femoral neck, or lumbar spine based upon the 
male reference range. 
3. Unevaluable hip BMD or subjects who have undergone bilateral hip replacement 
(unilateral hip replacement is acceptable). 
4. Fragility fracture within the prior 12 months. 
5. History of severe vertebral fracture or > 2 moderate vertebral fractures. 
6. History of bone disorders (e.g., Paget’s disease) other than osteoporosis. 
7. Subjects with clinical signs of hypogonadism present at screening who plan to initiate 
testosterone replacement. 
8. History of prior external beam or implant radiation therapy involving the skeleton, other 
than radioiodine. 
9. History of chronic or recurrent renal, hepatic, pulmonary, allergic, cardiovascular, 
gastrointestinal, endocrine, central nervous system, hematologic or metabolic diseases, or 
immunologic, emotional and/or psychiatric disturbances to a degree that would interfere 
with the interpretation of study data or compromise the safety of the subject. 


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10. History of Cushing’s disease, growth hormone deficiency or excess, hyperthyroidism, 
hypo- or hyperparathyroidism or malabsorptive syndromes within the past year. 
11. History of significantly impaired renal function (serum creatinine > 177 μmol/L or 
> 2.0 mg/dL). If the serum creatinine is > 1.5 and ≤ 2.0 mg/dL, the calculated creatinine 
clearance (Cockcroft-Gault) must be ≥ 37 mL/min. 
12. History of any cancer within the past 5 years (other than basal cell or squamous cancer of 
the skin). 
13. History of osteosarcoma at any time. 
14. Subjects with hereditary disorders predisposing them to osteosarcoma. 
15. History of nephrolithiasis or urolithiasis within the past 5 years. 
16. Subjects known to be positive for Hepatitis B, Hepatitis C, human immunodeficiency 
virus (HIV)-1 or HIV-2. Testing is not required in the absence of clinical signs and 
symptoms suggestive of HIV infection or acute or chronic hepatitis. 
Medication-related exclusion criteria: 
17. Known history of hypersensitivity to any of the test materials or related compounds. 
18. Prior treatment with PTH- or PTHrP-derived drugs, or bone anabolic drugs including 
abaloparatide or teriparatide, or PTH(1-84). 
19. Prior treatment with intravenous (IV) bisphosphonates at any time or oral 
bisphosphonates within the past 3 years. Subjects who had received a short course of oral 
bisphosphonate therapy (3 months or less) may be enrolled as long as the treatment 
occurred 6 or more months prior to enrollment. 
20. Treatment with fluoride or strontium in the past 5 years or prior treatment with gallium 
nitrate or other bone-acting investigational agents at any time. Limited use of gallium 
citrate/nitrate for diagnostic purposes (i.e., a gallium scan) is not exclusionary.  
21. Prior treatment with calcitonin or tibolone in the past 6 months. 
22. Prior treatment with denosumab in the past 18 months. 
23. Treatment with anticonvulsants that affect vitamin D metabolism (phenobarbital, 
phenytoin, carbamazepine, or primidone) or with chronic heparin within the 6 months 
prior to the Screening Period. 
24. Treatment with anabolic steroids or calcineurin inhibitors (cyclosporin, tacrolimus) 
within the past 90 days 
25. Daily treatment with oral, intranasal, or inhaled corticosteroids within the 12 months 
prior to the Screening Period. Occasional use of all corticosteroids (for seasonal allergies 
or asthma) is not exclusionary. 
26. Exposure to an investigational drug within the 12 months prior to the Screening Period. 


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Lifestyle-related exclusion criteria: 
27. Abnormal nutritional status (as assessed by the Investigator), vitamin D intake of 
≥ 4,000 IU/day or vitamin A intake of ≥ 10,000 IU/day. Short term use of high doses of 
vitamin D to increase endogenous vitamin D levels for study entry is not exclusionary. 
28. Subject is known to consume > 2 alcoholic drinks per day, to use illegal drugs, or to 
abuse tobacco or marijuana (medicinally or recreationally where legal) within 12 months 
of the Screening Period. The Investigator must determine and document use vs. abuse of 
tobacco or marijuana. 
4.3. 
Participant Withdrawal or Termination 
4.3.1. 
Reasons for Withdrawal or Termination 
Subjects will be informed that they have the right to withdraw from the study at any time for any 
reason without prejudice to their medical care. 
The Investigator must withdraw subjects from the study for the following reasons: 
• Continuing significant deterioration from baseline (≥ 7%) of BMD at spine or hip 
(after confirmation of the finding) 
• Hypercalcemia as described in Section 4.7.1 
• Severe hypersensitivity to abaloparatide 
• Refusal of treatment 
• Inability to complete study procedures 
• Lost to follow-up 
The Investigator also has the right to withdraw subjects from the study for any of the following 
reasons: 
• Serious AEs (as described in Section 7.1.3) 
• A complex of AEs which, in the judgment of the Investigator justifies treatment 
cessation 
• Serious intercurrent illness 
• Noncompliance 
• Protocol deviations 
• Administrative reasons 
Subjects will be offered the opportunity to discontinue from the study for the following reasons 
after site consultation with the Study Medical Monitor: 
• Incident vertebral or nonvertebral fragility fracture 


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Should a subject who experiences a clinical vertebral or nonvertebral fragility fracture choose to 
remain in the study, they will be asked to sign an additional ICF further explaining the potential 
risks and benefits of remaining in the study. 
If a subject withdraws from the study due to the ongoing coronavirus disease 2019 (COVID-19) 
global pandemic, this information will be captured in the eCRF so that it can be described in the 
clinical study report at the end of the study, in line with the Food and Drug Administration 
(FDA) Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency (FDA 2021).  
The reason for the withdrawal should be recorded in the eCRF as COVID-19, if applicable, and 
include as many details as possible (e.g., the subject had a positive test result or decided to 
withdraw from the study due to personal choice related to COVID-19 concerns). 
4.3.2. 
Handling of Participant Withdrawals or Terminations 
If a subject is withdrawn or discontinued from the study, the reason for withdrawal from the 
study is to be recorded in the source documents and on the CRF. All subjects withdrawn prior to 
completing the study should be encouraged to complete study procedures scheduled for the 
Month 12/Early Termination visit as soon as possible, and to return in 1 month for a Follow-up 
Visit. All AEs should be followed as described in Section 7. Subjects who discontinue or are 
withdrawn from the study will not be replaced. 
4.4. 
Concomitant Medications 
Calcium (500–1000 mg/day) and vitamin D (400–800 IU/day) supplements, or a dose 
determined by the Investigator and approved by the Sponsor Medical Monitor, according to the 
subject’s need, are required to be administered daily from the Pretreatment Period until the end 
of the Treatment Period. The doses and schedule of calcium and vitamin D supplements, which 
are part of the study medication protocol, should be adhered to and not be changed other than for 
medical necessity. The supplements should be taken in the evening with or without food or as 
otherwise instructed by the Investigator. 
For any required concomitant chronic medication, such as statins or antihypertensives, the 
subject must be on a stable dose for 90 days prior to study entry and every effort should be made 
to maintain a stable dose during study participation. If a medication or dose has not been 
consistent for 90 days prior to study entry, recent changes must have been due to reasons other 
than lack of control of the underlying medical condition, i.e., the underlying medical condition 
for which chronic medication is required must be well-controlled.  
The occasional use of over-the-counter medications at labeled doses (e.g., ibuprofen or 
acetaminophen) for headache or minor discomfort is allowed. These are to be recorded in the 
source records and entered in the appropriate CRF. Subjects should not take any other 
medications, including over-the-counter medications, herbal medications, or mega-doses of 
vitamins during the study without prior approval of the Investigator. 
If it becomes necessary for a subject to take any other medication during the study, the specific 
medication(s) and indication(s) must be discussed with the Investigator. All concomitant 


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medications taken during the course of the study must be recorded in the subject’s medical 
record or source document and transcribed into the eCRF. 
4.5. 
Prohibited Medications 
Please refer to Section 4.2 for medication-related exclusion criteria. 
Subjects cannot take any medications, including over-the-counter, non-prescription medication, 
with the exception of those noted in Section 4.4, within 72 hours prior to dosing on Day 1. 
In addition, subjects are ineligible for the study if they have an abnormal nutritional status 
(abnormal diets, excessive or unusual vitamin or herbal intakes, malabsorption). 
Occasional short term (≤ 3 months) use of corticosteroids for seasonal allergies or asthma is not 
prohibited. Subjects who require chronic treatment with either an anticonvulsant (phenobarbital, 
phenytoin, carbamazepine, or primidone), or with heparin will be discontinued. 
4.6. 
Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification documenting the reason for study suspension or 
termination will be provided by the suspending or terminating party to the principal investigator 
(PI), and regulatory authorities. If the study is prematurely terminated or suspended, the PI will 
promptly inform the Institutional Review Board (IRB) / Independent Ethics Committee (IEC) 
and will provide the reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants. 
• Insufficient compliance with protocol requirements. 
• Data that are not sufficiently complete and/or evaluable. 
• Decision of Sponsor. 
Study may resume once concerns about safety, protocol compliance, or data quality are 
addressed and satisfy the Sponsor, IRB/IEC, and/or regulatory agencies, if applicable. 
4.7. 
Temporary Suspension of Treatment 
The Investigator has the right to suspend treatment with study medication for up to 
14 continuous days or 28 cumulative days, without withdrawal of the subject from the study. 
Reasons for temporary suspension of treatment may include a medical reason unrelated to an 
adverse event (e.g., a planned procedure), or important social or administrative events. The 
reason for the suspension of treatment is to be documented in the CRF and in source documents. 
Such subjects should not be unblinded as to study medication. 
When treatment is restarted, the subject should resume treatment with the next scheduled dose 
and continue until the scheduled End-of-Treatment. If the treatment suspension is due to a 
medical emergency and study medication needs to be unblinded, please refer to Section 5.7 for 
the procedures to be followed. 


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 Subjects who develop hypercalcemia or hypercalciuria during the study are to have treatment 
with calcium and vitamin D temporarily suspended as described below. 
4.7.1. 
Treatment Algorithm in Subjects Who Develop Hypercalcemia 
Hypercalcemia is defined as any serum calcium (albumin-corrected) that is ≥ 0.3 mg/dL 
(equivalent to > 0.08 mmol/L) above the upper limit of normal (ULN). For this study, the normal 
range, ULN and lower limit of normal (LLN) for serum calcium (albumin-corrected) are 
determined by the central laboratory. 
For any predose serum calcium (albumin-corrected) value which is ≥ 0.3 to 1.0 mg/dL, 
corresponding to ≥ 0.08 to 0.25 mmol/L, above the ULN (inclusive), confirm hypercalcemia by 
drawing a new serum sample as soon as possible after the result is received (Figure 5). 
• If the repeat serum calcium (albumin-corrected) is above the LLN up to < 0.3 mg/dL 
(equivalent to < 0.08 mmol/L) above the ULN, the subject should continue study drug 
administration together with Calcium and vitamin D supplementation. 
• If a subject’s predose serum calcium is elevated on repeat testing, calcium and 
vitamin D supplementation should be withheld. The subject is to continue study drug 
administration during this interval. 
• If the subject’s predose serum calcium remains elevated 1-2 weeks after calcium and 
vitamin D supplementation is withheld, dosing of study drug should be stopped.  
Treatment can be restarted if other causes of hypercalcemia are excluded after consultation with 
the Sponsor. Treatment with study drug should not be suspended for greater than 14 days. 
If the subject continues in the study (with calcium and vitamin D supplements) and had an 
episode of a predose serum calcium (albumin-corrected) value of ≥ 0.3 to 1.0 mg/dL 
(corresponding to ≥ 0.08 to 0.25 mmol/L) above the ULN, repeat testing of the predose serum 
calcium (albumin-corrected). 
• If the subject’s serum calcium (albumin-corrected) value again returns to normal 
when not taking calcium and vitamin D supplements, the subject may continue in the 
study without calcium and vitamin D supplements. 
• If the retest is still elevated, contact the Sponsor Medical Monitor to assess whether 
the subject is to be discontinued from the study. 
For any serum calcium (albumin-corrected) value > 1.0 mg/dL above the ULN: 
• Discontinue calcium and vitamin D supplements and discontinue the study drug as 
soon as the result is received. Confirm hypercalcemia by drawing a new serum 
sample as soon as possible. 
• If the result of the retest remains > 1.0 mg/dL above the ULN, perform a second retest 
after 3 days without calcium and vitamin D supplements and study drug. 
− If the second retest is normal, the subject may continue in the study and resume 
study drug including the calcium and vitamin D supplements. 


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− If the second retest is still elevated, contact the Sponsor Medical Monitor to assess 
whether the subject is to be discontinued from the study. 
• If the subject continues in the study and has a repeat episode of serum calcium 
> 1.0 mg/dL above the ULN, contact the Sponsor Medical Monitor to assess whether 
the subject is to be discontinued from the study. 
4.7.2. 
Treatment Algorithm in Subjects Who Develop Hypercalciuria 
For a urine calcium:creatinine ratio > 0.4 mg/mg, corresponding to > 1.131 mmol/mmol, check 
the subject’s predose serum calcium and apply the algorithm outlined in Section 4.7.1 if calcium 
is elevated. 
If the calcium:creatinine ratio is > 0.4 mg/mg and the serum calcium is normal: 
• Discontinue calcium and vitamin D supplements and recheck urine calcium:creatinine 
values after 7 days. 
− If the urine calcium:creatinine ratio continues to be > 0.4 mg/mg in the presence 
of normal serum calcium, the subject may continue in the study under medical 
supervision (and without receiving additional calcium and vitamin D 
supplements). 
− If the urine calcium:creatinine ratio returns to normal, the subject may restart 
calcium and vitamin D supplements and continue in the study. 
• If the subject restarts the serum calcium and vitamin D supplements and 
hypercalciuria returns, calcium and vitamin D supplementation should be terminated. 
The subject may continue in the study under medical supervision. 
Therefore, subjects with hypercalciuria will not be discontinued from the study in the absence of 
hypercalcemia except at the discretion of the Investigator. 


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Figure 5: 
Treatment Algorithm in Subjects Who Develop Hypercalcemia 
 
*For any predose serum calcium (albumin-corrected) > 1.0 mg/dL (> 0.25 mmol/L) above the upper limit of normal (ULN), immediately discontinue calcium, vitamin D, 
and study drug 
**ULN, lower limit of normal, and normal ranges are determined per the central laboratory 
*** If applicable, also consider restarting/continuing vitamin D and calcium supplementation after consultation with the Sponsor 


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5. 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
5.1. 
Study Medication 
5.1.1. 
Abaloparatide-SC and Placebo 
Abaloparatide-SC injection is supplied as a sterile, colorless, clear solution in a glass 
cartridge which is pre-assembled into a disposable single-subject-use pen. The pen is 
intended to deliver 30 once daily abaloparatide doses of 80 µg in 40 µL of solution. Each pen 
contains 3120 μg/1.56 mL.  
Placebo is formulated similarly but without active abaloparatide and will be similarly 
supplied as a sterile, colorless, clear solution in a glass cartridge which is pre-assembled into 
a disposable single-subject-use pen. The pen is intended to deliver 30 once daily placebo 
doses of 80 µg in 40 µL of fluid when inserted into the Pen Injector device. 
Additional information will be provided to clinical sites in a separate Pharmacy Manual 
including instructions on how to use the injection pen. 
5.1.2. 
Calcium and Vitamin D Supplements 
Calcium (500–1000 mg) and vitamin D (400–800 IU) supplements will be sourced locally by 
the site and provided to subjects at the expense of the Sponsor. 
5.2. 
Packaging, Labeling and Storage 
5.2.1. 
Packaging and Labeling 
Abaloparatide-SC and placebo will be supplied and packaged as identical injection pens. All 
packaging operations will be performed in accordance with Good Manufacturing Practices 
(GMP). 
Study medication will be provided and replaced via the interactive response technology (IRT) 
on clinic visit days. If clinic visits are not possible, study medication may also be delivered to 
the subject’s home. Labeling will include a caution statement and other information required 
by local regulatory authorities. A detailed study drug dispensation plan will be provided in 
the Pharmacy Manual. 
Calcium and vitamin D supplements will be provided as packaged by the manufacturer and 
will not be relabeled for the study. 
5.2.2. 
Storage 
While at the clinical site, abaloparatide and placebo injection pens must be stored in a secure, 
limited access, temperature monitored refrigerator at 2° to 8°C (36° to 46°F) until dispensed 
for use to a study subject or until returned to the Sponsor. 
After the abaloparatide-SC or placebo injection pen is used for the first time, the pen may be 
stored for 30 days at room temperature, 68°F to 77°F (20°C to 25°C). Unused pens should be 
refrigerated until initial use. Instructions regarding the storage and handling of the study drug 
after dispensation to subjects will be provided to sites in the Pharmacy Manual. 
Calcium and vitamin D supplements should be stored according to the manufacturer 
recommendations on the bottle. 


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5.3. 
Treatment Assignment 
All subjects who sign informed consent for the study will be assigned a unique 6-digit subject 
number which will be used to identify subjects throughout the study and in the eCRFs. 
 
 
 
 
 
 
Subjects who meet all inclusion criteria and none of the exclusion criteria and successfully 
complete the Screening and Pretreatment Periods of the study will be assigned sequentially to 
a randomized treatment group on Day 1 of the Treatment Period. Subjects will only receive 
one study ID at the time of screening and therefore will not receive a new identifier at 
randomization. During the randomization transaction, the IRT will randomly allocate a 
treatment assignment and dispense the appropriate kit number for the subject’s treatment. 
Information regarding treatment assignment will reside solely within the IRT, as part of the 
study blinding. Once a kit number has been assigned, it may not be reused. Refer to the IRT 
manual for additional details on IRT instructions. 
Prior to study start, the Sponsor statistician will be responsible for overseeing the preparation 
of the master randomization scheme that will be used to package study medication into kits 
and for the IRT. 
5.4. 
Dosing and Administration 
Subjects will self-administer a single daily dose of 80 µg of study medication during the 
Treatment Period. 
The first self-administration is to occur at the study site under observation. On the days of 
clinic visits, study medication must be administered in the clinic to accommodate pre-
injection and post-injection procedures; study personnel may administer the study 
medication. For the Month 12 visit, subjects should be instructed to bring the study drug 
dispensed at the last study visit and to administer the study drug onsite. 
Subjects will be trained by study personnel during the Pretreatment Period how to self-inject 
study medication with the abaloparatide-SC/Placebo injection pen. If a subject requires 
assistance with study medication administration, an individual (e.g., a family member) who 
has been trained by study personnel may provide assistance. 
Subjects will also be provided written instructions on how to use the abaloparatide-
SC/Placebo injection pen. Subjects will be instructed by the study site to inspect the contents 
of their injection pen before each injection. If the cartridge contents are not clear and 
colorless, or if the contents contain particles, the subjects will be instructed not to use the pen 
and to contact the study site for further guidance. Injections should be administered in the 
morning and preferably at the same time each day. If a dose is missed, the dose should be 
administered as soon as possible up to 12 hours after the missed injection. Any time 
thereafter, the dose should be skipped and the drug should be administered at the next 
scheduled time the following day. All injections are to be given in the periumbilical region, 
rotating the site of injection each day. If it is deemed medically necessary by the Investigator 
for an injection to be administered at a site other than the abdomen, the alternate site of 
injection is to be recorded and the reason for the change documented in the medical chart and 
eCRF as a protocol deviation. On the first day of study medication administration, the subject 
should self-inject while in a sitting or lying position at the study site and remain in that 


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position for approximately 5 minutes. Within 5 minutes, and 1 hour post-injection, the 
injection site will be evaluated by the Investigator using the scale provided by RADIUS. The 
subject is to remain under observation for a minimum of 60 minutes after the initial injection. 
An orthostatic blood pressure measurement will be taken 60 minutes after the injection. On 
the days when blood sampling is required after study medication injection, the subject is to 
remain in the vicinity of the clinic for the blood collections scheduled up to 4 hours post-
injection. Subjects are to be instructed to self-inject at home in a location where they have the 
ability to sit or lie down. 
To assess injection site reactions, the location, date, and time that each dose of study 
medication was administered must be recorded by the subject in the diary beginning on Day 2 
and continuing through Day 7 in Month 1 (Visit 4) and beginning on Day 2 and continuing 
through Day 7 in Month 9 and entered in the diary. 
Subjects will be instructed to use a new pen after each 30-day period. At each clinic visit 
during the Treatment Period, the used and unused abaloparatide-SC or placebo injection pens 
must be returned. Compliance, AEs, and use of concomitant medications should be reviewed 
upon drug re-supply and documented accordingly in the drug accountability log and eCRF. 
5.5. 
Treatment Compliance 
To ensure treatment compliance, the Investigator or designee will supervise all study drug 
administration that occurs at the site. At each study visit, the Investigator or designee will 
review subject compliance with study drug administration and remind the subject of study 
drug dosing requirements. Subject compliance will be ascertained by 2 methods: subject 
diaries and measuring the residual drug in the cartridge. 
Discrepancies will be discussed with the subjects, documented in the medical charts, and 
recorded in the eCRF as appropriate. If a subject does not take all study medication 
(abaloparatide-SC, placebo, calcium, and vitamin D supplements), the reason for the missed 
dosing is to be recorded by the subject in their diary. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the Investigator should contact the Medical Monitor to discuss discontinuation of the 
subject from the study. 
5.6. 
Drug Accountability 
The Investigator or designated site staff will maintain records documenting the dates and 
amounts of the following: 
• Study drug received 
• Study drug dispensed to the subjects 
• Study drug returned by the subjects 
• Study drug returned to RADIUS/designee or destruction of study drug on site 
Subjects will be instructed to return all used and unused study drug to the site. The study drug 
will be retained at the site until inventoried by the study monitor and approved for destruction 
or return. The study monitor will verify study drug records and inventory throughout the 
study. 


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5.7. 
Unblinding of Study Medication 
5.7.1. 
Medical Emergency 
Breaking the treatment blind for a subject should be done only in the event of a medical 
emergency where the identity of study medication is necessary to appropriately treat the 
subject. The Investigator may unblind the treatment received by the subject through the IRT. 
The IRT will automatically document and record any such unblinding and notify the Sponsor 
Medical Monitor of the unblinding event. The study monitor will not be apprised of the actual 
treatment assignment. In addition, the Sponsor Medical Monitor has the ability to unblind the 
study medication in a medical emergency. 
If the Investigator determines that the medical event that resulted in unblinding of the study 
medication is not treatment related (relationship is documented as “none”; see Section 7.1.1 
for definitions of relationship), the subject may continue treatment and participation in the 
study, providing no more than 14 days has elapsed since the last dose of study medication 
(refer to Section 4.7 for details regarding temporary suspension of treatment). If the subject 
discontinues from further treatment with study medication, they should undergo the 
Month 12/Early Termination and the Month 13 Follow-up Visit as outlined in Section 6.2.7, 
and the Schedule of Assessments and Procedures (Table 3). 


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6. 
STUDY PROCEDURES AND SCHEDULE 
6.1. 
Study Procedures 
6.1.1. 
Study-Specific Procedures 
The study-specific assessments are detailed in this section and outlined in Table 3. Any 
results falling outside of the reference ranges may be repeated once time during the Screening 
Period at the discretion of the Investigator. 
6.2. 
Study Schedule 
This study is comprised of 9 clinic visits. Study assessments are to be performed according to 
the Schedule of Assessments and Procedures (Table 3). There is a ± 4-day window for each 
clinic visit. 
The study will consist of a Screening Period (up to 2 months), a Pretreatment Period 
(1 week), a Treatment Period (12 months), and a Follow-up Visit (1 month). During the 
Treatment Period, subjects will have clinic visits for study-related protocol procedures at 
Day 1, Month 1, Month 3, Month 6, Month 9, and Month 12. The active phase of the study 
will be considered complete when the last subject undergoes the last visit. For the purpose of 
this study, 1 month is equal to 30 days. 
6.2.1. 
Schedule of Assessments and Procedures 
A comprehensive Schedule of Assessments and Procedures is presented in Table 3. 
Due to the ongoing COVID-19 pandemic, arrangements may also be made, contingent on the 
subject’s consent and in compliance with country, state, and local requirements, to have a 
study visit conducted at the subject’s home by site staff. If this occurs, blood and/or urine 
samples may be collected at the subject’s home and then sent to the central laboratory for 
processing and analysis. Study drug may also be delivered to the subject’s home, if needed, to 
enable the subject to continue administering their study drug daily. 
 


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Table 3: 
Schedule of Assessments and Procedures 
 
Visit 
1 
2 
3 
4 
5 
 
6 
7 
8 
9 
Procedure 
Study Day/Month: 
Screening 
Pretreatmen
t 
Day 1 
Month 
1 
Month 3 
Month 
6 
Month 9 
Month 12/ 
Early 
Termination 
Month 13 
Follow-
up 
Visit Window (Days) 
N/A1 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 7 
Informed consent 
X 
 
 
 
 
 
 
 
 
Verification of entry criteria 
X 
X 
 
 
 
 
 
 
 
Physical examination 2 
X 
 
 
 
 
 
 
 
 
Review of medical history 3 
X 
 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight measurement 
X 
 
X 
X 
 
X 
 
X 
 
Height measurement5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram6 
X 
 
X 
 
 
 
 
X 
X 
Urinalysis (dipstick)7 
X 
 
 
X 
 
X 
 
X 
 
Chemistry blood collection 
X 
 
 
X 
 
X 
 
X 
 
Hematology blood collection 
X 
 
 
X 
 
X 
 
X 
 
Coagulation (PT and PTT) blood 
collection 
X 
 
 
 
 
 
 
X 
 
PTH (1–84) 
X 
 
 
 
 
 
 
X 
 
25-hydroxyvitamin D level 
X 
 
 
 
 
 
 
X 
 
1,25-dihydroxy vitamin D level 
X 
 
 
 
 
 
 
X 
 
Total testosterone and SHBG 
X 
 
 
 
 
 
 
X 
 
Estradiol 
X 
 
 
 
 
 
 
 
 
Thyroid stimulating hormone8 
X 
 
 
 
 
 
 
 
 
PK samples (see Table 4) 
 
 
 
 
 
X 
X 
X 
 
Study medication assignment via IRT 
 
 
X 
 
 
 
 
 
 
Injection training for subjects 
 
X 
 
 
 
 
 
 
 


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Table 3: 
Schedule of Assessments and Procedures (Continued) 
 
Visit 
1 
2 
3 
4 
5 
 
6 
7 
8 
9 
Procedure 
Study 
Day/Month: 
Screening Pretreatment 
Day 1 
Month 
1 
Month 3 
Month 
6 
Month 9 
Month 12/ 
Early 
Termination 
Month 13 
Follow-up 
Visit Window (Days) 
N/A1 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 7 
Calcium and vitamin D supplements 
 
Daily administration 
 
Study medication administration 
 
 
Daily administration 
 
Serum markers of bone metabolism  
(s-PINP and s-CTX) 
 
 
X 
X 
X 
X 
 
X 
 
Serum calcium and albumin9 
 
 
X 
X 
X 
X 
X 
 
 
24-hour urine collection (for 
calcium:creatinine and creatinine 
clearance)10 
 
 
X 
 
X 
 
 
 
 
Radiologic (lumbar and thoracic 
vertebrae) assessments 
X 
 
 
 
 
 
 
 
 
Symptom driven spinal radiologic 
assessment 
 
At any time 
Clinical assessment of new fractures11 
 
X 
X 
X 
X 
X 
X 
X 
 
BMD of lumbar spine, total hip, and 
femoral neck by DXA12 
X 
 
 
 
X 
X 
 
X 
 
BMD of wrist by DXA13 
 
 
X 
 
X 
X 
 
X 
 
vBMD of hip by QCT14 
 
 
X 
 
 
 
 
X 
 
Sample for immunogenicity testing15 
 
 
X 
X 
X 
X 
X 
X 
X 
Investigator assessment of local 
tolerance (dermal reactions assessment) 
 
 
X 
X 
X 
X 
X 
 
 
Subject assessment of local tolerance16 
 
 
X 
 
 
 
X 
 
 
Subject diary review17 
 
 
X 
X 
X 
X 
X 
X 
 
Document AEs and concomitant18 
medications  
At any time, question subjects at every visit 
Drug supply/resupply/accountability 
 
 
X 
X 
X 
X 
X 
X 
 


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1. The window for screening activities is 60 days. Due to the ongoing COVID-19 pandemic or other local/widespread emergencies, if there is a delay in the screening process 
that would result in a subject remaining in screening for greater than 60 days, the Medical Monitor should be contacted. All safety laboratory results must be reported 
within 30 days prior to randomization. 
2. A complete physical examination includes a review of the following systems: head/neck/thyroid, eyes/ears/nose/throat, respiratory, cardiovascular, lymph nodes, abdomen, 
skin, musculoskeletal, and neurological. Breast, anorectal, and genital examinations will be performed when medically indicated. After screening, any clinically 
significant abnormal findings in physical examinations should be reported as AEs. 
3. Including alcohol and tobacco use assessment. 
4. Blood pressure, heart rate, body temperature, and respiration rate are to be recorded predose at each study visit. Only blood pressure, heart rate and respiration rate are to be 
recorded one-hour post dose at each study visit during the Treatment Period. All blood pressure assessments need to be orthostatic. 
5. Height is to be measured at each visit in the standing position using a medical stadiometer. 
6. ECGs are to be performed predose and one-hour postdose during the Treatment Period. 
7. All routine urinalysis will be performed on a sample freshly voided during the visit and sent to a central lab for microscopy if test is positive for micro-organisms via 
dipstick. 
8. Reflex testing of T3 and free T4 will be performed by the central laboratory for any out-of-range TSH result. 
9. Serum calcium and albumin will be measured predose from the standard chemistry panel on Month 1 and Month 6, and from a separate blood draw at Day 1, Month 3 and 
Month 9 and 4 hours post dose at Day 1, Month 1, Month 3, Month 6, and Month 9. 
10. A 24-hour urine collection will be collected at Day 1 and Month 3 and will be used for urinary calcium and urinary creatinine measurements. Subjects will discard the 
first void and begin a 24-hour urine collection on the day prior to the clinic visit. 
11. If the subject reports that a fracture has occurred, remind the subject to bring X-rays and any medical reports of the fracture to the next clinic visit. Documentation must 
be obtained on all new fractures that occur during the study. This documentation should be maintained in the source documents. 
12. Each DXA for a given subject should be performed on the same machine, and if available, preferably by the same technician. For screening purposes, DXA scans of the 
lumbar spine, total hip, and femoral neck taken up to 35 days prior to the beginning of the Screening Period, with a study-approved scanner, may be used to determine 
study eligibility. 
13. The first wrist DXA will be performed prior to study drug administration on Day 1 and should be performed on the same machine, and if available, preferably by the 
same technician. 
14. QCT performed in a subset of subjects at selected study sites. 
15. Samples will be drawn prior to treatment on Day 1, Months 1, 3, 6, 9, and 12, and the Follow-up Visit scheduled at 1 month after the last dose of study medication. 
16. The subject will maintain a diary of their assessment of local tolerance beginning on Day 2 and continuing through Day 7 in Month 1, and beginning on Day 2 and 
continuing through Day 7 in Month 9. 
17. The subject medication diary will be reviewed by study personnel at each study visit to ensure subject compliance. 
18. AEs and SAEs will be recorded on the case report forms starting from the time of subject entry into the Screening Period (Visit 1) of the study (signed informed consent) 
until 30 days after the last dose of study medication. All AEs will be followed until resolution or stabilization. Any SAEs that occur at any time after completion of the 
study, which are considered by the Investigator to be related to study treatment, must be reported to the Sponsor or its designee. 
 
AE = adverse event; BMD = bone mineral density; DXA = dual energy X-ray absorptiometry; IRT = Interactive response technology; PT = Prothrombin time; PTH = 
Parathyroid hormone; PTT = Partial thromboplastin time; QCT = quantitative CT; s-CTX = serum carboxyl-terminal cross-linking telopeptide of type I collagen; s-PINP = 
serum procollagen type I N-terminal propeptide; SAE = serious adverse event; SHBG = Sex hormone binding globulin; vBMD = volumetric bone mineral density 
 


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Table 4: 
Schedule for Pharmacokinetic Sample Collections 
Study Visit 
Predose 
Postdose 
Within 10 min 
before injection 
20 min ±  
10 min 
45 min ±  
15 min 
1.5 hours 
± 0.5 hours 
2.5 hours 
± 0.5 hours 
4 hours 
± 0.5 hours 
Month 6 
X 
 
X 
 
Month 9 
 
X 
 
 
X 
Month 12 
X 
 
X 
 
 
Note: This schedule only applies to those subjects who consent to have PK samples collected during the study. 
min = minute; PK = pharmacokinetics 
 


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6.2.2. 
Informed Consent Process 
Each subject must sign and date a study-specific informed consent form (ICF) before any study-
specific procedures can be performed. The consent forms will comply with all applicable 
regulations governing the protection of human subjects. An ICF, approved by RADIUS and the 
site's IRB/IEC must be used. The Investigator or designee must record the date when the ICF 
was signed in the subject’s source document. 
6.2.3. 
Assigning Subject Numbers 
Once a subject has signed an ICF, a subject number will be assigned. The subject will retain this 
number for the entire study. 
6.2.4. 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. 
Medical history will be elicited from each subject during screening. Based on the medical 
history, the subject will be assessed for any disqualifying medical conditions as specified in the 
inclusion and exclusion criteria. The medical history shall include a complete review of systems, 
past medical and surgical histories, and any allergies. 
Subjects included into the study based on a history of low-trauma nonvertebral fractures must 
have sufficient source documentation in the form of a medical report or radiographic films as 
evidence of such history.  
6.2.5. 
Screening Period (Visit 1) 
Signed informed consent will be obtained and eligibility for study entry assessed. The following 
baseline screening evaluations will be performed: 
• Physical examination 
• Review of medical history, including alcohol, tobacco, and drug use 
• Review of concomitant medications 
• Height 
• Weight 
• ECG 
• Orthostatic blood pressure and vital signs 
• Lumbar and thoracic spine radiographs (anteroposterior and lateral) 
• BMD assessments of lumbar spine, total hip, and femoral neck by DXA 
− BMD T scores may be rounded off to the nearest tenth (i.e., rounded off to one 
decimal point) for the purpose of assessing study eligibility per protocol. 


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− For screening purposes, DXA scans of the lumbar spine, total hip, and femoral 
neck taken with a study-approved scanner up to 35 days prior to the beginning of 
the Screening Period may be used to determine subject eligibility. 
• Laboratory testing of serum chemistry, hematology, coagulation, and urine dipstick 
• PTH, 25-hydroxyvitamin D, and 1,25-dihydroxy vitamin D level 
• Serum total testosterone and sex hormone binding globulin (SHBG) 
• Estradiol and TSH level 
Subjects who do not meet the 25-hydroxyvitamin D entry criterion may receive vitamin D 
supplementation and be retested once during the Screening Period. Similarly, subjects with 
minor elevations of PTH may be retested one time after vitamin D supplementation. Subjects 
whose laboratory tests do not fall within the specified ranges as detailed in the 
inclusion/exclusion criteria may have the samples redrawn and the tests repeated once during the 
Screening Period. If upon retesting, the values fall within the inclusion/exclusion criteria, the 
subject may enter the study. All subjects enrolled following retesting must have safety laboratory 
results reported within 30 days prior to randomization.  
The window for screening activities is 60 days. Due to the ongoing COVID-19 pandemic or 
other local/widespread emergencies, there may be screening process delays. In the case of 
screening process delays that result in a subject remaining in the Screening Period for greater 
than 60 days, the Medical Monitor should be contacted. All safety laboratory results must be 
reported within 30 days prior to randomization. 
Any AEs will be recorded beginning on the day that the subject signs the informed consent. 
6.2.6. 
Pretreatment Period (Visit 2) 
Subjects who are eligible for the study on the basis of screening evaluations will enter the 
Pretreatment Period of the study and will be provided the calcium and vitamin D supplements 
required until the next study visit. All subjects will be required to commence calcium 500–
1000 mg/day and vitamin D supplements 400–800 IU/day (or doses determined by the 
Investigator and agreed by the Sponsor Medical Monitor, according to the subject’s need). 
Subjects will also undergo training for medication self-administration during this period; AEs 
will be recorded, and the following procedures will be performed: 
• Symptom-directed physical exam, including assessment for potential vertebral 
fracture 
• Verification of study entry criteria 
• Height 
• Orthostatic blood pressure and vital signs 
• Clinical assessment of new fractures 
• Instruct subject on procedures and provide with supplies for collecting a 24-hour 
urine sample (the sample is to be collected on the day prior to Day 1) 
• Injection training for subjects 


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6.2.7. 
Treatment Period 
Subjects who remain eligible for study participation will be randomly allocated through the IRT, 
using a 2:1 randomization ratio on Day 1 to receive treatment with either blinded abaloparatide-
SC 80 µg per day or daily 80-μg placebo injections, respectively. Treatment will be blinded to 
the Sponsor, subjects, and Investigators throughout the study except in a medical emergency 
where the identity of study medication is necessary to appropriately treat the subject 
(Section 5.7). The Sponsor pharmacovigilance/regulatory personnel may also be unblinded for 
SUSAR reporting purposes. During the Treatment Period, subjects will self-administer a single 
subcutaneous dose of study medication once a day.  
At each clinic visit during this period, recent health status will be obtained, the diary reviewed, 
AEs collected, and orthostatic blood pressure and vital signs performed. Laboratory assessments 
of chemistry and hematology and urinalyses will be obtained at Month 1, Month 6, and 
Month 12, and a 24-hour urine will be collected on the day prior to Visit 1 and on the day prior 
to Visit 5 (Month 3). Clinical assessments for fracture will be performed at each visit. Source 
documentation (imaging report and/or film along with other supporting documentation as 
appropriate) will be collected from each site to confirm fracture. 
Subjects will have BMD assessed by DXA at the lumbar spine, total hip, and femoral neck at 
screening and Months 3, 6 and 12, and at the wrist on Day 1 and Months 3, 6 and 12. Volumetric 
BMD at the hip will be assessed by QCT on Day 1 and at Month 12. QCT will be performed in a 
subset of subjects at a selected number of study sites based upon availability. Bone turnover 
marker assessments (s-PINP and s-CTX) will be performed on Day 1, and Months 1, 3, 6, and 
12.  
6.2.8. 
Visit 3 (Day 1) 
• A 24-hour urine collection will be collected. Subjects will discard the first void and 
begin a 24-hour urine collection on the day prior to the clinic visit 
• Symptom driven physical exam, including assessment for potential vertebral fracture 
• Collect blood for immunogenicity testing 
• ECGs (predose and one-hour postdose) 
• Orthostatic blood pressure and vital signs 
• Height 
• Weight 
• Serum calcium and albumin (predose and 4 hours post dose) 
• Measurement of volumetric bone density at the hip by QCT 
• Clinical assessment of new fractures 
• AE and concomitant medication review 
• Wrist DXA 
• Bone turnover markers (s-PINP and s-CTX) 


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• Randomization and study medication (abaloparatide-SC or placebo) will be assigned 
through the IRT 
• Dispense study medication 
• First dose of study medication will be administered by the subject in clinic 
• Investigator assessment of local tolerance, within 5 minutes and at 1 hour following 
administration 
• Instruct subject on completion of diary, including subject assessment of local 
tolerance, within 5 minutes and at 1 hour following administration, will need to be 
done beginning on Day 2 and continuing through Day 7 of Month 1. 
6.2.9. 
Visit 4 (Month 1) 
• Symptom driven physical exam, including assessment for potential vertebral fracture 
• Collect blood for immunogenicity testing 
• Orthostatic blood pressure and vital signs 
• Height 
• Weight 
• Laboratory testing of serum chemistry, hematology, and urine dipstick 
• Serum calcium and albumin (predose and 4 hours post dose) 
• Dispense study medication 
• Self-administration of study medication when directed by site staff after completion 
of predose activities 
• Clinical assessment of new fractures 
• AE and concomitant medication review 
• Bone turnover markers (s-PINP and s-CTX) 
• Investigator assessment of local tolerance, within 5 minutes and at 1 hour following 
administration 
• Review subject diary 
• Provide subject with supplies for collecting a 24-hour urine sample (the sample is to 
be collected on the day prior to the Month 3 visit). 
6.2.10. 
Visit 5 (Month 3) 
• A 24-hour urine collection will be collected. Subjects will discard the first void and 
begin a 24-hour urine collection on the day prior to the clinic visit 
• Symptom-directed physical examination, including assessment for potential vertebral 
fracture 
• Collect blood for immunogenicity testing 


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• Orthostatic blood pressure and vital signs 
• Height 
• BMD assessments of lumbar spine, total hip, femoral neck, and wrist by DXA 
• Bone turnover markers (s-PINP and s-CTX) 
• Dispense study medication 
• Self-administration of study medication when directed by site staff after completion 
of predose activities 
• Serum calcium and albumin (predose and 4 hours post dose) 
• Clinical assessment of new fractures 
• AE and concomitant medication review 
• Investigator assessment of local tolerance, within 5 minutes and at 1 hour following 
administration 
• Review subject diary 
6.2.11. 
Visit 6 (Month 6) 
• Symptom-directed physical examination, including assessment for potential vertebral 
fracture 
• Collect blood for immunogenicity testing 
• Height 
• Weight 
• Orthostatic blood pressure and vital signs 
• Dispense study medication 
• Self-administration of study medication when directed by site staff after completion 
of predose activities 
• Only for subjects who consent to provide PK samples: Collect PK samples at 45 
minutes (±15 minutes) and 2.5 hours (±0.5 hour) after injection 
• Laboratory testing of serum chemistry, hematology, and urine dipstick 
• Serum calcium and albumin (predose [from chemistry panel] and 4 hours post dose) 
• BMD assessments of lumbar spine, total hip, femoral neck, and wrist by DXA 
• Bone turnover markers (s-PINP and s-CTX) 
• Clinical assessment of new fractures 
• AE and concomitant medication review 
• Investigator assessment of local tolerance, within 5 minutes and at 1 hour following 
administration 


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• Review subject diary 
6.2.12. 
Visit 7 (Month 9) 
• Symptom-directed physical examination, including assessment for potential vertebral 
fracture 
• Collect blood for immunogenicity testing 
• Orthostatic blood pressure and vital signs 
• Height 
• Dispense study medication 
• Self-administration of study medication when directed by site staff after completion 
of predose activities 
• Only for subjects who consent to provide PK samples: Collect PK samples at 20 
minutes (±10 minutes) and 4 hours (±0.5 hour) after injection 
• Serum calcium and albumin (predose and 4 hours postdose) 
• Clinical assessment of new fractures 
• AE and concomitant medication review 
• Investigator assessment of local tolerance, within 5 minutes and at 1 hour following 
administration Instruct subject on completion of diary, including subject assessment 
of local tolerance, within 5 minutes and at 1 hour following administration, beginning 
on Day 2, and continuing through Day 7 in Month 9 
• Review subject diary 
6.2.13. 
Visit 8 (Month 12)/Early Termination Visit 
• Symptom-directed physical examination, including assessment for potential vertebral 
fracture 
• Collect blood for immunogenicity testing 
• ECG 
• Weight 
• Height 
• Orthostatic blood pressure and vital signs 
• Only for subjects who consent to provide PK samples and attend the Month 12 visit: 
Collect a predose sample within 10 minutes before injection 
• Self-administration of study medication when directed by site staff after completion 
of predose activities using medication dispensed at Visit 7 (Note: Applicable only to 
subjects completing a Month 12 visit) 


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• Only for subjects who consent to provide PK samples and attend the Month 12 visit: 
Collect a postdose sample at 1.5 hours (±0.5 hour) after injection 
• PTH, 25-hydroxyvitamin D, and 1,25-dihydroxy vitamin D level 
• Laboratory testing of serum biochemistry, hematology, coagulation and urine dipstick 
• BMD assessments of lumbar spine, total hip, femoral neck, and wrist by DXA 
• Measurement of volumetric bone density at the hip by QCT 
• Bone turnover markers (s-PINP and s-CTX) 
• Serum total testosterone and SHBG 
• Clinical assessment of new fractures 
• AE and concomitant medication review 
• Review subject diary 
6.2.14. 
Visit 9/Safety Follow-up 
• Symptom-directed physical examination, including assessment for potential vertebral 
fracture 
• Collect blood for immunogenicity testing 
• Record vital signs 
• Height 
• ECG 
• All AEs, including SAEs, will be recorded from the time of signing of the informed 
consent and up to the 30 days after the last dose of study medication 
• All subjects who remain antibody positive will continue to be followed for 
immunogenicity testing every 6 months until their result is antibody negative 
6.2.15. 
Unscheduled Visit 
If the subject returns to the clinic for an unscheduled visit (e.g., to follow-up on an abnormal 
laboratory test), the procedures performed at this visit will be recorded in the eCRF and source 
documentation. 
6.3. 
Vital Signs and Physical Examinations 
A complete physical examination (review of all body systems), height, weight, and vital signs 
assessment will be performed at screening. 
A complete physical examination includes a review of the following systems: head/neck/thyroid, 
eyes/ears/nose/throat, respiratory, cardiovascular, lymph nodes, abdomen, skin, musculoskeletal, 
and neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated. After screening, any clinically significant abnormal findings in physical examinations 
should be reported as AEs. 


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Height and weight will be measured with shoes off. Height is to be measured using a wall 
mounted stadiometer. When height cannot be accurately measured such as in cases of severe 
kyphosis or loss of height from vertebral compression fractures, a documented historical height 
(i.e., from government IDs, medical records, etc.) may be used. 
Vital signs include orthostatic blood pressure (systolic and diastolic), temperature (oral), heart 
rate, and respiratory rate. These will be assessed following a 5-minute rest (seated or supine) and 
before blood sample collection. At visits when study drug is administered at the site, vital sign 
assessments will be collected before the dose of study drug. Supine and standing blood pressure 
measurements will be performed at each visit during the Treatment Period.  
6.4. 
12-Lead Electrocardiogram 
Standard, 12-lead ECGs will be performed. A hard copy of the ECG should be printed and 
signed by the Investigator at the site. Any abnormalities should be noted and clinical relevance 
should be documented. An ECG will be recorded immediately prior to dosing and 1 hour 
postdose during the Treatment Period. 
6.5. 
Laboratory Evaluations 
6.5.1. 
Clinical Laboratory Evaluations 
Hematology, serum chemistry, and urinalysis will be collected at time points indicated in the 
Schedule of Assessments and Procedures in Table 3. All clinical laboratory blood and 24-hour 
urine samples will be sent to a central laboratory for analysis and testing. A list of study clinical 
laboratory tests is in Table 5. 


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Table 5: 
Clinical Laboratory Tests 
Hematology 
 
Serum Chemistry 
Urinalysis (Dipstick)a 
Additional Tests 
Hemoglobin 
Sodium 
pH 
PTH (1–84)b 
Hematocrit 
Potassium 
Glucose 
25-hydroxyvitamin Db 
1,25-dihydroxy vitamin Db 
 
WBC count with 
differential in absolute 
counts 
Chloride 
Protein 
BSAP 
RBC count 
Inorganic phosphorus 
Ketones 
Estradiolc 
Testosteroneb 
SHBG b 
TSH (T3 and Free T4)c 
MCV 
Albumin 
Bilirubin 
MCHC 
Total protein 
Blood 
MCH 
Glucose 
Urobilinogen 
Platelet count 
BUN 
Specific gravity 
 
Creatinine 
Nitrite 
 
Uric acid 
Leukocytes 
 
AST 
 
 
ALT 
 
 
GGT 
 
 
CPK 
 
 
Alkaline phosphatase 
 
 
Total bilirubin 
 
 
LDH 
 
 
Total Cholesterol  
 
 
Triglycerides 
 
 
Total calcium 
 
a. Clinic only, if required by PI send to central lab for microscopy 
b. Only required at Screening and Visit 8 or early termination (Month 12 visit)  
c. Only required at Screening. Reflex testing for T3 and Free T4 will be performed by the central laboratory if TSH 
is outside the normal limits. Reflex testing for bone-specific alkaline phosphatase will be performed by the 
central laboratory if serum alkaline phosphatase is outside the normal limits. 
ALT = alanine aminotransferase; AST = Aspartate aminotransferase; BSAP = bone-specific alkaline phosphatase; 
BUN = blood urea nitrogen; CPK = Creatine phosphokinase; GGT = gamma-glutamyl transpeptidase; LDH = 
lactate dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin 
concentration; MCV = Mean corpuscular volume; PTH = parathyroid hormone; RBC = red blood cell; SHBG = sex 
hormone binding globulin; TSH = thyroid stimulating hormone; WBC = white blood cell 
In the event of medically significant, unexplained, or abnormal clinical laboratory test values, the 
test(s) should be repeated and followed up until the results have returned to within the normal 
range or an adequate explanation for the abnormality is found. Clinically significant changes in 
laboratory tests that occur during the course of the study are to be reported as AEs. 
The clinical laboratory will clearly mark all laboratory test values that are outside the normal 
range and the Investigator will indicate the clinical relevance of these out-of-range values. 
6.5.2. 
Serum Markers of Bone Metabolism 
Blood samples will be taken to measure efficacy related markers of bone metabolism at Day 1, 
Month 1, Month 3, Month 6, and Month 12 or early termination. S-PINP and s-CTX will be 
measured in all subjects. 


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6.5.3. 
Immunogenicity Testing 
Serum samples for immunogenicity testing will be collected at Day 1 (Visit 3), Month 1 
(Visit 4), Month 3 (Visit 5), Month 6 (Visit 6), Month 9 (Visit 7), Month 12 (Visit 8), and the 
Follow-up Visit scheduled at 1 month after the last dose of study medication (Visit 9). Samples 
will be tested for the presence of binding anti-abaloparatide antibodies, including determination 
of antibody titer. Any positive samples will be tested for the potential to neutralize abaloparatide 
in a cell-based assay. Additionally, positive samples will be tested for cross-reactivity to 
endogenous PTH and PTHrP. Any subjects who show presence of antibodies at the Follow-up 
Visit scheduled at 1 month following the last dose of study medication (Visit 9) will be retested 
at 6-month intervals post-study until antibody status return to negative. 
The serum samples for immunogenicity testing will be analyzed and reported separately. All the 
planned analyses related to the immunogenicity results and antibody status will also be reported 
separately. 
6.5.4. 
Pharmacokinetic Testing 
A blood sample for PK analysis of abaloparatide will be collected using a 5 mL K3 EDTA tube 
with 0.1 mg/mL aprotinin at each time point indicated in the PK sample collection schedule 
(Table 4). 
6.5.5. 
Specimen Preparation, Handling and Storage 
The procedures for the collection, handling, and shipping of clinical laboratory samples are 
specified in a separate Laboratory Manual provided to each clinical site. 
6.6. 
Imaging Procedures 
All imaging measurements (BMD according to DXA and QCT) will be performed according to 
the procedures outlined in the Imaging Charter and Imaging Manuals which will be provided as a 
separate document. A central imaging laboratory will be utilized for all DXA and QCT readings. 
QCT will be performed in a subset of subjects at a selected number of study sites. 
6.6.1. 
Dual Energy X-ray Absorptiometry 
All subjects will have areal bone density (aBMD) measurements taken via DXA of the lumbar 
spine, total hip, femoral neck, at Screening (Visit 1), wrist at Day 1 (Visit 3); spine, total hip, 
femoral neck, and wrist at Month 3 (Visit 5), Month 6 (Visit 7), and Month 12 (Visit 8). Lumbar 
spine scans must include L1 through L4. Hip scans will include the entire proximal femur to 
about 2 cm below the lesser trochanter. DXA bone density assessments will be performed at the 
forearm to measure BMD of the distal one-third radius and ultra-distal radius. For hip and wrist 
scans, the same side should be used for all scans at all visits. If a subject fractures a hip or 
forearm being examined during the study, no further scans of either hip or forearm will be 
acquired. 
For screening purposes, DXA scans of the lumbar spine, total hip, and femoral neck taken up to 
35 days prior to the beginning of the Screening Period may be used to determine study 
eligibility. DXA scans should be performed using a study-approved scanner (and read by the 
study central DXA reader) up to 35 days prior to the subject’s Screening Visit. 


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6.6.2. 
Quantitative Computed Tomography 
A subset of subjects at a selected number of study sites will have volumetric BMD (vBMD) 
measurements taken via QCT of the hip on Day 1 (Visit 3) and Month 12 (Visit 8). 
6.6.3. 
Clinical and Radiologic Evaluation of Fractures 
All spine radiographs will be performed according to the procedures outlined in the Imaging 
Charter and Imaging Manual which will be provided as separate documents. All subjects will 
have X-rays taken to document fractures of the lumbar and thoracic vertebrae at Screening to 
confirm entry criteria. Radiographs of the lateral thoracic and lumbar spine will include coverage 
of T3 to S1. The lateral spine radiographs will be assessed for prevalent and incident vertebral 
fractures using the Genant Semiquantitative Scoring method (Genant et al, 1993). 
• Grade 0: Normal (approximately < 20% reduction in anterior, middle, or posterior 
height) 
• Grade 1: Mild fracture (approximately 20%–25% reduction in anterior, middle, or 
posterior height) 
• Grade 2: Moderate fracture (approximately 25%–40% reduction in anterior, middle, 
or posterior height) 
• Grade 3: Severe fracture (> 40% reduction in anterior, middle, or posterior height) 
Incident radiological vertebral fractures occur in vertebrae with an increase in SQ score ≥ 1 at a 
Follow-up Visit. New incident radiological vertebral fractures occur in vertebrae that are not 
fractured (i.e., SQ score of 0) at Screening. Worsening incident radiological vertebral fractures 
occur in vertebrae with prevalent (i.e., pre-existing) fractures at baseline. Subjects will also be 
clinically evaluated for vertebral and nonvertebral fractures (wrist, hip, rib, etc.) which occur 
during the study. Should a clinical fracture occur, X-ray images and reports associated with the 
fracture must be obtained and maintained in the subject’s medical record. 
All fractures will be identified and evaluated as part of the disease assessment and will be 
documented in the case report forms and source documents. 
6.7. 
Discontinuation from the Study 
Subjects may voluntarily discontinue from the study for any reason at any time. 
Any subject who demonstrates decreases in BMD ≥ 7% from baseline of this study at the lumbar 
spine or total hip will have the assessment repeated and, if confirmed, will be notified by the 
Investigator, and be withdrawn from the study. Subjects sustaining a radiologically confirmed 
incident vertebral or nonvertebral fragility fracture will be informed of the finding and will be 
counseled as to treatment options and may discontinue or choose to remain on the study. Those 
subjects who sustain an incident fracture during the study and elect to remain in the study will be 
asked to sign an additional informed consent document advising them of an increased risk for 
subsequent fracture.  
Subjects who decide they do not wish to participate in the study further should return for the 
assessments indicated for the Month 12/Early Termination and 30 days later for the 
Month 13/Follow-up Visit in the Schedule of Assessments and Procedures (Table 3). If they fail 


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to return for these assessments for unknown reasons, every effort (e.g., telephone, email, and 
letter) should be made to contact them. 
6.7.1. 
Withdrawal of Consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study-related contact. 
If a subject withdraws consent, the Investigator must make every effort to determine the primary 
reason for this decision and record this information. Further attempts to contact the subject are 
not allowed unless safety findings require communicating or follow-up. 
6.7.2. 
Early Study Termination 
The study can be terminated at any time for any reason by the Sponsor. Should this be necessary, 
subjects should be seen as soon as possible and treated as a prematurely withdrawn subject. The 
Investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the subject’s interests. 
The Investigator will be responsible for informing IRBs/IECs of the early termination of the 
study. 


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7. 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
DOCUMENTATION 
7.1. 
Evaluation of Safety 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects and is mandated by regulatory agencies worldwide. All 
clinical studies sponsored by RADIUS will be conducted in accordance with Standard Operating 
Procedures (SOPs) that have been established to conform to regulatory requirements worldwide 
to ensure appropriate reporting of safety information. 
All AEs are collected from the time of the informed consent until 30 days after last dose of 
investigational product. Where possible, a diagnosis rather than a list of symptoms should be 
recorded. All AEs should be captured on the appropriate AE pages in the eCRF and in source 
documents. The Investigator will assess all AEs for relationship to study drug. For information 
on the safety profile obtained to date for abaloparatide, please refer to the IB. 
7.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH, 
1995). 
AEs include: 
• Worsening (change in nature, severity, or frequency) of conditions present at the 
onset of the study 
• Intercurrent illnesses 
• Drug interactions 
• Events related to or possibly related to concomitant medications 
• Abnormal laboratory values (this includes significant shifts from Baseline within the 
range of normal that the Investigator considers to be clinically important) 
• Clinically significant abnormalities in physical examination, vital signs, and weight 
An abnormal laboratory value will not be assessed as an AE unless it requires a therapeutic 
intervention or is considered by the Investigator to be clinically significant. 
7.1.2. 
Serious Adverse Event 
A SAE is any AE that results in any of the following: 
• Death 
• Life-threatening: The term “life-threatening” in the definition of “serious” refers to an 
event/reaction in which the subject was at risk of death at the time of the 


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event/reaction; it does not refer to an event/reaction which hypothetically might have 
caused death if it were more severe. 
• Required in-subject hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity (i.e., substantial disruption of the 
ability to conduct normal life function) 
• Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in in-subject hospitalization, or the development of drug 
dependency or drug abuse.  
All AEs of osteosarcoma will be reported as SAEs. All reports of osteosarcoma, regardless of 
causality or expectedness, will be expedited to the FDA within 15 days of receipt. MedDRA 
preferred terms include osteosarcoma, osteosarcoma metastatic, osteosarcoma recurrent, 
extraskeletal osteosarcoma, extraskeletal osteosarcoma metastatic, extraskeletal osteosarcoma 
recurrent. 
All treatment-related SAEs must be followed until resolution (subject has returned to baseline 
status of health) or until stabilization (the Investigator does not expect any further improvement 
or worsening of the reported event). 
7.1.3. 
Recording an Adverse Event 
All AEs/SAEs will be entered into the electronic database. 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the subject was enrolled in the study are not to be considered AEs unless they occur at a time 
other than the planned date or the pre-existing illness or disease worsens after enrollment into the 
study. 
Fractures identified during the study are not to be recorded as AEs unless the subject is 
hospitalized, the fracture is complicated, or the Investigator considers the fracture to be unrelated 
to the subject’s underlying osteoporosis. All fractures will be identified and evaluated as part of 
the disease assessment and will be documented in the CRF and by collection of source 
documents. 
For both serious and non-serious AEs, the Investigator must determine the intensity of the event 
and the relationship of the event to study drug administration (abaloparatide and placebo). 
Intensity for each AE will be defined according to the following criteria: 


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Intensity 
Definition  
Mild 
Awareness of sign or symptom, but easily 
tolerated. 
Moderate  
Discomfort enough to cause interference 
with normal daily activities. 
Severe 
Inability to perform normal daily activities. 
If the intensity of an adverse event changes within a day, the maximum intensity should be 
recorded. If the intensity changes over a longer period of time, the changes should be recorded as 
separate events (having separate onset and stop dates for each intensity). 
Relationship to blinded study drug administration will be determined by the Investigator 
according to the following criteria: 
Relationship 
Definition  
None 
No relationship between the event and the 
administration of study drug. The event is 
related to other etiologies, such as 
concomitant medications or subject’s 
clinical state. 
Unlikely 
The current state of knowledge indicates that 
a relationship to study drug is unlikely or the 
temporal relationship is such that study drug 
would not have had any reasonable 
association with the observed event. 
Possible 
A reaction that follows a plausible temporal 
sequence from administration of the study 
drug and follows a known response pattern 
to the suspected study drug. The reaction 
might have been produced by the subject’s 
clinical state or other modes of therapy 
administered to the subject. 
Probable 
A reaction that follows a plausible temporal 
sequence from administration of the study 
drug and follows a known response pattern 
to the suspected study drug. The reaction 
cannot be reasonably explained by the 
known characteristics of the subject’s 
clinical state or other modes of therapy 
administered to the subject. 


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For the purpose of safety analyses, all AEs that are classified with a relationship to study 
medication administration of possible or probable will be considered treatment-related events. 
7.1.3.1. 
Serious and Unanticipated Adverse Device Effects for Abaloparatide-SC 
An adverse device effect (ADE) is defined as any adverse event related to the use of an 
investigational medical device (IMD). For the purposes of this protocol, abaloparatide-SC is the 
IMD. All ADEs should be reported as an AE per Section 7.1, which includes AEs resulting from 
insufficient or inadequate instructions for use, deployment, implantation, installation, operation, 
any malfunction of the IMD, use error, or intentional misuse of the IMD (ISO/DIS 14155). 
An unanticipated adverse device effect (UADE) is defined as any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, the 
abaloparatide-SC device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the application/IB, or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects (21 CFR 
812.3(s)). 
Any UADE that occurs during the study from the time the subject signs the ICF until 30 days 
after the last dose of study medication must be reported within 24 hours of first awareness of the 
event using the SAE and the UADE report forms and emailing to PV@radiuspharm.com. 
The Investigator and the Sponsor will immediately conduct an evaluation of any UADE 
occurring with abaloparatide-SC. The results of the evaluation will be reported to the IRB within 
10 days of the Sponsor becoming aware of the event. 
If it is determined by the Investigator and the Sponsor to present an unreasonable risk to study 
subjects, all investigations or parts of the investigation presenting that risk will be terminated as 
soon as possible. Termination will occur not later than 5 working days after the Investigator and 
the Sponsor makes this determination and not later than 15 working days after the Sponsor first 
receiving notice of the event. The Investigator and the Sponsor will not resume an investigation 
terminated under these conditions without an additional IRB approval. 
7.1.4. 
Serious Adverse Event Reporting 
Any SAEs that occur during the study from the time the subject signs the ICF until 30 days after 
the last dose of study medication must be reported within 24 hours of first awareness of the event 
using the SAE report form and emailing to PV@radiuspharm.com. Data should also be entered 
in the clinical trial eCRF. 
Treatment-related SAEs will be followed until resolution or stabilization. The reference safety 
information for this study is the IB, which will be provided under separate cover to all 
Investigators. 
Any SAEs that occur at any time after completion of the study, which the Investigator considers 
to be related to study drug, must be reported to the Sponsor or its designee. 
The Investigator must submit the SAE to the IRB/ IEC in accordance with 21 CFR parts 56 and 
312 as well as with applicable local regulations. Documentation of these submissions must be 
retained in the site study file. 


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7.1.5. 
Device Reporting 
Abaloparatide-SC is a drug-device combination product. In order to fulfill regulatory reporting 
obligations worldwide, the Investigator is responsible for the detection and documentation of 
events meeting the definition of a UADE that occurs with abaloparatide-SC (Section 7.1.3.1). 
Any UADEs that occur during the study with abaloparatide-SC, from the time the subject signs 
the ICF until 30 days after the last dose of study drug, must be reported within 24 hours of first 
awareness that the event meets the definition of a reportable incident by entering data in the 
clinical trial eCRF. Treatment-related UADEs will be followed until resolution or stabilization, 
the condition is otherwise explained, or until the subject is lost to follow-up. 
SAEs (initial reports and follow-up information) must be reported by the Investigator using the 
SAE report form; the form must be completed and emailed to PV@radiuspharm.com. 
The Investigator will comply with the applicable local regulatory requirements relating to 
reporting to the IRB/IEC. 
7.1.6. 
Follow-up of Adverse Events 
All treatment-related AEs will be followed with appropriate medical management until resolved 
or stabilized. 
UADEs will be followed until their medical outcome is determined, with periodic written reports 
about the status provided to the Sponsor. 
7.1.7. 
Abuse, Misuse, Overdose, or Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the Sponsor 
whether or not they result in an AE/SAE. 
• Abuse – Persistent or sporadic intentional intake of investigational medicinal product 
at a dose higher than prescribed per protocol (but below the dose defined for 
overdose) or when used for non-medical purpose (e.g., altering one’s state of 
consciousness). 
• Misuse – Intentional or unintentional use of investigational medicinal product other 
than as directed or indicated at any dose, which is at or below the dose defined for 
overdose Note: this includes a situation where the test article is not used as directed at 
the dose prescribed by the protocol. 
• Overdose – Intentional or unintentional injection of a dose of abaloparatide at least 
2 times higher than the protocol-specified dose and is associated with clinical 
symptoms. 
• Medication Error – A mistake made in prescribing, dispensing, administration and/or 
use of the investigational medicinal product. 
7.1.8. 
Pregnancy 
Any pregnancy for the partner of a study participant must be reported on the Partner’s Pregnancy 
Report Form within 24 hours and emailed to the RADIUS Pharmacovigilance Department at 
PV@radiuspharm.com. Every effort should be made to gather information regarding the 


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pregnancy outcome. It is the responsibility of the Investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
In subjects who have partners of childbearing potential, the subject and his partner should abstain 
from sexual intercourse, or use highly effective contraceptive measures (e.g., oral contraceptive 
and condom, IUD and condom, or diaphragm with spermicide and condoms; other forms of 
contraception must be approved by a Medical Monitor) when engaging in sexual intercourse 
throughout the study, and for at least 90 days after the last dose of abaloparatide. 
7.1.9. 
Regulatory Agency, Institutional Review Board, Ethics Committee and Site 
Reporting 
The Sponsor and/or the clinical contract research organization (CRO) are responsible for 
notifying the relevant regulatory authorities/US central IRBs/EU central IEC committees of 
related, unexpected SAEs. 
The Investigator is responsible for notifying the Sponsor, CRO, and local IRB/IEC, or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required. 
If a death occurs during the study or within 30 days after Month 12/Early Termination visit 
(Visit 8), and it is determined to be related either to a study procedure or a study drug, the 
Investigator or his/her designee must notify the Sponsor and will communicate that information 
to the IRB/IEC within one business day of knowledge of the event. The contact may be by phone 
or email. 
7.2. 
Study Completion and Post-Study Treatment 
The Investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study due to an adverse event or must refer them for appropriate ongoing 
care. 
7.3. 
Lost to Follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating an 
intention to discontinue or withdraw, the Investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g., dates of telephone 
calls, registered letters. A subject should not be formally considered lost to follow-up until 
multiple attempts to contact the subject have been made, including at least 2 attempts to reach 
the subject by phone followed by a certified letter sent to the subject’s last known mailing 
address.  
 


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Statistical and Analytical Plans 
A comprehensive SAP will be completed and approved prior to database lock. All statistical tests 
will be 2-sided with a significance level of 1%, unless otherwise specified. 
8.2. 
Statistical Hypotheses 
The primary objective of this study is to evaluate the efficacy and safety of abaloparatide-SC 
80 µg per day compared to placebo in men with osteoporosis. The hypotheses to be tested are 
that abaloparatide is superior to placebo, and that the safety profile of abaloparatide-SC in 
osteoporotic men is similar to that of abaloparatide-SC in postmenopausal women with 
osteoporosis. 
8.3. 
Analysis Datasets 
8.3.1. 
Populations for Analysis 
The primary population for all efficacy analyses will be the Intention-to-Treat (ITT) Population, 
which is defined as all subjects randomized into this study. The primary population for safety 
analyses will be the Safety Population, defined as all subjects who received at least one dose of 
study medication. The Per-Protocol (PP) Population will include all ITT subjects who did not 
have any significant protocol deviations and will be used for supportive analyses. The criteria for 
the exclusion from the PP Population will be appropriately documented prior to database lock 
and treatment unblinding.  
8.4. 
Description of Statistical Methods 
8.4.1. 
General Approach 
Analyses will be presented by treatment group (abaloparatide-SC and placebo) and overall, when 
appropriate. Baseline is defined as the last value obtained prior to the first dose of study 
medication. 
For categorical data, summary tabulations of the number and percentage of subjects within each 
category of the parameter will be presented. For continuous data, the number of subjects, mean, 
median, standard deviation (SD), minimum, interquartile range (Q1 and Q3), and maximum will 
be presented. 
8.4.2. 
Analysis of the Primary Efficacy Endpoint(s) 
The primary efficacy endpoint will be the percent change in lumbar spine BMD from baseline to 
12 months. The analyses will be based on the ITT Population.  
The missing data from this study will be reviewed carefully to evaluate any missing data 
patterns. As this study was not designed to systematically collect data from subjects who 
discontinue treatment early, the “retrieved dropouts” approach for handling missing data is not 
applicable for this study. To appropriately address the possibility of data missing not at random, 
the primary analysis will be based on a pattern-mixture model (PMM) analysis with multiple 


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imputation using the wash-out imputation method. This method uses sequential regression and 
wash-out imputation methodology to impute missing values after a subject’s discontinuation 
from the study. The missing primary endpoint values for subjects in the abaloparatide-SC group 
will be imputed with the observed baseline and data from the placebo group; no intermediate 
values from the abaloparatide-SC group will be used in the imputation for the abaloparatide-SC 
group. For subjects in the placebo group, intermediate observed values from the completers in 
the placebo group will be used while imputing missing values during the 12-month Treatment 
Period. The PROC MI methodology for imputation of monotone missing data patterns will be 
used to impute the outcome variables at consecutive visits in a sequential (chain) manner. Each 
of these imputed datasets will be analyzed using analysis of covariance (ANCOVA) with 
treatment and DXA instrument manufacturer as fixed effects and the baseline lumbar spine BMD 
as a covariate. Results from all imputed datasets will be combined using PROC MIANALYZE 
for overall statistical inference. The statistical tests will be 2-sided comparing abaloparatide-SC 
to placebo; 99% CIs will be presented together with the estimated p-values.  
As a sensitivity analysis, the primary efficacy endpoint will also be analyzed using a Mixed 
Model for Repeated Measures (MMRM) analysis. The MMRM model will include the fixed 
effects of treatment, DXA instrument manufacturer, visit, and treatment-by-visit interaction, with 
the baseline lumbar spine BMD as a covariate. For the MMRM model, an unstructured variance-
covariance matrix shared between the 2 treatment groups will be used to model the within-
subject errors over the visits. The treatment comparison will be obtained by testing the contrast 
(difference in least squares mean) between the 2 treatment groups at Month 12 (Visit 8). The 
statistical tests will be 2-sided comparing abaloparatide-SC to placebo; 99% CIs will be 
presented together with the estimated p-values. 
Sensitivity analyses for addressing the effect of the COVID-19 pandemic and supportive 
analyses using the last observation carried forward (LOCF) method to impute missing data will 
also be conducted.  
8.4.3. 
Analysis of Secondary Endpoint(s) 
The key secondary efficacy endpoints are: 
• Percent change from baseline in total hip BMD at 12 months 
• Percent change from baseline in femoral neck BMD at 12 months 
Additional secondary efficacy endpoints are: 
• Percent change from baseline in: 
− Lumbar spine BMD at 3 and 6 months 
− Total hip BMD at 3 and 6 months 
− Femoral neck BMD at 3 and 6 months 
− Ultra-distal radius BMD at 3, 6, and 12 months 
− Distal one-third radius BMD at 3, 6, and 12 months 


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• Log ratio of post-baseline over baseline in: 
− s-PINP at 1, 3, 6, and 12 months 
− s-CTX at 1, 3, 6, and 12 months 
• Proportion of subjects experiencing BMD gains from baseline of > 0%, > 3%, and 
> 6% at the lumbar spine, femoral neck, and total hip at 3, 6, and 12 months 
• Incidence of new clinical fractures at 12 months 
• Proportion of subjects converting from the categories of osteoporosis to osteopenia or 
to normal at 12 months, where: 
− Osteoporosis is defined as lumbar spine or total hip BMD T-score ≤ -2.5.  
− Osteopenia is defined as one of the following: 
o Lumbar spine > -2.5 and total hip BMD T-score > -2.5 and < -1.0 
o Lumbar spine > -2.5 and < -1.0 and total hip BMD T-score > -2.5  
− Normal is defined as lumbar spine and total hip BMD T-score ≥ -1.0.  
• The percent change in total hip and femoral neck volumetric BMD as measured by 
QCT from baseline to 12 months. QCT will be performed in a subset of subjects at a 
selected number of study sites. 
Analyses of the primary and key secondary endpoints will follow a fixed-sequence testing 
approach to control the overall Type 1 error rate at the 2-sided significance level of 1%. To claim 
statistical significance at the 2-sided level of 1%, the following 3 fixed-sequence tests will be 
performed in sequential order. At any step of the sequential testing, if the treatment difference is 
not statistically significant at the 1% level then all the subsequent comparisons following the 
fixed sequence cannot be claimed statistically significant. 
1. Percent change from baseline in BMD at the lumbar spine at 12 months 
2. Percent change from baseline in BMD at the total hip at 12 months 
3. Percent change from baseline in BMD at the femoral neck at 12 months 
P-values for treatment comparisons of all other efficacy endpoints will be generated to support 
the study findings without any adjustments for multiplicity. 
The analyses of the key secondary BMD endpoints will be performed using a PMM analysis 
with multiple imputation using the wash-out imputation method similar to the analysis for the 
primary efficacy endpoint, as stated in Section 8.4.2, with the appropriate baseline covariate. 
Sensitivity analyses using MMRM models, sensitivity analyses for addressing the effect of the 
COVID-19 pandemic, and supportive analyses using the LOCF method, as with the primary 
efficacy endpoint, will also be conducted. 
The bone formation marker, s-PINP, and the bone resorption marker, s-CTX, will be analyzed 
based on the ratio of the post-baseline value relative to the baseline using a natural log 
transformation at each visit. The analysis will use a PMM analysis with multiple imputation 
using the wash-out imputation method similar to that described in Section 8.4.2. 


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Percent changes from baseline in BMD over time will be summarized using descriptive statistics 
by visit for each treatment group. 
The bone formation marker, s-PINP, and the bone resorption marker, s-CTX, will be 
summarized descriptively by treatment group, with values, changes and percent changes from 
baseline, geometric mean values, and geometric mean values relative to baseline at each visit. 
A BMD responder analysis by visit will be performed for those subjects who have both baseline 
and the relevant post-baseline BMD values. Three categories of BMD response will be 
evaluated: %BMD increase > 0%, > 3%, and > 6%. The response will be assessed at the lumbar 
spine, total hip, and femoral neck. Subjects who have BMD increase at all 3 skeletal sites at the 
same visit will be considered responders, with the primary time point at 12 months. No 
imputation of missing data will be implemented. The number and percentage of responders in 
each treatment group will be compared using either the Chi-square test or Fisher’s exact test. 
Kaplan-Meier estimates for the time to new clinical fracture at 12 months and the hazard ratio 
(99% CI) will be presented, with treatment comparisons based on the log-rank test. 
The number and percentage of subjects for whom disease status (categories as defined in the 
secondary endpoints listed earlier in this section) has changed from osteoporosis at baseline to 
osteopenia, normal, or no change at 12 months will be analyzed using the Chi-square test. 
The percent change from baseline in total hip and femoral neck volumetric BMD (vBMD) at 
12 months, as measured by quantitative CT will be analyzed using a similar ANCOVA model as 
stated in Section 8.4.2. 
The primary analyses of the secondary efficacy variables will be based on the ITT Population 
and will be repeated using the PP Population. 
Subgroup analysis (e.g., age, geography, FRAX, prior fracture, and baseline BMD, s-PINP, 
testosterone, and estradiol levels) may be performed. Details of the subgroup analyses will be 
described in the SAP. 
8.4.4. 
Pharmacokinetic Analyses 
A population PK analysis will be performed on the sparse plasma concentration data of 
abaloparatide as described in the Pharmacometric Analysis Plan. This analysis may be expanded 
to include a population PK/exposure-response analysis of the percent change in BMD from 
baseline over time. 
8.4.5. 
Safety Analyses 
Unless otherwise specified, safety analyses will be conducted using the Safety Population and 
will be descriptive in nature. 
Study drug exposure and study drug compliance will be calculated. The duration of study drug 
exposure, total dose received, and percent compliance will be summarized by treatment group. 
All AEs will be coded using MedDRA. The number and percent of subjects who experienced 
TEAEs will be summarized by MedDRA system organ class (SOC), preferred term, and 
treatment group. Summaries will also be provided for severe TEAEs, SAEs, TEAEs leading to 


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study drug withdrawal, drug-related TEAEs (with probable or possible relationship to study 
drug), and TEAEs by maximum severity (mild, moderate, severe). 
The number and percent of subjects who report TEAEs associated with hypercalcemia and 
hypercalciuria will be summarized by treatment group. 
All AEs collected prior to the first dose of study drug will be summarized separately. 
A listing of subjects who experience an UADE will be provided. 
Descriptive statistics for laboratory data (including serum calcium and albumin), vital signs 
(including orthostatic blood pressure [BP]), ECGs, Investigator assessment of local tolerance, 
and subject assessment of local tolerance will be provided by treatment group and visit. For 
laboratory data, vital signs, and ECGs, absolute results and changes from baseline will be 
presented. In addition, laboratory test results will be classified as above normal limit, within 
normal limit, or below normal limit. Laboratory shift frequencies will be tabulated between the 
Screening Visit and relevant post-baseline visit(s). 
For subjects in the abaloparatide-SC group, the anti-abaloparatide antibody assessment in the 
serum samples for immunogenicity testing will be categorized by 2 outcomes: 
• Negative for anti-abaloparatide antibodies 
• Positive for anti-abaloparatide antibodies 
The number (%) of subjects in the above categories of abaloparatide antibodies will be 
summarized on Day 1 (Visit 3) and at Month 1 (Visit 4), Month 3 (Visit 5), Month 6 (Visit 6), 
Month 9 (Visit 7), Month 12 (Visit 8), and the Follow-up Visit scheduled approximately 1 month 
after the last dose of study medication (Visit 9) using the Antibody Population.  
For those subjects with a positive anti-abaloparatide antibody present, the titer level, presence of 
neutralizing anti-abaloparatide antibodies (negative or positive), and assessment outcomes for 
cross-reactivity to PTH (negative or positive) and PTHrP antibodies (negative or positive), 
together with the neutralizing antibody status in subjects that are positive for PTH (negative or 
positive for the presence of PTH-neutralizing antibodies) or PTHrP (negative or positive for the 
presence of PTHrP-neutralizing antibodies), will be summarized by study visit.  
The results of antibody analyses will be included in a separate report. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary and summarized by number and percentage of subjects using each class and preferred 
drug term by treatment group. 
8.4.6. 
Adherence and Retention Analyses 
The number and percentage of subjects who withdraw from the study, with primary reason, will 
be summarized by treatment group. 
8.4.7. 
Baseline Descriptive Statistics 
Medical history, physical examination, demographics, and baseline characteristics will be 
summarized and presented by treatment group and overall. Medical history will be presented by 
MedDRA SOC and PT, summarizing the proportion of subjects who have a condition noted. 


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Results from the baseline physical examination will be summarized by body system as recorded 
in the eCRF.  
8.4.8. 
Interim Analyses 
There are no interim analyses planned for this study.  
8.4.9. 
Additional Subgroup Analyses 
Subgroup analysis (e.g., age, geography, FRAX (if applicable), prior fracture, and baseline 
BMD, s-PINP, testosterone, and estradiol levels) may be performed and will be described in the 
SAP. 
8.4.10. 
Multiple Comparison/Multiplicity 
As stated in Section 8.4.3, a fixed-sequence testing approach will be employed to control the 
Type 1 error rate at the 2-sided significance level of 1% for testing the primary and secondary 
efficacy endpoints. No other adjustments for multiple comparisons will be made. 
8.4.11. 
Tabulation of Individual Response Data 
Individual efficacy, PK, and safety data will be tabulated as appropriate. 
8.4.12. 
Exploratory Analyses 
Prespecified exploratory variables and analyses are described in Section 8.4.3. 
8.5. 
Sample Size Calculation 
A study sample size of 225 subjects (150 in the abaloparatide-SC group and 75 in the placebo 
group) will provide at least 99% power to detect a mean difference of 6.5% in the percentage 
change from baseline in lumbar spine BMD at 12 months between the abaloparatide-SC and the 
placebo groups at a 2-sided alpha level of 0.01, assuming a SD of 6.0% and a drop-out rate of 
10%. For the key secondary endpoints, this total sample size of 225 subjects will have 96% 
power to detect a 2.2% mean difference (SD = 3.5%) of percent change in total hip BMD at 
12 months, and 80% power to detect a 2.0% mean difference (SD = 4.1%) of percent change in 
femoral neck BMD at 12 months. 
8.6. 
Measures to Minimize Bias 
Not applicable. 
8.7. 
Enrollment/Randomization/Masking Procedures 
Abaloparatide-SC and placebo study medications will be prepared in a blinded fashion. Data will 
be reviewed in a blinded fashion and the analysis populations defined prior to database lock and 
unblinding. 


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9. 
ADMINISTRATIVE REQUIREMENTS 
9.1. 
Ethical Considerations 
This clinical study will be conducted in accordance with the current version of the ICH 
Harmonized Guideline for Good Clinical Practice (GCP), with applicable local laws and 
regulations, and with the ethical principles laid down in the Declaration of Helsinki. 
The Investigator will ensure that this study is conducted in full conformity with ICH GCP 
E6(R2). 
The IRB/IEC will review all appropriate study documentation to safeguard the rights, safety, and 
well-being of the subjects. The study will only be conducted at sites where IRB/IEC approval has 
been obtained. The protocol, IB, ICF, advertisements (if applicable), written information given to 
the subjects, safety updates, annual progress reports, and any revisions to these documents will 
be provided to the IRB/IEC by the Investigator or RADIUS or designee, as allowable by local 
applicable laws and regulations. 
9.2. 
Subject Information and Informed Consent 
The Investigator is responsible for obtaining written, informed consent from each subject 
interested in participating in this study before conducting any study-related procedures. 
Written informed consent should be obtained after adequate, thorough, and clear explanation of 
the study objectives, procedures, as well as the potential hazards of the study. The method of 
obtaining and documenting the informed consent and the contents of the consent will comply 
with ICH GCP and all applicable laws and regulations and will be subject to approval by 
RADIUS or its designee. 
9.3. 
Investigator Compliance 
No modifications to the protocol should be made without the approval of both the Investigator 
and RADIUS. Changes that significantly affect the safety of the subjects, the scope of the 
investigation, or the scientific quality of the study (i.e., efficacy assessments) will require 
IRB/IEC notification before implementation, except where the modification is necessary to 
eliminate an apparent immediate hazard to human subjects. RADIUS will submit all protocol 
modifications to the required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the Investigator will contact RADIUS to discuss the planned course of action. If possible, contact 
should be made before the implementation of any changes. Any departures from protocol must 
be fully documented in the source documentation. 
9.4. 
Access to Records 
The Investigator must make the office and/or hospital records of subjects enrolled in this study 
available for review by site monitors at the time of each monitoring visit, audit by RADIUS 
Quality Assurance (QA) and inspection by the regulatory agencies. The records must also be 
available for inspection, verification, and copying, as required by applicable laws and 
regulations, by officials of the regulatory health authorities (FDA and others). The Investigator 


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must comply with applicable privacy and security laws for use and disclosure of information 
related to the research set forth in this protocol. 
9.5. 
Subject and Data Confidentiality 
To maintain subject confidentiality, all eCRFs, study reports and communications relating to the 
study will identify subjects by assigned subject numbers. As required by federal regulations, the 
Investigator will allow RADIUS and/or its representatives access to all pertinent medical records 
to allow for the verification of data gathered in the eCRFs/SAE Forms and the review of the data 
collection process. The FDA (or other regulatory authority) may also request access to all study 
records, including source documentation, for inspection. 
As applicable, in accordance with the Health Insurance Portability and Accountability Act 
(HIPAA) and associated privacy regulations, a subject authorization to use personally 
identifiable health information may be required from each subject before research activities 
begin. 
Subject confidentiality is strictly held in trust by the participating Investigators, their staff, and 
RADIUS and their representatives. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of RADIUS. 
9.6. 
Research Use of Stored Human Samples, Specimens, or Data 
With the subject’s approval, and as approved by the site’s IRB/IEC, biological samples may be 
stored at a centralized facility determined by RADIUS. These samples could be used for 
retrospective biomarker research or analysis of clinical response to therapy and to improve 
current and future treatment outcomes. The storage facility will maintain the masking of the 
identity of the subject. 
During the conduct of the study, any individual subject can choose to withdraw consent to have 
biological specimens stored for future research. When the study is completed, access to study 
data and/or samples will be provided through RADIUS. 
9.7. 
Data Quality Assurance 
RADIUS or its designated representative will conduct a study site visit to verify the 
qualifications of each Investigator, inspect clinical study site facilities as needed, and inform the 
Investigator of responsibilities and procedures for ensuring adequate and correct study 
documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study subject. 
Study data for each enrolled subject will be entered into an eCRF by site personnel using a 
secure, validated web-based electronic data capture (EDC) application. RADIUS will have read-
only access to all data upon entry in the EDC application. 


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Instances of missing, discrepant, or uninterpretable data will be queried with the Investigator for 
resolution. Any changes to study data will be made to the eCRF and documented in an audit trail, 
which will be maintained within the clinical database. 
To ensure compliance with GCP and all applicable regulatory requirements, a quality assurance 
audit may be conducted. Regulatory agencies may also conduct a regulatory inspection of this 
study. Such audits/inspections can occur at any time during or after completion of the study. If an 
audit or inspection occurs, the Investigator and institution agree to allow the auditor/inspector 
direct access to all relevant documents and to allocate his/her time and the time of his/her staff to 
the auditor/inspector to discuss findings and any relevant issues. In the case of an audit or 
inspection, the Investigator or a delegate will alert RADIUS, as soon as he/she becomes aware of 
the audit or inspection. 
The Investigator and study staff are responsible for maintaining a comprehensive and accurate 
filing system of all study-related documentation that will be suitable for inspection at any time 
by RADIUS, its designees, and/or regulatory agencies. In signing this protocol, the Investigator 
understands and agrees to give access to the necessary documentation and files. 
9.8. 
Monitoring 
RADIUS is responsible for ensuring the proper conduct of the study with regard to protocol 
adherence and validity of data recorded in the clinical database. The study will be monitored by 
RADIUS or its designee. Monitoring will be done by personal visits from a representative of 
RADIUS, or designee (site monitor), who will review the eCRFs, SAE Forms and source 
documents. The site monitor will ensure that the investigation is conducted according to the 
protocol design and regulatory requirements. 
9.9. 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical study staff at the site under the supervision of 
the Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
RADIUS will provide the study sites with secure access to and training on the EDC application 
sufficient to permit site personnel to enter and correct information in the eCRFs on the subjects 
for which they are responsible for.  
An eCRF will be completed for each subject who receives at least one dose of study drug. It is 
the Investigator's responsibility to ensure the accuracy, completeness, clarity, and timeliness of 
the data reported in the subject’s eCRF. Source documentation supporting the eCRF data should 
indicate the subject’s participation in the study and should document the dates and details of 
study procedures, AEs, other observations, and subject status. 
The Investigator, or designated representative, should complete the eCRF in a timely manner 
after information is collected. 
The audit trail entry will show the user's identification information and the date and time of any 
correction. The Investigator must provide formal approval of all the information in the eCRFs, 
including any changes made to the eCRFs, to endorse the final submitted data for the subjects for 
whom the Investigator is responsible. 


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RADIUS will retain the eCRF data, queries, and corresponding audit trail. A copy of the final 
archival eCRF in the form of a compact disc or other electronic media will be provided to the site 
for placement in the Investigator's study file. 
9.10. 
Study Records Retention 
The Investigator will maintain study documents for a minimum of 2 years after the last approval 
of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period, however, if required by local regulations. If the Investigator 
withdraws from the responsibility of keeping the study records, custody must be transferred to a 
person willing to accept the responsibility and RADIUS must be notified. No records will be 
destroyed without the written consent of RADIUS. 
9.11. 
Publication and Data Sharing Policy 
Publication of complete data from the study is planned. It is anticipated that the results of this 
study will be presented at scientific meetings and/or published in a peer reviewed scientific or 
medical journal. A Publications Committee composed of Investigators participating in the study 
and representatives from RADIUS as appropriate will be formed to oversee the publication of the 
study results, which will reflect the experience of all participating study sites. 
Subsequently, individual Investigators may publish results from the study in compliance with 
their agreement with RADIUS. 
 


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10. 
LITERATURE REFERENCES 
Bilezikian JP. Anabolic therapy for osteoporosis. Women’s Health (Lond). 2007;3:243-253. 
Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. Anabolic actions of parathyroid 
hormone on bone. Endocr Rev. 1993;14:690–709. 
Ebeling PR. Osteoporosis in men. New Engl J Med. 2008;358:1474-1482. 
Food and Drug Administration (FDA). FDA Guidance on Conduct of Clinical Trials of Medical 
Products During the COVID-19 Public Health Emergency. 2021; accessed via 
https://www.fda.gov/media/136238/download 
Genant HK, Wu CY, van Kuijk KC, Nevitt MC. Vertebral fracture assessment using a 
semiquantitative technique. J Bone Miner Res. 1993;8:1137-1148. 
Hattersley G, Dean T, Corbin BA., Bahar H, Gardella TJ. Binding selectivity of abaloparatide for 
PTH-type-1-receptor conformations and effects on downstream signaling. Endocrinology. 
2016;157:141-49. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) Guideline for Industry - Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting (ICH E2A). 1995 
International Organization of Standardizations. (2018). Clinical investigation of medical devices 
for human subjects — Good clinical practice, ISO/DIS 14155. 
https://www.iso.org/obp/ui/#iso:std:iso:14155:dis:ed-3:v1:en. Accessed 11-Nov-2019 
International Osteoporosis Foundation. Osteoporosis in men. 2014; accessed via 
http://www.iofbonehealth.org/WOD/2014/thematic-report/WOD14-Report.pdf 
Khosla S, Amin S, Orwoll E. Osteoporosis in men. Endocrine Rev. 2008;29:441-464. 
Litwic A, Lekarz, Warwick D, Denniston E. Distal radius fracture: Cinderella of the osteoporotic 
fractures. Orthop Muscul Syst. 2014; 3:162-8. 
Makino M, Takagi H, Sugiyama H, Kobayashi T, Kasahara Y. Effects of abaloparatide on the 
expression of bone resorption and formation-related factors in osteoblastic cells; a comparison 
with teriparatide. Annual Meeting of the American Society for Bone and Mineral Research 2015; 
MO0121. 
Mannstadt M, Juppner H, Gardella TJ. Receptors for PTH and PTHrP: Their biological 
importance and functional properties. Am J Physiol. 1999; 277:F665-F675 
Miller PD, Hattersley G, Riis BJ, Williams GC, Lau E, Russo LA, Alexandersen P, Zerbini CA, 
Hu M, Harris AG, Fitzpatrick LA, Cosman F, Christiansen C. Effect of abaloparatide vs placebo 
on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical 
trial. J Am Med Assoc. 2016;316:722-733. 
Newcombe RG. Interval estimation for the difference between independent proportions: 
Comparison of eleven methods. Stat Med. 1998; 17:873-890. 
Rizzoli R. Osteoporosis, genetics and hormones. J Mol Endocrinol. 2001;26:79-94. 
Rosen CJ. Clinical practice. Postmenopausal osteoporosis. N Engl J Med. 2005;353:595-603. 


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WHO. Assessment of osteoporosis at the primary health care level. Summary of a WHO 
Scientific Group 2007 [16 Feb 2017]. Available from: 
www.who.int/chp/topics/rhuematicrheumatic/en/index.html 


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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A Randomized, Double-blind, Placebo-controlled, Phase 3 Multicenter Study 
to Evaluate the Safety and Efficacy of Abaloparatide-SC for the 
Treatment of Men with Osteoporosis 
Protocol BA058-05-019 
Protocol Version and Date: 
Amendment 6 (30 March 2021) 
Name of Test Drug: 
Abaloparatide-SC 
Phase: 
Phase III 
Methodology: 
International, Multicenter, Randomized, 
Double-Blind, Placebo-Controlled 
Sponsor: 
Radius Health, Inc. 
22 Boston Wharf Road, 7th floor 
Boston, MA 02210  
Tel: 617-551-4000 
Fax: 617-551-4701 
Analysis Plan Date:     
  25 August 2021 
Analysis Plan Version: 
Final 1.0 
CONFIDENTIALITY STATEMENT 
This information contained herein is confidential and the proprietary property of Radius Health, 
Inc. and any unauthorized use or disclosure of such information without the prior written 
authorization of Radius Health, Inc. is expressly prohibited. 
NCT #NCT03512262


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Protocol Title: 
A Randomized, Double-blind, Placebo-controlled, Phase 3 
Multicenter Study to Evaluate the Safety and Efficacy of 
Abaloparatide-SC for the Treatment of Men with Osteoporosis 
Protocol Number: 
BA058-05-019, Amendment 6 (30 March 2021) 
Study Drug: 
Abaloparatide-SC or Placebo 
Version (Document Date): 
Final 1.0 (25 August 2021) 
Prepared By: 
 
 
 
 
 
 
                                                                                          Date       
 
Radius Health, Inc. 
 
 
 
 
REVIEWED AND APPROVED BY: 
 
 
 
 
 
 
Radius Health, Inc.  
                                           Date 
 
 
 
 
 
 
 
 
 
Radius Health, Inc. 
                                           Date 
 
 
 
 
 
 
 
 
 
Radius Health, Inc. 
                                           Date 
 
 
  


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ....................................................................................................................... 5 
1 
INFORMATION FROM THE STUDY PROTOCOL ......................................................................... 7 
1.1 
Introduction and Objectives .......................................................................................................... 7 
1.1.1 
Introduction ........................................................................................................................... 7 
1.1.2 
Study Objectives ................................................................................................................... 7 
1.2 
Study Design ................................................................................................................................. 7 
1.2.1 
Synopsis of Study Design ..................................................................................................... 7 
1.2.2 
Randomization Methodology ................................................................................................ 8 
1.2.3 
Blinding ................................................................................................................................. 8 
1.2.4 
Study Procedures................................................................................................................... 9 
1.2.5 
Efficacy and Safety Parameters .......................................................................................... 14 
2 
ANALYSIS POPULATIONS............................................................................................................. 16 
2.1 
Population Definitions ................................................................................................................ 16 
2.2 
Protocol Deviation ...................................................................................................................... 16 
3 
GENERAL STATISTICAL METHODS ........................................................................................... 16 
3.1 
Sample Size Planned and Specified in the Protocol .................................................................... 17 
3.2 
General Methods ......................................................................................................................... 17 
3.3 
Computing Environment ............................................................................................................. 18 
3.4 
Baseline Definitions .................................................................................................................... 18 
3.5 
Data Pooling ................................................................................................................................ 18 
3.6 
Adjustments for Covariates ......................................................................................................... 18 
3.7 
Fixed-Sequence Tests of the Primary and Key Secondary Efficacy Endpoints for Multiple 
Comparisons ........................................................................................................................................... 18 
3.8 
Subgroups ................................................................................................................................... 18 
3.9 
Anti-Abaloparatide Antibody Status ........................................................................................... 19 
3.10 
Withdrawals, Dropouts, Loss to Follow-up ................................................................................ 19 
3.11 
Missing, Unused, and Spurious Data .......................................................................................... 20 
3.12 
Visit Windows ............................................................................................................................ 20 
3.13 
Interim Efficacy Analyses ........................................................................................................... 21 
4 
STUDY ANALYSES ......................................................................................................................... 22 
4.1 
Subject Disposition ..................................................................................................................... 22 
4.2 
Demographics and Baseline Characteristics ............................................................................... 23 
4.3 
Efficacy Analyses ....................................................................................................................... 24 


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4.3.1 
Primary Efficacy Endpoint .................................................................................................. 24 
4.3.2 
Secondary Efficacy Endpoints .......................................................................................... 277 
4.4 
Population PK Analyses.............................................................................................................. 31 
4.5 
Safety Analyses ........................................................................................................................... 31 
4.5.1 
Study Drug Exposure .......................................................................................................... 31 
4.5.2 
Nutritional Supplements Exposure ..................................................................................... 33 
4.5.3 
Adverse Events ................................................................................................................... 33 
4.5.4 
Anti-Abaloparatide Antibody ............................................................................................. 36 
4.5.5 
Local Tolerance................................................................................................................... 37 
4.5.6 
Laboratory Data .................................................................................................................. 38 
4.5.7 
Vital Signs and Physical Examination ................................................................................ 41 
4.5.8 
Electrocardiogram ............................................................................................................... 42 
4.5.9 
Concomitant Medications ................................................................................................... 44 
5 
CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES .................................................... 45 
 
APPENDIX A. Algorithm to Identify Significant Protocol Deviations that Exclude Subjects from the Per-
Protocol Population. .................................................................................................................................... 46 
APPENDIX B. Criteria for Potentially Clinically Significant Laboratory Values ..................................... 47 
APPENDIX C. Criteria for Potentially Clinically Significant Vital Signs Values ..................................... 48 
APPENDIX D. Conventions for Imputing Missing Dates .......................................................................... 49 
  
 
Tables Included in the Text 
Table 1: 
Schedule of Assessments and Procedures .................................................................. 10 
Table 2: 
Schedule for Pharmacokinetic Sample Collections .................................................... 13 
Table 3: 
Allowable Time Period for Collection of DXA and QCT Assessments .................... 20 
Table 4: 
Analysis Visit Windows for BMD, vBMD, s-PINP and s-CTX ................................ 20 
Table 5: 
Visit Windows for DXA Assessments for Sensitivity Analysis................................. 27 
 
Figures Included in the Text 
Figure 1: Study BA058-05-019 Study Design ................................................................................ 8 


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LIST OF ABBREVIATIONS 
Abbreviation  
Term 
°C 
 
Degree Celsius  
°F 
 
Degree Fahrenheit 
µg 
 
Microgram 
µmol 
 
Micromole 
ADA 
 
Anti-Drug Antibody 
AE 
 
Adverse event 
ALT 
 
Alanine aminotransferase  
AST 
 
Aspartate aminotransferase  
BMD  
 
Bone mineral density 
BMI 
 
Body mass index  
bpm 
 
Beats per minute 
cm 
 
Centimeter 
CSR 
 
Clinical study report 
s-CTX 
 
Serum carboxy-terminal cross-linking telopeptide of type I collagen 
DXA 
 
Dual energy X-ray absorptiometry  
ECG 
 
Electrocardiogram 
eCRF 
 
Electronic case report form 
FDA 
 
Food and Drug Administration 
g 
 
Gram 
HLT 
 
High level term 
ITT 
 
Intent-to-treat 
IRT 
 
Interactive response technology 
IU 
 
International unit 
IV 
 
Intravenous 
kg 
 
Kilogram 
L 
 
Liter 
LDH 
 
Lactate dehydrogenase  
LOCF 
 
Last observation carried forward 
MedDRA 
 
Medical dictionary for regulatory activities 
µL 
 
Microliter 
mg 
 
Milligram 
mL 
 
Milliliter 
mmHg 
 
Millimeter of mercury 
msec 
 
Millisecond 
NAb 
 
Neutralizing antibody 
ng 
 
Nanogram 
PD 
 
Protocol deviation 
pg 
 
Picogram 


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Abbreviation  
Term 
PI 
 
Principal Investigator 
s-PINP 
 
Serum procollagen type I N propeptide 
PK 
 
Pharmacokinetic 
PT 
 
Preferred term  
PTH  
 
Parathyroid hormone 
PTHrP  
 
Parathyroid hormone related peptide 
PTT 
 
Partial thromboplastin time  
QT  
 
Total depolarization and repolarization time 
QTc  
 
Total depolarization and repolarization time corrected with heart rate 
SAE 
 
Serious adverse event 
SAP 
 
Statistical Analysis Plan 
SC 
 
Subcutaneous 
SD 
 
Standard deviation 
SHBG 
 
Sex-hormone binding globulin 
SMQ 
 
Standardized MedDRA Query 
SOC 
 
System organ class 
TEAEs 
 
Treatment emergent adverse events 
TSH 
 
Thyroid stimulating hormone 
ULN 
 
Upper limit of normal 
WBC  
 
White blood cells 
WHO 
 
World Health Organization 


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1 
INFORMATION FROM THE STUDY PROTOCOL 
1.1 
Introduction and Objectives 
1.1.1 Introduction 
Abaloparatide (marketed as TYMLOS® in the United States) is a novel, synthetic, 34 amino acid 
peptide designed to be a potent and selective activator of the PTH/PTH-related protein (PTHrP) 
type 1 receptor (PTHR1) signaling pathway with 41% homology to PTH[1–34] and 76% 
homology to human PTHrP[1–34]. It was developed with the expectation that it would be 
effective at increasing bone mineral density (BMD) and reducing fracture risk in individuals with 
osteoporosis, but with a limited effect on bone resorption and a reduced risk of hypercalcemia.  
Abaloparatide has been approved in the United States for the treatment of women with 
postmenopausal osteoporosis at high risk for fracture defined as a history of osteoporotic 
fracture, multiple risk factors for fracture, or subjects who have failed or are intolerant to other 
available osteoporosis therapy. While other agents from both anabolic and antiresorptive classes 
of anti-osteoporosis therapies have been approved for the treatment of osteoporosis in men, the 
safety and efficacy of abaloparatide has yet to be demonstrated in osteoporotic men. However, 
given the existence of an enhanced therapeutic response to abaloparatide-SC in postmenopausal 
women at high risk of fracture, as well as the substantive morbidity and mortality burden 
associated with osteoporotic fractures, confirmation of a similarly robust effect of abaloparatide-
SC in men is a clinical priority. The present study seeks to determine if abaloparatide-SC is 
effective in increasing bone mass in men with osteoporosis. 
1.1.2 Study Objectives 
The primary objective of this prospective controlled study is to evaluate the efficacy and the 
safety of abaloparatide-SC 80 µg per day compared to placebo in men with osteoporosis. 
1.2 
Study Design 
1.2.1 Synopsis of Study Design 
This is a randomized, double-blind, placebo-controlled, Phase 3, multicenter study enrolling 
approximately 225 subjects at up to 40 study centers designed to evaluate the efficacy and safety 
of abaloparatide-SC 80 µg per day for the treatment of osteoporosis in men at high risk for 
fracture. The study will consist of a Screening Period (up to 2 months), a Pretreatment Period (1 
week), a Treatment Period (12 months), and a final study visit one month after the last dose of 
study medication (Follow-up visit). Eligible subjects will be randomized, on a 2:1 basis, to 
receive either abaloparatide-SC 80 µg per day or placebo injections for 12 months to determine 
the effect of abaloparatide on lumbar spine BMD and other bone health-related endpoints. All 
subjects will receive calcium 500-1000 mg/day and vitamin D 400-800 IU/day, or a dose 
determined by the Investigator and agreed by the Sponsor Medical Monitor, according to the 
subject’s need. Both treatment groups of subjects will undergo protocol-specified procedures 
(Schedule of Events, Table 1), including BMD and fracture assessment. The study design is 
presented in Figure 1. 


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Figure 1: Study BA058-05-019 Study Design 
1.2.2 Randomization Methodology 
It is planned to enroll approximately 225 subjects at up to 40 study sites in 3 to 5 countries to 
receive either abaloparatide-SC 80 µg or placebo in a 2:1 ratio on Day 1 using permuted block 
randomization. 
Study medication kits will be shipped to each study site. Once a subject has been deemed eligible 
to be randomized into the study on Day 1 (Visit 3), the study site will use the Interactive 
Response Technology (IRT) system to assign a medication kit to the subject. Throughout the 
study, medication kits will be assigned to the subject based on information provided by the IRT. 
1.2.3 Blinding 
Abaloparatide-SC 80 µg and placebo study medications will be prepared in a blinded fashion and 
will be supplied to the study sites in identical packaging. Information regarding treatment 
assignment will reside solely within the IRT, as part of the study blinding. 
The central imaging laboratory responsible for measuring BMD will be blinded to treatment 
assignment throughout the study. Radius will not receive post-baseline BMD measurements until 
database lock. 
The Pharmacokinetic (PK) samples and the blood samples for serum markers of bone 
metabolism (s-PINP and s-CTX) will be analyzed during study. The results of the PK and bone 
turnover markers data will only be provided to Radius after database lock. 
In order to follow subjects who are antibody positive at their completion visit (Visit 9, or Visit 8 
for early terminations), the appropriate procedures for maintaining the integrity of the study blind 
are documented in the Blind Management Plan for Immunogenicity Testing and the 
Immunogenicity Testing Operations Manual. 


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In the event of a medical emergency where the identity of study medication is necessary to 
appropriately treat the subject, the Investigator may unblind the subject’s treatment through the 
IRT. Unblinding at the end of the study will occur after the data cleaning has occurred, the SAP 
has been finalized, and the database is locked. 
1.2.4 Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1 and 
Table 2.


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Table 1: 
Schedule of Assessments and Procedures 
 
Visit 
1 
2 
3 
4 
5 
 
6 
7 
8 
9 
Procedure 
Study 
Day/Month: 
Screening Pretreatment 
Day 1 
Month 1 
Month 
3 
Month 
6 
Month 9 
Month 
12/Early 
Termination 
Month 13 
Follow-up 
Visit Window (Days) 
N/A 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 7 
Informed consent 
X 
 
 
 
 
 
 
 
 
Verification of entry criteria 
X 
X 
 
 
 
 
 
 
 
Physical examination1 
X 
 
 
 
 
 
 
 
 
Review of medical history2 
X 
 
 
 
 
 
 
 
 
Symptom directed physical 
examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight measurement 
X 
 
X 
X 
 
X 
 
X 
 
Height measurement4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram5 
X 
 
X 
 
 
 
 
X 
X 
Urinalysis (dipstick)6 
X 
 
 
X 
 
X 
 
X 
 
Chemistry blood collection 
X 
 
 
X 
 
X 
 
X 
 
Hematology blood collection 
X 
 
 
X 
 
X 
 
X 
 
Coagulation (Prothrombin Time 
and PTT) blood collection 
X 
 
 
 
 
 
 
X 
 
PTH (1–84) 
X 
 
 
 
 
 
 
X 
 
25-hydroxyvitamin D level 
X 
 
 
 
 
 
 
X 
 
1,25-dihydroxy vitamin D level 
X 
 
 
 
 
 
 
X 
 
Total testosterone and SHBG 
X 
 
 
 
 
 
 
X 
 
Estradiol 
X 
 
 
 
 
 
 
 
 
Thyroid stimulating hormone7 
X 
 
 
 
 
 
 
 
 
PK samples (see Table 2) 
 
 
 
 
 
X 
X 
X 
 
Study medication assignment via 
IRT 
 
 
X 
 
 
 
 
 
 


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Table 1: 
Schedule of Assessments and Procedures (Continued) 
 
Visit 
1 
2 
3 
4 
5 
 
6 
7 
8 
9 
Procedure 
Study 
Day/Month: 
Screening Pretreatment 
Day 1 
Month 1 
Month 
3 
Month 
6 
Month 9 
Month 
12/Early 
Termination 
Month 13 
Follow-up 
Visit Window (Days) 
N/A 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 7 
Injection training for subjects 
 
X 
 
 
 
 
 
 
 
Calcium and vitamin D 
supplements 
 
Daily Administration 
 
Study medication administration 
 
 
Daily administration 
 
Serum markers of bone 
metabolism (s-PINP and s-CTX) 
 
 
X 
X 
X 
X 
 
X 
 
Serum calcium and albumin8 
 
 
X 
X 
X 
X 
X 
 
 
24-hour urine collection (for 
calcium:creatinine and creatinine 
clearance)9 
 
 
X 
 
X 
 
 
 
 
Radiologic (lumbar and thoracic 
vertebrae) assessments 
X 
 
 
 
 
 
 
 
 
Symptom driven spinal radiologic 
assessment 
 
At any time 
Clinical assessment of new 
fractures10 
 
X 
X 
X 
X 
X 
X 
X 
 
BMD of lumbar spine, total hip 
and femoral neck by DXA11 
X 
 
 
 
X 
X 
 
X 
 
BMD of wrist by DXA12 
 
 
X 
 
X 
X 
 
X 
 
vBMD of hip by QCT13 
 
 
X 
 
 
 
 
X 
 
Sample for immunogenicity 
testing14 
 
 
X 
X 
X 
X 
X 
X 
X 
Investigator assessment of local 
tolerance (dermal reactions 
assessment) 
 
 
X 
X 
X 
X 
X 
 
 


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Visit 
1 
2 
3 
4 
5 
 
6 
7 
8 
9 
Procedure 
Study 
Day/Month: 
Screening Pretreatment 
Day 1 
Month 1 
Month 
3 
Month 
6 
Month 9 
Month 
12/Early 
Termination 
Month 13 
Follow-up 
Visit Window (Days) 
N/A 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 4 
± 7 
Subject assessment of local 
tolerance15 
 
 
X 
 
 
 
X 
 
 
Subject diary review16 
 
 
X 
X 
X 
X 
X 
X 
 
Document AEs and concomitant17 
medications  
At any time, question subjects at every visit 
Drug 
supply/resupply/accountability 
 
 
X 
X 
X 
X 
X 
X 
 
1.A complete physical examination includes a review of the following systems: head/neck/thyroid, eyes/ears/nose/throat, respiratory, cardiovascular, lymph nodes, 
abdomen, skin, musculoskeletal, and neurological. Breast, anorectal, and genital examinations will be performed when medically indicated. After screening, any 
clinically significant abnormal findings in physical examinations should be reported as AEs. 
2. Including alcohol and tobacco use assessment. 
3. Blood pressure, heart rate, body temperature, and respiration rate are to be recorded pre-dose at each study visit. Only blood pressure, heart rate and respiration rate 
are to be recorded one-hour post-dose at each study visit during the Treatment Period. All blood pressure assessments need to be orthostatic. 
4. Height is to be measured at each visit in the standing position using a medical stadiometer. 
5. ECGs are to be performed pre-dose and one-hour post-dose during the Treatment Period. 
6  All routine urinalysis will be performed on a sample freshly voided during the visit and sent to a central lab for microscopy if test is positive for micro-organisms via 
dipstick. 
7. Reflex testing of T3 and free T4 will be performed by the central laboratory for any out-of-range TSH result. 
8. Serum calcium and albumin will be measured pre-dose from the standard chemistry panel on Month 1 and Month 6, and from a separate blood draw at Day 1, Month 
3 and Month 9 and four hours post-dose at Day 1, Month 1, Month 3, Month 6 and Month 9. 
9. A 24-hour urine collection will be collected at Day 1 and Month 3, and will be used for urinary calcium and urinary creatinine measurements. Subjects will discard 
the first void and begin a 24-hour urine collection on the day prior to the clinic visit. 
10. If the subject reports that a fracture has occurred, remind the subject to bring X-rays and any medical reports of the fracture to the next clinic visit. Documentation 
must be obtained on all new fractures that occur during the study. This documentation should be maintained in the source documents. 
11. Each DXA for a given subject should be performed on the same machine, and if available, preferably by the same technician. For screening purposes, DXA scans of 
the lumbar spine, total hip, and femoral neck taken up to 35 days prior to the beginning of the Screening Period may be used to determine study eligibility. 
12. The first wrist DXA will be performed prior to study drug administration on Day 1 and should be performed on the same machine, and if available, preferably by the 
same technician. 
13. QCT performed in a subset of subjects at selected centers. 
14. Samples will be drawn prior to treatment on Day 1, Months 1, 3, 6, 9,12 and the Follow-up Visit scheduled at 1 month after the last dose of study medication. 


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15. The subject will maintain a diary of their assessment of local tolerance beginning on Day 2 and continuing through Day 7 in Month 1, and beginning on Day 2 and 
continuing through Day 7 in Month 9. 
16. The subject medication diary will be reviewed by study personnel at each study visit to ensure subject compliance. 
17. AEs and SAEs will be recorded on the case report forms starting from the time of subject entry into the Screening Period (Visit 1) of the study (signed informed 
consent) until 30 days after the last dose of study medication.  All AEs will be followed until resolution or stabilization. Any SAEs that occur at any time after 
completion of the study, which are considered by the Investigator to be related to study treatment, must be reported to the Sponsor or its designee. 
 
AE = adverse event; BMD = bone mineral density; DXA = dual energy X-ray absorptiometry; IRT = Interactive response technology; PTH = Parathyroid hormone; PTT 
= Partial thromboplastin time; QCT = quantitative CT; s-CTX = serum carboxyl-terminal cross-linking telopeptide of type I collagen; s-PINP = serum procollagen type I 
N-terminal propeptide; SAE = serious adverse event; SHBG = Sex hormone binding globulin; vBMD = volumetric bone mineral density 
 
Table 2: 
Schedule for Pharmacokinetic Sample Collections 
 
Study Visit 
Predose 
Postdose 
Within 10 
minutes before 
injection 
20 min ±  
10 min 
45 min ±  
15 min 
1.5 hours 
± 0.5 hours 
2.5 hours 
± 0.5 hours 
4 hours 
± 0.5 hours 
Month 6 
 
 
X 
 
X 
 
Month 9 
 
X 
 
 
 
X 
Month 12 
X 
 
 
X 
 
 
Note: This schedule only applies to those subjects who consent to have PK samples collected during the study. 
min = minute; PK = pharmacokinetics 
 
 


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1.2.5 Efficacy and Safety Parameters 
Efficacy Parameters 
The primary efficacy endpoint is: 
• Percent change from baseline in lumbar spine bone mineral density (BMD) at 12 months. 
The key secondary efficacy endpoints are: 
• Percent change from baseline in total hip BMD at 12 months 
• Percent change from baseline in femoral neck BMD at 12 months 
Additional secondary efficacy endpoints are: 
• Percent change from baseline in: 
‒ Lumbar spine BMD at 3 and 6 months 
‒ Total hip BMD at 3 and 6 months 
‒ Femoral neck BMD at 3 and 6 months 
‒ Ultra-distal radius BMD at 3, 6 and 12 months 
‒ Distal one-third radius BMD at 3, 6 and 12 months 
• Log ratio of post-baseline over baseline in: 
‒ Serum procollagen type I N-terminal propeptide (s-PINP) at 1, 3, 6 and 12 months 
‒ Serum carboxy terminal cross linking telopeptide of type I collagen (s-CTX) at 1, 3, 6 
and 12 months. 
• Proportion of subjects experiencing BMD gains from baseline of >0%, >3%, and >6% at the 
lumbar spine, femoral neck, and total hip at 3, 6, and 12 months 
• Incidence of new clinical fractures at 12 months 
• Proportion of subjects converting from the categories of Osteoporosis to Osteopenia and 
Normal at end of treatment, where: 
‒ Osteoporosis is defined as lumbar spine or total hip BMD T-score ≤ -2.5,  
‒ Osteopenia is defined as: 
o lumbar spine > - 2.5 and total hip BMD T-score > -2.5 and < -1.0, or  
o lumbar spine > - 2.5 and < - 1.0 and total hip BMD T-score > -2.5,  
‒ Normal is defined as lumbar spine and total hip BMD T-score ≥ -1.0.  
• The percent change in total hip and femoral neck volumetric BMD as measured by 
quantitative CT (QCT) from baseline to 12 months. QCT will be performed in a subset of 
subjects at a selected number of study sites. 
For those subjects who consent to PK sample collection, the PK endpoints are: 
• The plasma concentration of abaloparatide based on sparse PK sampling at the following 
visits: 
‒ Month 6: post-dose PK samples collected 45 minutes (±15 minutes) and 2.5 hours (±0.5 
hour) after abaloparatide-SC injection 
‒ Month 9: post-dose PK samples collected 20 minutes (±10 minutes) and 4 hours (±0.5 
hour) after abaloparatide-SC injection 


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‒ Month 12: a pre-dose sample and a post-dose sample collected 1.5 hours (±0.5 hour) after 
abaloparatide-SC injection 
Safety Parameters 
Safety evaluations will be based on adverse events (AEs), vital signs, electrocardiograms 
(ECGs), laboratory evaluations (serum chemistry, hematology, urinalyses, and coagulation), 
investigator assessment of local tolerance, subject assessment of local tolerance, and anti-drug 
antibody assessments. 
In addition, the presence of hypercalcemia will be assessed. Hypercalcemia is defined as a serum 
calcium (albumin-corrected) value ≥ 0.3 mg/dL (or ≥ 0.08 mmol/L) above the upper limit of 
normal. The difference in the percentage of subjects with one or more incidents of hypercalcemia 
over the 12-month treatment period will be assessed. 
The presence of hypercalciuria will also be assessed. Subjects with a urine calcium/creatinine 
ratio > 0.4 mg/mg (or > 1.131 mmol/mmol) and a urine calcium/creatinine ratio > 0.3 mg/mg (or 
> 0.848 mmol/mmol) will be tabulated by treatment group. 
 
 


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2 
ANALYSIS POPULATIONS 
2.1 
Population Definitions 
Four subject populations will be considered in the statistical analyses of this study. 
Intention-to-treat (ITT) population 
The Intention-to-Treat (ITT) population is defined as all subjects randomized into this study.   
Safety population 
The Safety population is defined as all subjects who received at least one dose of study 
medication.  
Antibody Population  
The antibody population will include those abaloparatide-SC treated subjects in the Safety 
population who have at least one post-baseline anti-abaloparatide antibody assessment. 
Per-Protocol (PP) population 
The Per-Protocol (PP) population will include all ITT subjects who did not have any significant 
protocol deviations (PDs) (described in Section 2.2).  
The PP population will be a supportive population for the efficacy analyses. 
2.2 
Protocol Deviation  
A protocol deviation (PD) is any change, divergence, or departure from the study design or 
procedures defined in the protocol. The PD categories related to study conduct are described in 
the Management of Protocol Deviations/Waivers section of the Medical Management Plan. PDs 
are recorded by the contract research organization (ICON) in their Clinical Trial Management 
System (CTMS). Subjects with at least one protocol deviation will be presented in a data listing, 
with indicators for key and non-key PDs (as defined in Appendix 1 of the Medical Management 
Plan, where a key PD is a deviation requiring reporting to the Functional Lead, Medical Monitor 
and or Sponsor). A summary table of the key PDs identified during the study will be presented. 
Significant PDs are PDs that have the potential to impact the efficacy of the treatment on the 
subject. 
The algorithm to determine significant PDs is in Appendix A of this SAP. Subjects with at least 
one significant PD will be excluded from the PP population. A Per-Protocol Memo with the 
algorithm in Appendix A together with the programming specification (“Per Protocol Population 
Data Set Development”) will be developed and finalized prior to database lock to detail how 
each of the criteria in the algorithm can be programmed in SAS. The list of subjects with 
significant protocol deviations identified after applying the algorithm to the unblinded SDTM 
data after database lock will be reviewed and approved internally at Radius in a separate memo. 
A summary table of reasons for exclusion from the PP population will be presented. A data 
listing for subjects excluded from the PP population together with the exclusion reason(s) will be 
presented.  
  
 


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3 
GENERAL STATISTICAL METHODS 
3.1 
Sample Size Planned and Specified in the Protocol 
A study sample size of 225 subjects (150 in the abaloparatide-SC group and 75 in the placebo 
group) will provide at least 99% power to detect a mean difference of 6.5% in the percentage 
change from baseline in lumbar spine BMD at 12 months between the abaloparatide-SC and the 
placebo groups at a two-sided alpha level of 0.01, assuming a standard deviation (SD) of 6.0% 
and a drop-out rate of 10%. For the key secondary endpoints, a total sample size of 225 subjects 
will have 96% power to detect a 2.2% mean difference (SD=3.5%) of percent change in total hip 
BMD at 12 months, and 80% power to detect a 2.0% mean difference (SD=4.1%) of percent 
change in femoral neck BMD at 12 months. 
3.2 
General Methods 
Summary tables will be presented by treatment group (abaloparatide-SC and placebo) and 
overall, when appropriate. For categorical data, summary tabulations of the number and 
percentage of subjects within each category of the parameter will be presented. When tabulating 
categorical data, “missing” will be included as a category and the number of subjects with 
missing data will be presented. For continuous data, the number of subjects, mean, median, 
standard deviation (SD), minimum, interquartile range (Q1 and Q3), and maximum will be 
presented.  
All data listings that contain an evaluation date will contain a relative study day. Screening, pre-
treatment, and on-treatment study days will be numbered relative to the day of the first dose of 
study medication which is designated as Day 1. Study days prior to the first dose of study drug 
will be calculated as: [date of assessment – date of first dose of study drug]. Study days on or 
after the first dose of study drug will be calculated as: [date of assessment – date of first dose of 
study drug + 1]. 
Where applicable, confidence intervals about a parameter estimate will be presented using the 
same number of decimal places as the parameter estimate and p-values will be rounded to 4 
decimal places prior to assessment of statistical significance. 
If the date of last dose is missing, then the earlier of the following 2 dates will be used as the last 
dose date for analysis and summary purposes: the final visit/early termination visit date or the 
last study drug dispense date + 30 days. 
For subjects in the abaloparatide-SC group, the serum samples for immunogenicity testing will 
be analyzed and reported separately. All the planned efficacy and safety analyses related to 
immunogenicity results and antibody status described in this SAP will be reported separately.  
This study is being conducted during the COVID-19 pandemic. The COVID-19 outbreak 
emerged in December 2019 quickly became a global pandemic as declared by the World Health 
Organization in early March 2020. At that time, a variety of mitigations to assure safety of 
participants and address operational issues were implemented by Radius. To investigate the 
effect of the COVID-19 pandemic on study conduct, additional analyses comparing the subjects 
who completed or withdrew from the study before the onset of the COVID-19 pandemic, i.e, 
before 01 March 2020, with the subjects who were ongoing or randomized during the COVID-19 
pandemic, i.e, on or after 01 March 2020, will be conducted where applicable. 


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3.3 
Computing Environment 
All descriptive and statistical analyses will be performed using SAS statistical software Version 
9.4, or later version. Medical history and AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 24.0. Concomitant medications will be coded using 
the World Health Organization Drug Dictionary (WHO DRUG DDE+HD/2017-DEC-B3). 
3.4 
Baseline Definitions 
The baseline value is defined as the last non-missing value obtained prior to the first dose of 
study medication, including the screening value, if necessary. If a randomized subject is not 
treated, the baseline value is defined as the last non-missing assessment. 
3.5 
Data Pooling 
Data from all study sites and countries will be pooled together for all analyses, unless otherwise 
specified. 
3.6 
Adjustments for Covariates 
Adjustments for covariates will be employed in the Analysis of Covariance (ANCOVA) and 
Mixed-Effect Model for Repeated Measures (MMRM) analyses. Any adjustments will be pre-
specified in the description of the statistical analysis (Section 4). 
3.7 
Fixed-Sequence Tests of the Primary and Key Secondary Efficacy Endpoints for 
Multiple Comparisons 
The primary and key secondary efficacy endpoints will be analyzed using a fixed-sequence 
testing procedure to control the family-wise error rate for any joint distribution of hypothesis test 
statistics. To claim statistical significance at the 2-sided level of 1%, the following 3 fixed-
sequence tests will be performed in sequential order. At any step of the sequential testing, if the 
treatment difference is not statistically significant at the 1% level then all the subsequent 
comparisons following the fixed sequence cannot be claimed statistically significant. 
1. Percent change from baseline in BMD at the lumbar spine at 12 months 
2. Percent change from baseline in BMD at the total hip at 12 months 
3. Percent change from baseline in BMD at the femoral neck at 12 months 
P-values for treatment comparisons of all other efficacy endpoints will be generated to support 
the study findings without any adjustments for multiplicity. 
3.8 
Subgroups 
The following subgroups will be created for possible use in selected data analyses. Section 4.2 
will describe the specific analyses to be performed for each subgroup. 
‒ Age (<65, 65 - <75, ≥75)  
‒ Race (White, Black or African-American, Asian, and Other Races [i.e., American Indian 
or Alaska Native, Native Hawaiian or Other Pacific Islander, Other, and Multiple (more 
than 1 race category chosen)]) 
‒ BMI (< 25, 25 - < 30, ≥ 30) 


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‒ Region (North America including USA and Canada, Europe including Poland and Italy) 
‒ Prior clinical fracture (Yes = Subjects with a record in medical history with “fracture” in 
the preferred term, No) 
‒ Prevalent vertebral fracture (Yes = Subjects with any vertebral fracture with a score> 0, 
No) 
‒ Prior fracture (Yes =Subjects with a prevalent vertebral fracture and / or a prior clinical 
fracture, No) 
‒ Smoking status (current, former, never) 
‒ Lumbar spine BMD T-score at baseline (≤ -2.5, > -2.5) 
‒ Total hip BMD T-score at baseline (≤ -2.5, > -2.5)  
‒ Femoral neck BMD T-score at baseline (≤ -2.5, > -2.5) 
‒ s-PINP at baseline (tertile values) 
‒ Total testosterone level (<9.36 nmol/L, ≥9.36 nmol/L) 
‒ Estradiol level (≤73.4 pmol/L, >73.4 pmol/L) 
3.9 
Anti-Abaloparatide Antibody Status 
At Day 1, Month 1, Month 3, Month 6, Month 9, Month 12/EOT, and Month 13/EOS, for 
subjects in the abaloparatide-SC group, the anti-abaloparatide antibody (ADA) assessment in the 
serum samples for immunogenicity testing will be categorized by two outcomes: 
‒ Negative for the ADA (ADA-) 
‒ Positive for the ADA (ADA+) 
For those subjects with a positive ADA (i.e, ADA is present), the serum samples will be further 
assessed for the presence of neutralizing anti-abaloparatide antibodies (NAb), and the results will 
be categorized by two outcomes:   
‒ Negative for the NAb (NAb-) 
‒ Positive for the NAb (NAb+) 
Subjects’ ADA status and presence of NAb by Month 12 (ADA-, ADA+/NAb+, ADA+/NAb-, 
All ADA+) will be defined as follows: 
‒ Subjects will be classified as ADA- if they were ADA- in all post-baseline 
immunogenicity assessments during the 12 months treatment period.   
‒ Subjects will be classified as ADA+ and NAb+ if they were ADA+ at any post-baseline 
immunogenicity assessment and NAb+ at any subsequent tests during the 12 months 
treatment period. 
‒ Subjects will be classified as ADA+ and NAb- if they were ADA+ at any post-baseline 
immunogenicity assessment and NAb- at all subsequent tests during the 12 months 
treatment period.   
3.10 Withdrawals, Dropouts, Loss to Follow-up 
Subjects who are withdrawn or discontinue from the study will not be replaced. 


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3.11 Missing, Unused, and Spurious Data 
Statistical methods for addressing missing data for the analyses of the primary and secondary 
efficacy endpoints are described in Section 4.3. 
Rules for imputation of missing dates for onset of AEs and start of concomitant medications are 
included in Appendix D of this SAP. Unless otherwise specified, missing dates for onset of AEs 
and start of concomitant medications will be handled according to those imputation rules. 
In the event that incorrect data are discovered after database lock, the impact of such incorrect 
data will be assessed and a determination will be made as to whether the data need to be 
corrected in the database (and subsequently in the analysis). In cases where it is decided that the 
data need to be corrected, the decision will be documented, and the documentation will be saved 
in the Trial Master File.  
All available data will be included in data listings. 
3.12 Visit Windows 
In general, the nominal visit will be used for the safety and efficacy data summaries and 
analyses.  
During the COVID-19 pandemic, if a subject’s DXA and/or QCT assessment cannot be 
performed during the protocol specified visit windows, the site will contact the study Medical 
Monitor and the subject will be allowed to make up the visits within an allowed time period. The 
allowable time period for collection of DXA and QCT assessments are shown in Table 3, where 
the ideal visit date is defined as the date that represents the ideal number of days from the date of 
first dose of study drug to the nominal visit.  
 Table 3: 
Allowable Time Period for Collection of DXA and QCT Assessments. 
Visit 
Ideal Visit Day  
BMD or vBMD Assessment 
Month 3 
90 
Up to 30 days after ideal visit day 
Month 6 
180 
Up to 90 days after ideal visit day 
Month 12 
360 
Up to 30 days after ideal visit day 
Due to the expanded time periods for collection of efficacy assessments, analysis visit windows 
are defined below for the analyses of BMD, vBMD, and serum markers of bone metabolism 
(PINP and CTX) data to determine the assessment that will be used for a given study visit. 
Table 4: 
Analysis Visit Windows for BMD, vBMD, s-PINP and s-CTX. 
Visit / Month 
Allowable days from first dose of study drug 
BMD lumbar spine, total hip and 
femoral neck, BMD Wrist 
s-PINP, s-CTX 
vBMD 
Visit 3 / Baseline  
≤ 1 
≤ 1 
≤ 1 
Visit 4 / Month 1 
 
2—60 
 
Visit 5 / Month 3 
2—120 
61—120 
 
Visit 6 / Month 6 
121—270 
121—270 
 
Visit 7 / Month 9 
 
 
 
Visit 8 / Month 12 
≥ 271 
≥ 271 
≥2 


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It is possible that more than 1 assessment for a parameter may be obtained within the same 
analysis visit window. In such circumstances, the assessment with the date closest to the ideal 
visit day will be used. In the event that 2 assessments are equidistant to the ideal visit day, the 
later of the assessments will be used. 
The analysis visit window convention will not be applied to the data listings. The data listings 
will display all data as collected with the corresponding nominal visit. 
3.13 Interim Efficacy Analyses 
No interim analysis for efficacy is planned for this study. 
 


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4 
STUDY ANALYSES 
4.1 
Subject Disposition 
Subject disposition will be tabulated by treatment group including the number screened, the 
number randomized, the number treated, the number in each analysis population, the number 
who completed the study, the number who discontinued from the study treatment together with 
the primary reason for discontinuation, and the number who discontinued from the study together 
with the primary reason for discontinuation as recorded in the eCRF. The number of subjects 
excluded from the PP population together with the exclusion reasons will also be summarized. 
A Kaplan-Meier plot of the time from randomization to withdrawal from study will be presented 
by treatment. Subjects who complete the study will be censored at the date of their study 
completion. 
The total number of subjects randomized will be tabulated by region (North America, Europe), 
country, study site, and treatment group.    
Subject disposition data will be carefully reviewed with respect to the impact of the COVID-19 
pandemic on study conduct. Significant protocol deviations and study/treatment discontinuation 
related to the COVID-19 pandemic will be identified during the study. A summary of subject 
disposition by subject’s randomization date relative to COVID-19 pandemic onset (subjects 
randomized prior to 01 March 2020 vs subjects randomized on or after 01 March 2020) will be 
presented. A summary of subject disposition based on subject’s study status relative to COVID-
19 pandemic onset (subjects who completed or withdrew from the study before 01 March 2020 
vs subjects who completed or withdrew from the study on or after 01 March 2020) will also be 
presented. The number (%) of subjects with assessments impacted by COVID-19 pandemic as 
recorded on the COVID-19 Impact Log eCRF page will be summarized by visit and the 
following categories: 
• Altered Protocol Assessment/Procedure 
• Discontinuation 
• IP – Missed/Modified 
• Missing Data 
• Missed Visit 
• Out of Window Visit 
• Remote /Virtual Visit 
• Assessment Not Done 
• Other  
A listing of subjects with assessments impacted by COVID-19 pandemic as indicated on the 
COVID-19 Impact Log eCRF page will be provided. The listing will include subject ID, age, 
race, site, visit, CRF form used, impact category, and comment. 
A by-subject data listing of study completion information, including the primary reasons for 
premature study withdrawal as recorded in the eCRF, will be presented. A by-subject data listing 
of subject excluded from PP population and the reasons for exclusion will also be presented. 


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A summary of screening failures and listings of inclusion/exclusion criteria responses for 
screening failure subjects will also be presented. 
4.2 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized and presented by treatment group 
and overall.  Age will be calculated as of the date the subject provided signed informed consent 
for this study. Age, age group (<65, 65-<75, ≥75), height, weight, body mass index (BMI), and 
BMI group (BMI < 25, 25 ≤ BMI < 30, BMI ≥ 30) will be summarized using descriptive 
statistics (number of subjects, mean, SD, median, interquartile range, minimum and maximum). 
The number of subjects in each ethnicity and race category will also be presented. Subjects who 
report more than one race category will be counted under the race category “Multiple”. The 
usage of alcohol, tobacco, and other substances at baseline will be summarized by treatment 
group. 
The number and percentage of subjects with the following fracture history will be summarized: 
• Prior clinical fracture: Subjects with a record in medical history with “fracture” in the 
preferred term. 
• Prevalent vertebral fracture: Subjects with any vertebral fracture with a score > 0. 
• Prior fracture: Subjects with a prevalent vertebral fracture and / or a prior clinical fracture 
• Prior clinical vertebral fracture: Subjects with a record in medical history with "vertebral 
fracture" or "spinal fracture" in the preferred term  
• Prior vertebral fracture: Subjects with a prior clinical vertebral fracture or a prevalent 
vertebral fracture. 
Baseline values for BMD measurements and biomarker parameters including lumbar spine BMD 
T-score and T-score group (≤ -2.5, > -2.5), total hip BMD T-score and T-score group (≤ -2.5, > -
2.5), femoral neck BMD T-score and T-score group (≤ -2.5, > -2.5), s-PINP and s-PINP group 
(tertile values), s-CTX, total testosterone level and total testosterone level group (<9.36 nmol/L, 
≥9.36 nmol/L), and estradiol level and estradiol level group (<73.4 pmol/L, ≥73.4 pmol/L) will 
also be summarized for each treatment group and overall. 
BMD measurements via Quantitative Computed Tomography (QCT) will be collected in a subset 
of subjects at a selected number of centers. The summary of demographics and baseline 
characteristics will be repeated for this subset of subjects. 
Medical history will be presented by MedDRA system organ class (SOC), preferred term (PT), 
and treatment group, summarizing the proportion of subjects in each treatment group who have a 
condition noted. 
Results from the baseline physical examination will be summarized by body system as recorded 
in the eCRF and treatment group. 
All analyses described in this section will be performed on the ITT population, and repeated for 
the Safety and PP populations.  
All analyses described in this section will also be repeated for the Antibody population. The 
presentation of these analyses will be based on subjects’ ADA status and presence of neutralizing 


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antibody (NAb) during the study with columns for ADA-, ADA+/NAb+, ADA+/NAb-, All 
ADA+, and Overall. 
Additionally, demographics data and baseline characteristics will be tabulated by all subgroups 
listed in Section 3.8 using the ITT population. To address the effect of the COVID-19 pandemic, 
summaries of demographic data and baseline characteristics by subject’s randomization date 
relative to COVID-19 pandemic onset (subjects randomized prior to 01 March 2020 vs subjects 
randomized on or after 01 March 2020) will be presented. Summaries of demographic data and 
baseline characteristics based on subject’s study status relative to COVID-19 pandemic onset 
(subjects who completed or withdrew from the study before 01 March 2020 vs subjects who 
completed or withdrew from the study on or after 01 March 2020) will also be presented. 
Demographics including gender, race, ethnicity, age, and country for screen failure subjects will 
also be summarized descriptively. 
All subject data collected for demographics and baseline characteristics will be presented by 
treatment, study site, and subject number in data listings. 
4.3 
Efficacy Analyses 
The ITT population will be the primary population for all efficacy analyses. The PP population 
will be used for supportive analyses. In efficacy analyses, subjects will be analyzed according to 
the treatment to which they were randomized. 
The primary and BMD-related secondary efficacy endpoints will be derived from the Bioclinica-
corrected BMD measurements.  
BMD scans may be deemed unevaluable at the first reading and a repeat BMD scan may be 
performed. The re-scan BMD assessment will be recorded as an unscheduled visit for the 
corresponding nominal visit. To determine the assessment that will be used for a given study 
visit by the analysis window convention, all BMD assessments (including unscheduled BMD 
assessments) will be considered. In the efficacy analyses by nominal visit, unscheduled BMD 
assessments will be used if the BMD assessment at the nominal visit is not available but an 
unscheduled BMD assessment for the same nominal visit is available. 
Analyses of the BMD-related efficacy endpoints and the serum markers of bone metabolism (s-
PINP and s-CTX) will be conducted using the analysis visit windows defined in Table 4 of 
Section 3.12 as the primary analysis. Analyses of the BMD-related efficacy endpoints and the 
serum markers of bone metabolism (s-PINP and s-CTX) using the nominal visits will also be 
presented as supportive analyses.  
All confidence intervals, statistical tests, and p-values will be reported as nominal 2-sided. The 
primary and key secondary efficacy endpoints will be assessed at the significance level of 0.01. 
All other efficacy endpoints will be assessed at a significance level of 0.05. 
4.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change from baseline in lumbar spine BMD at 12 
months. The mean of percent changes from baseline in lumbar spine BMD to 12 months will be 
estimated for each treatment group, and the abaloparatide-SC will be compared to placebo using 


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difference in group means. The primary comparison of abaloparatide-SC with placebo will be 
based on the ITT population. 
The missing data from this study will be reviewed carefully to evaluate any missing data 
patterns. As this study is not designed to systematically collect data from subjects who 
discontinue treatment early, the “retrieved dropouts” approach for handling missing data is not 
applicable to this study. To appropriately address the possibility of data missing not at random, 
the primary analysis will be based on a pattern mixture model (PMM) analysis with multiple 
imputation using the wash-out imputation method. This method uses sequential regression and 
wash-out imputation methodology to impute missing values after a subject’s discontinuation 
from the study. The missing primary endpoint values for subjects in the abaloparatide-SC group 
will be imputed with observed baseline and data (including imputed values) from the placebo 
group; no intermediate values from the abaloparatide-SC group will be used in the imputation for 
the abaloparatide-SC group. For subjects in the placebo group, intermediate observed values 
from the completers in the placebo group will be used while imputing missing values during the 
12-month treatment period. The PROC MI methodology for imputation of monotone missing 
data patterns will be used to impute the outcome variables at consecutive visits in a sequential 
(chain) manner. Each of these imputed datasets will be analyzed using analysis of covariance 
(ANCOVA) model with treatment and DXA instrument manufacturer as fixed effects, and the 
baseline lumbar spine BMD as a covariate. Results from all imputed datasets will be combined 
using PROC MIANALYZE for overall statistical inference. The statistical test will be 2-sided 
comparing abaloparatide-SC to placebo; Both 99% and 95% confidence intervals (CIs) will be 
presented together with the estimated p-values. The detailed imputation and analysis steps are 
described below: 
1. Intermittent missing data in the placebo treatment group will be imputed using MCMC 
methods, assuming MAR. SAS PROC MI will be utilized for this step using the MCMC 
impute=monotone option. A total of 100 datasets will be created. These datasets will be 
utilized in Step #2. 
2. The remaining missing values in the placebo group with a monotone missing data pattern 
will be imputed in this step. Missing data will be imputed assuming data are MAR. Only data 
(both observed and imputed) from subjects in the placebo group will be utilized in this step. 
SAS PROC MI will be used to impute missing values utilizing the monotone reg option. This 
will be performed for the 100 datasets. After this step, the 100 datasets will be fully imputed 
for the placebo treatment group. 
3. The missing values at Month 12 in the abaloparatide-SC group will be imputed in this step. 
Control-based PMM imputation will be performed. With this imputation model, the missing 
values in the abaloparatide-SC group will not be constructed from the observed data in the 
abaloparatide-SC group but rather from the observed baseline and data (including imputed 
values) from the placebo group at Month 12. The MNAR statement in SAS PROC MI will be 
used to impute missing values. This will be performed for the 100 datasets. 
4. A total of 100 fully imputed datasets will be created for both treatment groups. Since 
multiple imputation is a stochastic method, slight differences in output can be expected for 
different initial states of the random number generator. The seed numbers will be identified 
in the SAS programs to allow for reproducibility. 


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5. After the missing data imputation is completed using the above steps, percentage change 
values will be calculated in each of the imputed datasets at each visit. 
6. These 100 datasets will be analyzed using ANCOVA models with fixed effect of treatment 
group and DXA instrument manufacturer, and baseline lumbar spine BMD as a covariate for 
the primary efficacy endpoint.   
7. Treatment effects (difference in LS means between treatments) from these 100 analyses will 
then be combined using Rubin’s Method via SAS PROC MIANALYZE procedure for the 
primary endpoint. 
As a sensitivity analysis, the primary efficacy endpoint will also be analyzed using a Mixed 
Model for Repeated Measures (MMRM) analysis. The MMRM model will include the fixed 
effects of treatment, DXA instrument manufacturer, visit, and treatment-by-visit interaction, with 
the baseline lumbar spine BMD as covariate. Imputation for missing data is not necessary for the 
MMRM analysis because the model uses a restricted maximum likelihood (REML) based on the 
repeated-measures approach. For the MMRM model, an unstructured variance-covariance matrix 
shared between the two treatment groups will be used to model the within-subject errors over the 
visits. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom and to adjust standard errors (Kenward, 1997). Analyses will be implemented using the 
SAS PROC MIXED procedure. The treatment comparison will be obtained by testing the 
contrast (difference in least squares mean) between the two treatment groups at Month 12 (Visit 
8). The statistical test will be 2-sided comparing abaloparatide-SC to placebo; 99% CIs will be 
presented together with the estimated p-values. 
As supportive analysis, the primary efficacy endpoint will also be analyzed using an ANCOVA 
model using the last observation carried forward (LOCF) method. The ANCOVA model will 
include treatment and DXA instrument manufacturer as fixed effects, and the baseline lumbar 
spine BMD as covariate. To test for statistically significant differences between the treatment 
groups, the treatment comparison will be derived by testing the contrast (difference in least 
squares mean) between the two treatment groups at the Month 12 (Visit 8) visit. Missing data 
imputation based on the LOCF method will be performed as follows: 
• If baseline BMD is missing, no imputation for post-baseline value will be done and this 
subject’s data will be excluded from the analysis. 
• If baseline BMD is observed, missing post-baseline BMD will be imputed by the last 
observed value prior to the missing assessment. That is, if a value is missing at a post-
baseline time point, the post-baseline BMD will be imputed using the last value observed at 
any time (could be a value obtained at an unscheduled visit) between baseline (inclusive) and 
the specified post-baseline time point. 
The primary analysis using the PMM with the wash-out imputation method, and the other 
analyses using the MMRM model and the ANCOVA model using LOCF method, will be 
repeated using the PP population to support the findings from the ITT population. 
For the primary efficacy endpoint using PMM analysis with wash-out imputation, subgroup 
analyses for each of the subgroups defined in Section 3.8 will be performed. The treatment 
groups will be compared within each subgroup. A forest plot of the estimated least square (LS) 
mean differences between the treatment groups (and corresponding 99% CIs) will be presented 


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by subgroup. Additional exploratory analyses examining subgroup effect and treatment by 
subgroup interaction may be performed, if warranted.  
The efficacy analysis using MMRM model will also be repeated for the Antibody population, in 
which the subjects who are ADA+ at any post-baseline time point will be compared with 
subjects who are ADA- at all post-baseline time points. The MMRM model will include the 
fixed effects of ADA status, DXA instrument manufacturer, visit, and ADA status-by-visit 
interaction, with the baseline lumbar spine BMD as covariate.  
To investigate the effect of the COVID-19 pandemic, the following sensitivity analyses will also 
be performed: 
a) PMM analysis with wash-out imputation for subjects who completed or withdrew from the 
study before 01 March 2020 and for subjects who completed or withdrew from the study on 
or after 01 March 2020. The analysis visit windows described in Table 4 will be used. 
b) PMM analysis with wash-out imputation using the nominal visit. 
c) PMM analysis with wash-out imputation excluding BMD measurements collected outside the 
allowable time period for data collection. In this analysis, BMD assessments are allocated to 
a Visit based on the inclusion rules shown in Table 5 below re: Sensitivity Analysis c).   
d) PMM analysis with wash-out imputation excluding BMD measurements which are more than 
30 days after the ideal visit day. In this analysis, BMD assessments are allocated to a Visit 
based on the inclusion rules shown in Table 5 below re: Sensitivity Analysis d). 
Table 5: 
Visit Windows for DXA Assessments for Sensitivity Analyses. 
Visit 
Ideal Visit Day  
Sensitivity Analysis c): 
Allowable days from first dose of 
study drug 
Sensitivity Analysis d): 
Allowable days from first dose of 
study drug 
Month 3 
90 
2 —120 days 
2 —120 days 
Month 6 
180 
121—270 days 
121—210 days 
Month 12 
360 
271—390 days 
271—390 days 
It is possible that more than 1 assessment for a parameter may be obtained within the same visit 
window. In such circumstances, the assessment with the date closest to the ideal visit day will be 
used. In the event that 2 assessments are equidistant to the ideal visit day, the later of the 
assessments will be used. 
4.3.2 Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are: 
• Percent change from baseline in total hip BMD at 12 months 
• Percent change from baseline in femoral neck BMD at 12 months. 
Additional secondary efficacy endpoints are: 
• Percent change from baseline in 
‒ Lumbar spine BMD at 3 and 6 months 


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‒ Total hip BMD at 3 and 6 months 
‒ Femoral neck BMD at 3 and 6 months 
‒ Ultra-distal radius BMD at 3, 6 and 12 months 
‒ Distal one-third radius BMD at 3, 6 and 12 months. 
• Log ratio of post-baseline over baseline in 
‒ s-PINP at 1, 3, 6 and 12 months 
‒ s-CTX at 1, 3, 6 and 12 months. 
• Proportion of subjects experiencing BMD gains from baseline of >0%, >3%, and >6% at the 
lumbar spine, femoral neck, and total hip at 3, 6, and 12 months 
• Incidence of new clinical fractures at 12 months 
• Proportion of subjects converting from the categories of Osteoporosis to Osteopenia and 
Normal at end of treatment, where: 
‒ Osteoporosis is defined as lumbar spine or total hip BMD T-score ≤ -2.5,  
‒ Osteopenia is defined as: 
o lumbar spine > - 2.5 and total hip BMD T-score > -2.5 and < -1.0, or  
o lumbar spine > - 2.5 and < - 1.0 and total hip BMD T-score > -2.5,  
‒ Normal is defined as lumbar spine and total hip BMD T-score ≥ -1.0.  
• The percent change in total hip and femoral neck volumetric BMD as measured by 
quantitative CT (QCT) from baseline to 12 months. QCT will be performed in a subset of 
subjects at a selected number of study sites. 
Analyses of Key Secondary Efficacy Endpoints: 
The primary population for the analysis of the key secondary efficacy endpoints will be the ITT 
population. The analyses will be performed using PMM analysis with wash-out imputation 
similar to the analysis model for the primary efficacy endpoint, with the appropriate baseline 
covariate.  
Analyses of the primary and key secondary efficacy endpoints will follow a fixed-sequence 
testing approach to control the overall Type 1 error rate at the 2-sided significance level of 1%, 
as described in Section 3.7.   
Sensitivity analyses using a MMRM model, sensitivity analyses for addressing the effect of the 
COVID-19 pandemic, and supportive analyses using LOCF method, as with the primary efficacy 
endpoint, will also be conducted. For the estimated treatment effects of the key secondary 
endpoints, 99% CIs will be presented together with the estimated p-values. 
The analyses of each of the key secondary efficacy endpoints using the PMM method with wash-
out imputation, the MMRM model, and the ANCOVA model using LOCF method will be 
repeated using the PP population to support the findings from the ITT population. 
Subgroup analyses using PMM analysis with wash-out imputation will be performed on the key 
secondary efficacy endpoints using the ITT population for each of the subgroups defined in 
Section 3.8. The analyses will use analysis models as described above using the subset of ITT 
subjects belonging to the specific subgroup. A forest plot of the estimated least square (LS) mean 


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differences between the treatment groups (and corresponding 99% CIs) will be presented by 
subgroup for each of the key secondary efficacy endpoints. 
The efficacy analysis using MMRM model for the key secondary endpoints will also be repeated 
for the Antibody population, in which the subjects who are ADA+ at any post-baseline time 
point will be compared with subjects who are ADA- at all post-baseline time points. 
Analyses of Additional Secondary Efficacy Endpoints: 
All analyses performed for the primary efficacy endpoint for the ITT and PP populations will 
also be performed for all additional secondary efficacy endpoints involving the percent change 
from baseline in BMD parameters. The primary analyses will use the PMM analysis with wash-
out imputation similar to the analysis model for the primary efficacy endpoint, with the 
appropriate baseline covariate. Sensitivity analyses, subgroup analyses, and other supportive 
analyses will be performed as described in Section 4.3.1; however, a two-sided alpha level of 
0.05 will be used. For these analyses, 95% CIs for the estimated treatment effects will be 
presented along with the estimated p-values. 
While no forest plot will be generated for the additional endpoints, LS mean (±SE) percent 
changes from baseline for lumbar spine, total hip, and femoral neck will be plotted by treatment 
group over time using the ITT population.  
Percent (%) changes from baseline in BMD will be summarized using descriptive statistics by 
visit (Month 3, 6, and 12) for each treatment group. LS Mean (±SE) percent changes from 
baseline BMD will be plotted by treatment group over time using the ITT population. 
The primary population for the analysis of the secondary efficacy endpoints involving the bone 
formation marker, s-PINP, and the bone resorption marker, s-CTX, will be the ITT population.  
These parameters will be analyzed based on the ratio of the post-baseline value relative to the 
baseline value at each visit (using analysis visit windows described in Table 4). The 
transformation of the loge ratio of post-baseline versus baseline value (derived by dividing the 
post-baseline value by the baseline value and then applying the natural log transformation) will 
be used to normalize the distributions of the s-PINP and s-CTX parameters. The analysis 
comparing abaloparatide-SC with placebo will use PMM analysis with wash-out imputation as 
described in Section 4.3.1. Because their distribution violates normality assumptions, the bone 
marker data will be transformed using natural log transformation before imputation; and the 
observed and imputed data will be back-transformed after imputation. The relative treatment 
effect, defined as the exponential of the least squares mean difference in loge ratio between the 
two treatment groups at each visit will be presented along with the estimated p-values and 95% 
confidence intervals. Sensitivity analyses using a MMRM model, as with the primary efficacy 
endpoint, will also be conducted. Any value of s-PINP or s-CTX that is provided as “< numeric 
value” or “> numeric value” will be imputed as the numeric value in all summary tables and 
analyses; but will be shown with the actual result in the listings. 
Geometric mean values, geometric mean values (±SE) relative to baseline, mean (±SD) change 
from baseline values, and mean (±SD) percent change from baseline values at each visit for s-
PINP and s-CTX will be tabulated using descriptive statistics. Geometric mean (±SE) of the ratio 
relative to baseline as well as mean (±SE) percent changes from baseline for s-PINP and s-CTX 
will be plotted by treatment group over time using the ITT population. Plots will also be 


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presented for the median (± interquartile range) for the raw values of s-PINP and s-CTX over 
time by treatment group. 
A BMD responder analysis will be performed for exploratory purposes. This analysis will be 
based on the ITT population. Three categories of BMD response will be evaluated: % BMD 
increase >0%, >3%, and >6%. The by-visit responses (using analysis visit windows described in 
Table 4) will be assessed at the lumbar spine, total hip, and femoral neck. For the “all sites” 
analysis, subjects who have the pre-specified percentage BMD increase at all three anatomical 
sites at the same visit will be considered responders. A subject must have non-missing BMD 
results at all three sites at the same visit to be included in the “all sites” analysis. No imputation 
of missing data will be implemented. For the “all sites” analysis, the BMD response status at end 
of study will also be summarized. In this analysis, the “all sites” response status will be based on 
the subject’s last BMD assessment during the study. If the last BMD assessment is missing the 
result for one or two anatomical site(s), the subject will be classified as a non-responder at End 
of Study. The denominator for the percentage of BMD responders at End of Study will be the 
number of subjects in the ITT population who had both a baseline and a post-baseline BMD. 
BMD responder analyses will also be performed at each of the three anatomical sites separately, 
using the same three categories of BMD response used in the “all sites” analysis. A subject must 
have non-missing BMD results at a given visit to be included in the by-visit analysis. No 
imputation of missing BMD data will be implemented.  
The primary time point for all BMD responder analyses is Month 12. The chi-square test will be 
used to explore the difference in the number (%) of responders between the two treatment groups 
at each visit (Months 3, 6 and 12) for each category of response. If the number of responders is 
less than five in any treatment group, the Fisher’s exact test will be used. No multiplicity 
adjustment to the p-values for the BMD responder analysis will be implemented. 
Analysis of the time to new clinical fracture during the study will be performed for exploratory 
purposes. Duration in days from the date of randomization to the first incidence of clinical 
fracture will be derived. The crude incidence rates of new clinical fracture, Kaplan-Meier 
estimates of the incidence rate at Month 12, hazard ratio (95% CI) based on a Cox proportional 
hazard model, Kaplan-Meier curves, and p-values from the log-rank test for the comparison of 
the treatment groups will be generated using the ITT and PP populations for this time-to-event 
variable. If a subject does not experience any clinical fracture over the 12 months of treatment 
plus the 30-day follow-up, this subject will be censored at the last known day in the study up to 
the follow-up visit.    
The number and percentage of subjects for whom disease status has changed from osteoporosis 
at baseline to osteopenia or to normal (Refer to Section 4.3.2 for the definitions of osteoporosis, 
osteopenia, and normal), or no change at end of treatment will be tabulated; and will be analyzed 
using the Cochran-Mantel-Haenszel (CMH) test stratified by baseline disease status for the ITT 
population. No imputation of missing BMD data will be implemented. 
The percent change from baseline in total hip and femoral neck volumetric BMD (vBMD) at 
Month 12, as measured by quantitative computed tomography (QCT), will be analyzed using an 
ANCOVA model with fixed effects of treatment and DXA instrument manufacturer, and with 
the relevant vBMD baseline value as covariate for the ITT population. No imputation of missing 
vBMD data will be implemented. 


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4.4 
Population PK Analyses 
PK data will be analyzed and reported separately. Details of the PK data summaries and analysis 
methods will be provided in a separate analysis plan.  
4.5 
Safety Analyses 
The primary population for all safety analyses will be the Safety population. In safety analyses, 
treatment classification will be based on the actual treatment received. Unless otherwise 
specified, no formal statistical hypothesis testing will be performed for safety endpoints, and the 
presentations will be based on descriptive summaries.  
The impact of the COVID-19 pandemic and the implementation of a variety of mitigations for 
study conduct will be reviewed and evaluated carefully for the safety assessment. The pandemic-
related protocol deviations including missed or delayed visits, missed safety-related tests, use of 
alternative assessment procedures for visit execution, use of alternative data collection or 
alternative modalities, use of rescue medications, or non-adherence to the planned course of 
treatment will be identified. Additional data summaries and analyses addressing the impact of the 
pandemic may be performed if necessary.  
4.5.1 Study Drug Exposure 
All doses of study medication are to be self-administered or administered by an individual 
trained in giving the injection. Study personnel may administer the injection on days of clinic 
visits. The overall duration of study drug exposure will be calculated using the data recorded on 
the eCRF as follows: 
• Overall duration of study drug exposure (days) = (date of last dose – date of first dose) + 1. 
The total number of doses delivered and study drug administration compliance will be calculated 
in two ways as follows:  
• Based on missed doses in subject diary: 
‒ Number of doses delivered = Overall duration of study drug exposure – Total number of 
missed doses per subject diary 
‒ Percent compliance (%) to study drug administration = (Number of doses delivered / 
Overall duration of study drug exposure) x 100% 
• Based on measurement of drug remaining in pen: 
‒ Number of doses delivered = [(45.5 mm × Number of used pens) - Sum of measurements 
of drug remaining in all used pens)] /1.08 mm. Here the 45.5mm is the initial 
measurement of unused study drug in an unused injection pen and 1.08mm is the distance 
the plunger travels for each 80 ug dose from the pen.  
o Note: If the measurement of drug remaining in any used pen is missing, then 100% 
compliance will be assumed for the treatment period for which the pen with missing 
measurement of drug remaining was dispensed. The number of doses taken from the 
pen with missing measurement of drug remaining is a value less than or equal to 30, 
which will be based on the number of doses taken from the pen(s) with non-missing 
measurement of drug remaining dispensed at the same visit as the pen with missing 


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measurement of drug remaining. The number of doses delivered would be the 
minimum of the following: 
▪ 
Total doses taken from pens with non-missing measurements of drug remaining 
(calculated as: [45.5 mm × Number of pens with non-missing measurements of 
drug remaining - Sum of measurements of drug remaining from all pens with non-
missing measurements of drug remaining] /1.08 mm) + 30 × number of pens with 
missing measurement of drug remaining 
▪ 
Duration of the treatment period for which the pen with missing measurement of drug 
remaining was dispensed.  
‒ Percent compliance (%) to study drug administration = (Number of doses delivered / 
Overall duration of study drug exposure) x 100% 
The duration of study drug exposure, duration category in months (≤ 1 month, 1< to ≤ 3 months, 
3 to ≤ 6 months, 6 to ≤ 9 months, and > 9 months), number of doses delivered, and percent 
compliance to study drug administration will be summarized by treatment group for the Safety, 
ITT, and PP populations. 
To evaluate the relationship between study drug exposure and the antibody status, the duration of 
study drug exposure and percent compliance to study drug administration will also be 
summarized by antibody status (ADA-, ADA+/Nab+, ADA+/Nab-, All ADA+, and Overall) 
using the Antibody Population. 
If a subject is shown to be <80% compliant with study drug administration using both 
calculations of study drug administration compliance, this subject will be considered as having a 
significant protocol deviation and thus excluded from the Per-Protocol Population. 
Subjects’ drug exposure and compliance will be carefully reviewed against the onset of the 
COVID-19 pandemic. Each subject’s study drug exposure and compliance prior to 01 March 
2020 and on or after 01 March 2020 will be calculated based on information collected from the 
subject diary:  
• For subjects with last dose date prior to 01 March 2020 and subjects with first dose date on or 
after 01 March 2020, their duration of study drug exposure (days), number of doses 
delivered, and percent compliance to study drug administration relative to 01 March 2020 
will be calculated as above based on missed doses in subject diary. 
• For subjects who started taking the study drug prior to 01 March 2020 and continued on or 
after 01 March 2020, their duration of study drug exposure and compliance before 01 March 
2020 and on or after 01 March 2020 will be calculated as follows:  
‒ Duration of study drug exposure relative to 01 March 2020:  
▪ Duration before 01 March 2020 = 29 February 2020 – date of first dose + 1 
▪ Duration on or after 01 March 2020 = Overall duration of study drug exposure – 
duration before 01 March 2020; where overall duration of study drug exposure = last 
dose date – first dose date + 1  
‒ The number of doses delivered relative to 01 March 2020: 


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▪ Number of doses delivered before 01 March 2020 = A – {B + ([C x D] / E)}, and will 
be rounded to the nearest integer; where: 
• A = Duration of study drug exposure before 01 March 2020 
• B = Total number of missed doses from pens dispensed before 01 March 2020 
and with scheduled return dates before or on 01 March 2020   
• C = Number of missed doses from pens dispensed during the last drug dispensing 
visit prior to 01 March 2020 but with scheduled return date after 01 March 2020  
• D = 01 March 2020 – last drug dispensing date prior to 01 March 2020 
• E = (number of dispensed pens during the last drug dispensing visit prior to 01 
March 2020 – 1) x 30.  
▪ Number of doses delivered on or after 01 March 2020 = Number of doses delivered 
during whole study – number of doses delivered before 01 March 2020. 
‒ The percent compliance (%) to study drug administration relative to 01 March 2020: 
▪ Percent compliance before 01 March 2020 = (Number of doses delivered before 01 
March 2020 / Duration of study drug exposure before 01 March 2020) x 100%  
▪ Percent compliance on or after 01 March 2020 = (Number of doses delivered on or 
after 01 March 2020 / Duration of study drug exposure on or after 01 March 2020) x 
100%. 
The study drug exposure and percent compliance to study drug administration before 01 March 
2020 and on or after 01 March 2020 will be summarized by treatment group respectively.  
The study drug exposure and compliance will also be summarized based on subject study status 
during the pandemic (completed or withdrew from the study before 01 March 2020 vs ongoing 
on or after 01 March 2020) and by region (North America and Europe). 
All study drug administration and accountability data will be listed by treatment, study site, and 
subject number.   
4.5.2 Nutritional Supplements Exposure 
Subject exposure to Vitamin D and calcium supplements will be tabulated separately in terms of 
total amount of IU (for Vitamin D) and mg received (for calcium), respectively, (equal to total 
dispensed minus total returned) and duration of exposure (date of last dose – date of first dose + 
1) by treatment group using the Safety population. 
Summary statistics for the average Vitamin D and calcium supplements exposure per day (= 
([total dispensed minus total returned] / Duration of exposure) will also be presented separately 
by treatment group. Similarly, summary statistics will be provided for the average calcium 
supplements exposure per day. 
4.5.3 Adverse Events 
All adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT) 
using the MedDRA (Version 24.0) coding system. Analyses of AEs will be performed for those 
events that are considered to be Treatment-Emergent Adverse Events (TEAEs). A TEAE is 
defined as any AE that was absent (i.e., had not occurred) or had resolved prior to the start of 


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study drug, and which occurred on or after the date of the first dose of study drug and within 30 
days of the last dose of study drug; or any AE that started prior to the first dose of study drug, 
was ongoing after study treatment started, and increased in severity after the start of study drug 
and within 30 days of the last dose of study drug. AEs with missing onset dates will be handled 
according to the Conventions for Imputing Missing Dates in Appendix D. 
In any tabulation of adverse events, a subject contributes only once to the count for a given SOC 
or PT.  For summaries by severity, a subject with multiple occurrences of an AE will be 
represented under the most severe occurrence.  For summaries by relationship to study drug, a 
subject with multiple occurrences of an AE will be represented under the most related 
occurrence. 
An overall summary of the adverse events will be provided, in which the number of subjects 
with any adverse events, number of subjects with any TEAEs, number of subjects with any 
treatment-related TEAEs, number of subjects with any severe TEAEs, number of subjects with 
any treatment-related severe TEAEs, number of subjects with any serious TEAEs, number of 
subjects with any treatment-related serious TEAEs, number of subjects with any TEAES leading 
to study drug withdrawal, number of subjects with any TEAEs leading to study drug interruption, 
number of subjects with any TEAEs leading to study discontinuation, and number of subjects 
with any TEAEs leading to death will be summarized by treatment groups. 
The following summaries will also be presented: 
• TEAEs by SOC and PT  
• TEAEs by SOC, PT, and region (North America and Europe)  
• TEAEs by PT. Note: TEAEs will be sorted in descending order of total number of subjects 
with the preferred term in the abaloparatide-SC treatment group  
• TEAEs by SOC, PT, and maximum severity  
• Severe TEAEs by SOC and PT 
• Treatment-related severe TEAEs by SOC and PT 
• TEAEs by SOC, PT, and relationship to study drug 
• Treatment-related TEAEs by SOC and PT  
• TEAEs leading to study drug interruption by SOC and PT  
• TEAEs leading to study drug withdrawal by SOC and PT  
• TEAEs leading to study discontinuation by SOC and PT 
• TEAEs leading to death by SOC and PT 
• Serious TEAEs by SOC and PT 
• Treatment-related serious TEAEs by SOC and PT  
• Most common (>=5% in any treatment group) TEAEs by SOC and PT 
• Non-TEAEs by SOC and PT 
SOCs will be sorted in alphabetical order. Within an SOC, AEs will be sorted in descending 
order of the total number of subjects with the preferred term in the abaloparatide group. 


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To explore the relationship between TEAEs and the duration of study drug exposure, the 
incidence of TEAEs by time of onset (≤1 month, 1< to ≤3 months, 3< to ≤6 months, 6< to ≤9 
months, and >9 months) will be summarized by treatment group, SOC and PT. Subjects with 
multiple occurrences of an AE within a time period will be counted once in each time period that 
an onset of the AE occurs. 
To evaluate the relationship between TEAEs and the antibody status, the incidence of TEAEs 
will be summarized by antibody status (ADA-, ADA+/Nab+, ADA+/Nab-, All ADA+, and 
Overall), SOC, and PT using the Antibody Population. A summary of TEAEs by PT and 
antibody status will also be presented, in which TEAEs will be sorted in descending order of 
total number of subjects with the preferred term in the overall abaloparatide-SC treatment group.  
During the COVID-19 pandemic, AEs may be assessed through phone/video by the investigator 
conducting the study visit with subjects remotely. To explore the effect of the COVID-19 
pandemic on reported AEs, summaries of TEAEs by SOC and PT, TEAEs leading to treatment 
discontinuation, and serious TEAEs will also be presented: 
• by subject’s study status relative to COVID-19 pandemic onset (subjects who completed or 
withdrew from the study before 01 March 2020, vs subjects who completed or withdrew 
from the study on or after 01 March 2020) 
• by AE onset dates relative to COVID-19 pandemic onset (AE occurs before 01 March 2020, 
vs AE occurs on or after 01 March 2020) 
• by region (North America and Europe) 
The number of subjects with any TEAEs, the number of subjects with any SAEs, and the number 
of subjects with TEAEs leading to study drug withdrawal will also be summarized by treatment 
group, SOC, PT and age group (< 65, 65 - < 75, and ≥ 75 years). Similar tables will be provided 
by treatment group, SOC, PT and BMI group (BMI < 25, 25 ≤ BMI < 30, and BMI ≥ 30). 
Subject listings will be provided for all AEs by SOC and PT. Listings will also be produced for 
deaths, SAEs, AEs leading to study drug withdrawal and study discontinuation, and severe AEs. 
A listing for subjects who are anti-PTH or anti-PTHrP positive and had adverse events will also 
be presented. 
A data listing for COVID-19 related AEs (AE PTs related to COVID-19 using MedDRA 
Version 24.0) will be prepared by SOC and PT. A listing of subjects who experience an 
Unanticipated Adverse Device Effect (UADE) will be provided from the Pharmacovigilance 
database.  
Adverse Events of Special Interest 
An adverse event of special interest (AESI) is an AE that is designated to be of special medical 
or scientific interest to the Sponsor. There are four major categories of AESIs as follows: 
• Injection site reaction AEs -- Skin reaction AEs at the injection site 
• Skin AESIs -- AEs of eschar, ulcer, or non-healing wounds at the injection site 
• Hypersensitivity AESIs -- TEAEs in the Hypersensitivity Standardized MedDRA Query 
(SMQ narrow)  
• Other AESIs: 
− Orthostatic hypotension 


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− Tachycardia 
− Nausea 
− Hypercalcemia  
− Hypercalciuria  
− Hypophosphataemia 
The MedDRA PTs, High Level Terms (HLT), and SMQs used to identify the AESIs are stored in 
the study folder in the Biometrics SAS Environment.  
An overall summary of the treatment emergent AESIs will be provided, in which the number of 
subjects with any adverse events, number of subjects with any TEAEs, number of subjects with 
any treatment-related TEAEs, number of subjects with any severe TEAEs, number of subjects 
with any treatment-related severe TEAEs, number of subjects with any serious TEAEs, number 
of subjects with any treatment-related serious TEAEs, number of subjects with any TEAES 
leading to study drug withdrawal, number of subjects with any TEAEs leading to study drug 
interruption, number of subjects with any TEAEs leading to study discontinuation, and number 
of subjects with any TEAEs leading to death will be summarized by treatment group. 
The treatment emergent AESIs will be summarized by PT and SOC for each of the AESIs. 
Summary of the onset time and duration of the treatment emergent AESIs will be provided by 
treatment group using descriptive statistics (number of subjects, mean, SD, median, interquartile 
range, minimum and maximum). The number of subjects in each of the onset time groups (1 day, 
2-3 days, 4-7 days, 8-15 days, 16-29 days, 1 to <2 months, 2 to <6 months, 6 to <10 months, and 
>=10 months) and duration groups (1 day, 2-3 days, 4-7 days, 8-15 days, 16-29 days, and >= 30 
days) will also be summarized by treatment group. 
To evaluate the relationship between AESIs and the antibody status, the incidence of treatment 
emergent AESIs will also be summarized by antibody status (ADA-, ADA+/Nab+, ADA+/Nab-, 
All ADA+, and Overall), SOC, and PT for the abaloparatide SC group. 
An overall summary of the treatment emergent AESIs, as described above, will also be presented 
by treatment group (and overall) and the following subgroups: 
• Age group (< 65, 65 - < 75, and ≥ 75 years).  
• BMI group (BMI < 25, 25 ≤ BMI < 30, and BMI ≥ 30)  
• Region (North America and Europe). 
Subject listings will be provided for each of the AESIs. 
4.5.4 Anti-Abaloparatide Antibody 
For subjects in the abaloparatide-SC group, the anti-abaloparatide antibody assessment in the 
serum samples for immunogenicity testing will be categorized by two outcomes: 
‒ Negative for anti-abaloparatide antibodies 
‒ Positive for anti-abaloparatide antibodies 
The number (%) of subjects in the above categories of abaloparatide antibodies will be 
summarized at Day 1 (Visit 3), Month 1 (Visit 4), Month 3 (Visit 5), Month 6 (Visit 6), Month 9 
(Visit 7), Month 12 (Visit 8) and the Follow-up Visit scheduled approximately 1 month after the 
last dose of study medication (Month 13/Visit 9) using the Antibody population.  


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For those subjects with anti-abaloparatide antibody present (i.e, are ADA positive), the titer 
level, the presence of neutralizing anti-abaloparatide antibodies (negative or positive), and the 
assessment outcomes for cross-reactivity to PTH (negative or positive) and PTHrP antibodies 
(negative or positive) together with the neutralizing antibody status in subjects that are positive 
for PTH (negative or positive for the presence of PTH-neutralizing antibodies) or PTHrP 
(negative or positive for the presence of PTHrP-neutralizing antibodies) will be summarized by 
study visit. Figures for the incidence of antibody and neutralizing antibody for the anti-
abaloparatide, anti-PTH, and anti-PTHrP will be presented by nominal visit. 
All antibody information collected for the abaloparatide-SC group will be presented in a data 
listing. 
The results of antibody analyses will be presented in a separate report. 
4.5.5 Local Tolerance 
Local tolerance will be assessed by the investigator and by the subject separately.  
Investigator Assessment of Local Tolerance  
For each local skin reaction symptom, descriptive statistics (number of subjects, mean, SD, 
median, interquartile range, minimum and maximum) will be used to summarize the responses 
on the 4-point scale (0=None, 1=Mild, 2=Moderate,3=Severe) by treatment, visit and timepoint. 
In addition, for each symptom, the number (%) of subjects in each response category (none, 
mild, moderate, and severe) will be provided by treatment per visit and timepoint.  
Investigator assessment of local tolerance was not scheduled for Month 12 in the protocol. 
Investigator assessments recorded on Month 12/Early Termination (Month 12/ET) CRFs will be 
summarized under the “End of Treatment” visit. 
The maximum severity of each symptom of local skin reaction per subject will be summarized 
with the number (%) of subjects in each response category (none, mild, moderate, and severe) by 
treatment and visit. The maximum severity of each symptom of local skin reaction per subject 
will also be summarized with the number (%) of subjects in each response category by treatment 
and timepoint (and at post-dose timepoint).  
The maximum severity of symptom scores will also be summarized descriptively (number of 
subjects, mean, SD, median, interquartile range, minimum and maximum) for each response on 
the 4-point scale (0=None, 1=Mild, 2=Moderate, 3=Severe) by treatment and visit, and by 
treatment and timepoint, respectively.  
During the COVID-19 pandemic, the investigator’s assessment of the symptoms of local skin 
reactions may be assessed through alternative methods other than direct on-site assessment. To 
explore the effect of the COVID-19 pandemic, summaries of the investigator’s assessment of 
local tolerance will also be presented by: 
• region (North America and Europe)  
• subject’s study status relative to COVID-19 pandemic onset (subjects who completed or 
withdrew from the study before 01 March 2020, vs subjects who completed or withdrew 
from the study on or after 01 March 2020) 


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• excluding local tolerance assessments made via alternative methods other than direct on-site 
assessment   
Subject Assessment of Local Tolerance 
Subject assessment of local tolerance using a 4-point scale will be done within 5 minutes and at 1 
hour following administration beginning on Day 2 and continuing through Day 7 of Month 1 and 
Month 9, as recorded in the subject diary. 
For each local skin reaction symptom, descriptive statistics (number of subjects, mean, SD, 
median, interquartile range, minimum and maximum) will be used to summarize the responses 
on the 4-point scale (0=None, 1=Mild, 2=Moderate,3=Severe) collected during Day 2 to Day 7 at 
Month 1 and at Month 9: 
‒ by treatment, visit, day, and timepoint.  
‒ maximum severity score by treatment, visit and day 
‒ maximum severity score by treatment, visit and timepoint  
‒ maximum severity score by treatment and visit 
‒ maximum severity score by treatment and day across visits 
‒ maximum severity score by treatment and timepoints  
In addition, for each symptom, the number (%) of subjects in each response category (none, 
mild, moderate, and severe) will be provided by treatment per visit, day, and timepoint in a 
similar manner as described above for the summary of responses by the 4-point scale. The 
maximum severity of symptom will be similarly summarized for each response category (none, 
mild, moderate, and severe):  
‒ by treatment, visit, and day 
‒ by treatment, visit, and timepoint 
‒ by treatment and visit 
‒ by treatment and days across visits 
‒ by treatment and timepoint across visits (and at post dose timepoint).  
All injection site local tolerability assessment scores will be presented in a listing. 
4.5.6 Laboratory Data 
Clinical laboratory values will be provided in conventional units and in standard international 
(SI) units by the central laboratory.  
Summaries of laboratory data using descriptive statistics by treatment group and study visit will 
be presented based on the SI units, including absolute results and changes from baseline. This 
includes serum chemistry, hematology, coagulation, hormones (including total testosterone, 
estradiol, SHBG, and PTH), 25-hydroxyvitamin D, 1,25-dihydroxy vitamin D, and urinalysis 
(for quantitative urinalysis assays). In the event of repeat assessments during a visit time point, 
the last non-missing value per study day/time will be used in the summary statistics. In the event 
of duplicate assessments at a visit time point, the worst value per study day/time will be used in 
the summary statistics. Results from unscheduled visits will not be included in the summaries. 
Shift analyses of laboratory data from baseline to the worst post-baseline value and from baseline 
to Month 12/ET (Visit 8) will be performed by treatment group. Results for serum chemistry, 


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hematology, coagulation, and urinalysis will be presented by category (above normal limit, 
within normal limit, below normal limit). For shift tables from baseline to worst post-baseline 
value, and for baseline to Month 12, percentages will only be calculated based on the number of 
subjects with valid data for baseline and post-baseline; subjects who are missing either 
assessment will not be included in the percentage calculation (numerator or denominator). 
Results from unscheduled visits will be included in the shift analyses, as applicable. 
To explore the effect of the COVID-19 pandemic, summaries of all laboratory parameters will 
also be presented for the following: 
• By region (North America and Europe)  
• By subject’s study status relative to COVID-19 pandemic onset (subjects who completed or 
withdrew from the study before 01 March 2020, vs subjects who completed or withdrew 
from the study on or after 01 March 2020) 
Any laboratory parameter value that is provided as “< numeric value” or “> numeric value” will 
be imputed as the numeric value in all summary tables and analyses; but will be shown with the 
actual result in the listings. 
All laboratory data, including repeated values and results from unscheduled visits, will be 
presented in data listings, with indication of higher or lower than the associated normal range of 
each laboratory test, where applicable. 
Potentially Clinically Significant Laboratory Values 
Criteria for determining values of laboratory tests that are considered Potentially Clinically 
Significant (PCS) are in Appendix B of this SAP. The number (%) of subjects with at least 1 
post-baseline PCS values who did not have PCS values at baseline will be presented for each 
laboratory parameter. Results from unscheduled visits will be included in identification of 
subjects with post-baseline PCS values, as applicable. For the calculation of the percentages of 
subjects, the denominator will be based on the number of subjects who had no PCS values at 
baseline and had at least one post-baseline assessment for the specific laboratory parameter of 
interest. The numerator will be based on the number of subjects from the denominator who had 
at least one PCS value post-baseline for the specific laboratory parameter of interest. A listing of 
subjects with any PCS values will be provided. 
Hypercalcemia 
A hypercalcemic event (hypercalcemia) is defined as an elevated serum calcium (albumin-
corrected) value ≥ 0.3 mg/dL (≥ 0.08 mmol/L) above the upper limit of the normal range (ULN).  
Three cutoff levels of serum calcium (albumin-corrected): 
a) ≥ ULN 
b) ≥ ULN+ 0.3 mg/dL (or + 0.08 mmol/L) 
c) ≥ ULN + 1.0 mg/dL (or + 0.25 mmol/L) 
The following summaries and analyses will be provided by treatment group for each of the cutoff 
levels above: 
• Number (%) of subjects with at least one occurrence of a serum calcium (albumin-corrected) 
value above the cutoff level at each visit, timepoint, and overall (entire treatment period): 


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− The corresponding 95% CI based on Wilson’s Score method will be provided per 
treatment group.  
− For the number of subjects with at least one occurrence of a serum calcium (albumin-
corrected) value above the cutoff level during the entire treatment period: 
o The treatment groups will be compared using the chi-square test. 
o The risk reduction between the treatment groups (calculated as Abaloparatide-SC − 
Placebo) will be provided together with the 95% CI based on Newcombe’s method. 
o The relative risk reduction between the treatment groups (calculated as 
(Abaloparatide-SC − Placebo)/Placebo) will be provided together with the 95% CI 
based on Wald’s method. 
• Number of occurrences of a serum calcium (albumin-corrected) value above the cutoff level 
per subject during the entire treatment period 
• The ratio of the total number of occurrences of a serum calcium (albumin-corrected) value 
above the cutoff level to the total number of serum calcium (albumin-corrected) blood 
samples per subject during the entire treatment period. 
Mean (±SE) serum calcium (albumin-adjusted) values will be plotted over study visit by 
treatment group. All serum calcium (albumin-corrected) results will be included in the plot, 
which will indicate the results at pre-dose and 4-hours post-dose at each visit. 
To evaluate the relationship between age and hypercalcemia, the number (%) of subjects with at 
least one occurrence of hypercalcemia at each visit and overall (entire treatment period) will be 
summarized by treatment group and age group (< 65, 65 - < 75, and ≥ 75 years). 
Hypercalciuria 
The number (%) of subjects with at least one occurrence of hypercalciuria (urine 
calcium/creatinine ratio > 0.4 mg/mg (> 1.131 mmol/mmol)) at Baseline (Day 1), Month 3, and 
overall will be summarized by treatment group. A 95% CI for the percentage based on the 
Wilson’s Score method will be calculated for each treatment group at each visit and overall. This 
analysis will be repeated for subjects with one or more occurrences of urine calcium/creatinine 
ratio > 0.3 mg/mg (> 0.848 mmol/mmol).   
To evaluate the relationship between age and hypercalciuria, the number (%) of subjects with at 
least one occurrence of hypercalciuria at each visit and overall will be summarized by treatment 
group and age group (< 65, 65 - < 75, and ≥ 75 years). 
Creatinine and Calcium Excretion and Creatinine Clearance 
The 24-hour urine for calcium:creatinine and creatinine clearance are collected at Day 1 and 
Month 3. The urine sample values will be adjusted for the time period to derive the urine result 
that is standardized for a 24-hour period. The 24-hour urine results will be summarized 
descriptively by treatment group and visit. If the end of the collection time of the 24-hour urine is 
on the same day as the first dose date or within 24 hours from the time of first dose, then the 24-
hour urine sample will be considered as a Day 1 sample and will be treated as the baseline 
sample. Otherwise, the 24-hour urine data will be considered as a post-Day 1 (i.e, post-baseline) 
sample.  


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The parameters to be summarized include: 
• Urine calcium:creatinine ratio 
• 24-hour urine calcium excretion (calcium concentration x 24-hour urine volume) 
• 24-hour urine creatinine excretion (creatinine concentration x 24-hour urine volume) 
• Creatinine clearance (CCr) calculated in two ways:  
a) Based on 24-hour urine collection 
b) Based on serum creatinine, calculated using the Cockcroft-Gault estimate, CCr: 
CCr (mL/min) = [(140 −age) ∗weight ∗1.23] ÷ SCr 
            Where: 
o Age in years 
o Weight in kilograms 
o SCr = Serum creatinine in µmol/L. 
The following categories of renal function will be defined: 
 
Cockcroft-Gault Estimated Serum Creatinine Clearance 
Normal 
≥ 90 mL/min (≥ 1.5 mL/s) 
Mild 
≥ 60 mL/min to < 90 mL/min (≥ 1.0 mL/s to < 1.5 mL/s) 
Moderate 
≥ 30 mL/min to < 60 mL/min (≥ 0.5 mL/s to < 1.0 mL/s) 
Severe 
≥ 15 mL/min to < 30 mL/min (≥ 0.25 mL/s to < 0.5 mL/s) 
The number (%) of subjects in each renal function category at each visit and overall (across all 
visits) will be presented by treatment group. A similar summary table will be presented by 
treatment group and age group (< 65, 65 - < 75, and ≥ 75 years). 
4.5.7 Vital Signs and Physical Examination 
The actual value, the change from baseline to each visit, the change from baseline to the worst 
post-baseline value during the treatment period, and the change from baseline to Month 13 
(Follow-up visit) will be summarized for vital signs using descriptive statistics by treatment 
group. If a subject has repeat assessments on the vital signs at a particular scheduled visit/time 
point, the last non-missing value will be used for the by-visit summary. Unscheduled 
assessments will be included in the summaries for the worst post-baseline value or PCS, they 
will not be included in the descriptive by-visit summary tables. 
The number (%) of subjects experiencing post-dose orthostatic hypotension will be summarized 
by treatment group, visit and time point, and across all visits. Orthostatic hypotension will be 
defined as a decrease in systolic blood pressure (SBP) of ≥ 20 mmHg from supine to standing or 
in diastolic blood pressure (DBP) of ≥ 10 mmHg supine to standing. Results from unscheduled 
visits will be included in the summaries.  
The number (%) of subjects experiencing heart rate increase from pre-dose to post-dose and the 
number of occurrences per subject will be summarized with various threshold values (ranging 
from >5 bpm to >40 bpm, with threshold values increasing by 5 BPM). The median, minimum 
and maximum heart rate increase (in BPM) will be provided per threshold value. The number of 
occurrences per subject will be summarized using the median, minimum and maximum values. 


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All heart rate data, including repeat and unscheduled assessments, will be included in 
determining the increase from pre-dose in this summary. 
Criteria for determining values of vital sign measurements that are considered PCS are in 
Appendix C of this SAP. The number (%) of subjects who have at least 1 PCS vital sign values 
for each vital sign parameter of interest after the first dose of study drug, but had no PCS values 
at baseline, will be presented by treatment. Results from unscheduled visits will be included in 
identification of subjects with post-baseline PCS values, as applicable. For the calculation of the 
percentages of subjects, the denominator will be based on the number of subjects who had no 
PCS values at baseline and had at least one post-baseline assessment for the specific vital sign 
parameter of interest.  
A listing of subjects with any PCS vital sign values will be provided. 
To explore the effect of the COVID-19 pandemic, the above planned summaries will also be 
presented for the following:  
• By region (North America and Europe)  
• By subject’s study status relative to COVID-19 pandemic onset (subjects who completed or 
withdrew from the study before 01 March 2020, vs subjects who completed or withdrew 
from the study on or after 01 March 2020) 
To evaluate the relationship between age and orthostatic hypotension, the number (%) of subjects 
with at least one occurrence of post-dose orthostatic hypotension at each visit, timepoint, and 
overall (across all visits) will be summarized by treatment group and age group (< 65, 65 - < 75, 
and ≥ 75 years). 
To evaluate the relationship between age and heart rate increase, the number (%) of subjects with 
at least one occurrence of heart rate increase from pre-dose to post-dose will be summarized with 
various threshold values (ranging from >5 bpm to >40 bpm, with threshold values increasing by 
5 bpm) by treatment group and age group (< 65, 65 - < 75, and ≥ 75 years). Descriptive statistics 
for heart rate increase per threshold value and the number of occurrences of heart rate increase 
per subject per threshold value will be provided. 
Physical examination is performed only at screening visit and will be summarized as described in 
Section 4.2. 
4.5.8 Electrocardiogram 
Electrocardiogram (ECG) parameters collected at study visits are heart rate, PR interval, QRS 
duration, QT, and QTcF (QT corrected by Fridericia’s formula). The actual value, change from 
baseline value, changes from baseline to worst value during the treatment period, and change 
from baseline to Month 13 (follow-up visit) will be summarized for quantitative ECG results by 
treatment group, study visit, and time point (pre-dose and 1-hour post-dose). The overall ECG 
assessments will be summarized categorically (normal, abnormal without clinical significance, 
and abnormal with clinical significance) as a shift table by treatment group, study visit, and 
timepoint. With the exception of change from baseline to the worst post-baseline value during 
the treatment period, results from unscheduled visits will not be included in the summaries. 


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Summaries will also be provided for the change from predose values for ECG heart rate, where 
the predose value is the last value obtained prior to dosing at each visit where ECG is assessed. If 
a subject has multiple ECG results at a particular visit/time point, the repeat measurement reason 
will be checked to determine if the first or the last non-missing value will be used for the 
summary. If the reason for the repeat assessment is abnormal value, then the first value will be 
used. If the reason is misplacement of the limb lead electrodes, the last value will be used. 
Results from unscheduled visits will not be included in these descriptive summary tables. 
The number (%) of subjects experiencing heart rate increase from pre-dose to post-dose and the 
number of occurrences per subject will be summarized with various threshold values (ranging 
from >5 bpm to >40 bpm, with threshold values increasing by 5 bpm). The median, minimum, 
and maximum heart rate increase (in bpm) will be provided per threshold value. The number of 
occurrences per subject will be summarized using the median, minimum, and maximum values. 
All ECG heart rate data, including repeat and unscheduled assessments, will be included in 
determining the increase from pre-dose in this summary. To evaluate the relationship between 
age and heart rate increase, the above summary of heart rate increase with various threshold 
values will also be repeated by treatment and age group (< 65, 65 - < 75, and ≥ 75 years).  
The number (%) of subjects with the following clinically important QTcF values will be 
presented by treatment group, visit, and timepoint. Results from repeat/unscheduled visits will be 
included in shift analyses, as applicable: 
‒ Post-baseline QTcF > 450 msec 
‒ post-baseline QTcF > 480 msec 
‒ post-baseline QTcF > 500 msec 
‒ change from baseline > 30 msec in QTcF 
‒ change from baseline > 60 msec in QTcF 
‒ post-baseline QTcF > 500 msec and change from baseline >60 msec in QTcF 
Shift tables from baseline to post-baseline QTcF values using the following categories will be 
presented for each post-baseline visit and time point. Results from repeat/unscheduled visits will 
be included in shift analyses, as applicable 
‒ ≤ 450 msec and > 450 msec 
‒ ≤ 480 msec and > 480 msec 
‒ ≤ 500 msec and > 500 msec. 
All ECG data will be provided by subject in a data listing. Listings will also be provided for 
those subjects who have any QTcF values greater than 450 msec, 480 msec, and 500 msec, and 
those with QTcF change from baseline values >30 msec and >60 msec. 
During the COVID-19 pandemic, ECG may be conducted at a subject’s home (home visit) by 
authorized personnel and then be processed and assessed by a central reader. To explore the 
effect of the COVID-19 pandemic, summaries for ECG parameters will also be presented for the 
following: 
• By region (North America and Europe)  
• By subject’s study status relative to COVID-19 pandemic onset (subjects who completed or 
withdrew from the study before 01 March 2020, vs subjects who completed or withdrew 
from the study on or after 01 March 2020) 


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4.5.9 Concomitant Medications 
Medication history and concomitant medications will be coded using the WHO Drug Dictionary. 
Medications will be tabulated by anatomic therapeutic class (ATC), preferred term (PT), and 
treatment group. Medications and concomitant medications will be summarized using the Safety 
population. All recorded medications will be presented in a by-subject listing. 
Summary of concomitant medications will include medications taken from the date of the first 
dose of study medication (Day 1) until 30 days after the last dose of study medication. 
Medications that did not end prior to the first dose of study medication will be included in the 
summary.  
Prior medications (those with start date prior to the first dose of study medication) will also be 
summarized by ATC, PT, and treatment group. 
If both start date and stop date are missing, the medication will be assumed to occur both prior 
and concomitantly. 
To explore the effect of the COVID-19 pandemic, summaries for the prior medications and 
concomitant medications will also be presented for the following: 
• By region (North America and Europe)  
• By subject’s study status relative to COVID-19 pandemic onset (subjects who completed or 
withdrew from the study before 01 March 2020, vs subjects who completed or withdrew 
from the study on or after 01 March 2020). 
• By medication start dates relative to COVID-19 pandemic onset (medications start before 01 
March 2020, vs medications start on or after 01 March 2020). For the calculation of 
percentages, the denominator includes all subjects in the safety population for the relevant 
treatment group. 
 


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5 CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES 
The following changes from the protocol-specified analyses are included in this SAP: 
• 
In Section 1.2.5, a word “Serum” is added to the additional secondary efficacy endpoint 
“carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX) at 1, 3, 6, and 12 
months”  
• 
In Section 1.2.5, the words “12 months” are replaced by “end of treatment” in the additional 
secondary efficacy endpoint “Proportion of subjects converting from the categories of 
osteoporosis to osteopenia or to normal at 12 months” to clarify the timepoint at which the 
endpoint is assessed. 
• Section 2.2 defines the Antibody Population  
• Section 3.12 defines analysis visit windows for the analyses of BMD, vBMD, and serum 
markers of bone metabolism (s-PINP and s-CTX) data to determine the assessment that will 
be used for a given study visit.   
• In Section 4.3.1, the primary analysis will use a pattern mixture model (PMM) analysis with 
multiple imputation using the wash-out imputation method, instead of the protocol-specified 
ANCOVA model using LOCF technique to impute missing values. The LOCF method has 
been shown to lead to substantial bias in estimating treatment effects and is no longer 
recommended by regulatory authorities. While the PMM analysis with wash-out imputation 
is an appropriate approach to address the possibility of data missing not at random. The 
PMM analysis with wash-out imputation method was recommended by the FDA in their 
comment on the primary analysis of this study: Advice-Information Request IND 73176, 
dated 05 March 2021. 
• In Section 4.3.1, age is removed from the MMRM and ANCOVA models as a covariate. 
From previous clinical studies, there is little evidence to suggest that age is associated with 
the BMD response in subjects who have taken abaloparatide-SC. 
• In Section 4.5.3, definitions and summary of AESIs are added. AESIs were not defined in the 
protocol. 
• Additional analyses to evaluate the impact of the COVID-19 pandemic on study conduct 
were added for safety and efficacy endpoints where applicable. 
• The results of antibody analyses will be presented in a separate report. 
All other statements in this SAP are enhancements to the statistical considerations described in 
the protocol. 
 
 


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Appendix A.  Algorithm to Identify Significant Protocol Deviations that Exclude Subjects 
from the Per-Protocol (PP) Population 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. Significant PDs are a subset of PDs that have the potential to impact the 
effect of the treatment on the subject. 
The below algorithm outlines the criteria for identifying significant protocol deviations. Subjects 
with at least one of these significant protocol deviations will be excluded from the PP population. 
A. Deviations of subject eligibility (Inclusion/Exclusion criteria) that will result in exclusion 
from PP population: 
1. Inclusion Criterion #2: A BMD T-score above the required level. 
2. Exclusion Criterion #2: A BMD T-score below the required limit. 
3. Exclusion Criterion #1: Presence of abnormalities of the lumbar spine that would prohibit 
assessment of spinal bone mineral density. 
4. Exclusion Criterion #3: Unevaluable hip BMD or subjects who have undergone bilateral 
hip replacement.  
5. Exclusion Criterion #4: Fragility fracture within the 12 months prior to signing of 
informed consent. 
6. Exclusion Criterion #5: History of severe vertebral fracture or > 2 moderate vertebral 
fractures. 
7. Exclusion Criteria #6, #8, and #10: Diseases and treatments affecting the bone strength. 
8. Inclusion Criterion #5: Laboratory tests affecting the bone strength 
9. Exclusion Criteria #18, #19, #20, #21, #22, #23, #24, #25, and #27. Prior treatment with 
bone acting agents within the specified time period. 
B. Deviations of study drug administration that will result in exclusion from PP population: 
1. The blinding of the study drug was broken during the subject’s participation in this study 
before database lock. 
2. Duration of study drug exposure is less than 3 months (90 days) 
3. Compliance to study drug administration < 80% 
C. Deviations of efficacy measurements that will result in exclusion from PP population: 
1. Lumbar spine BMD is missing at baseline  
2. No post-baseline lumbar spine BMD measurements recorded 
D. Other significant protocol deviations 
1. Any protocol deviation with potential major impact on the primary efficacy endpoint will 
exclude a subject from the PP population. This will include subjects taking any prohibited 
medications during study. 
 
 
 


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Appendix B. Criteria for Potentially Clinically Significant Laboratory Values  
Lab Parameter 
Conventional Unit 
SI Unit 
 
Low 
High 
Low 
High 
Hematology 
Absolute Eosinophils 
 
>5000 cells/mm3 
 
>5.00 109/L 
Absolute Lymphocytes 
≤499 cells/mm3 
 
≤0.499 109/L 
 
Absolute Neutrophils 
≤999 cells/mm3 
 
≤0.999 109/L 
 
Hemoglobin 
≤10.4 g/dL (male) 
 
change from baseline 
≥2.1 g/dL 
≤104 g/L (male) 
change from 
baseline ≥21 g/L 
Platelets 
≤99000 cells/mm3 
 
≤99 109/L 
 
White Blood Cells 
≤1499 cells/mm3 
≥20001 cells/mm3 
≤1.499 109/L 
≥20.0 109/L 
Coagulation 
Activated Partial 
Thromboplastin Time 
 
≥1.41*ULN 
 
≥1.41*ULN 
 
Serum Chemistry 
Alanine Aminotransferase 
 
≥5.1*ULN  
 
≥5.1*ULN 
Albumin 
<2.5 g/dL 
 
<25 g/L 
 
Alkaline Phosphatase IFCC 
 
≥3.1*ULN  
 
≥3.1*ULN 
Aspartate Aminotransferase 
 
≥5.1*ULN   
 
≥5.1*ULN   
Bilirubin Total 
 
≥1.51*ULN (with 
ALT and/or 
AST>ULN) 
 
≥2.0*ULN (with 
normal liver function 
tests) 
 
≥1.51*ULN 
(with ALT and/or 
AST>ULN) 
 
≥2.0*ULN (with 
normal liver 
function tests) 
Calcium 
≤7.4 mg/dL  
≥11.6 mg/dL  
≤1.85 mmol/L  
≥2.9 mmol/L  
Cholesterol Total 
 
>226 mg/dL 
 
>5.8534 mmol/L 
Creatine Kinase 
 
≥3.1*ULN  
 
≥3.1*ULN 
Creatinine 
 
≥2.1 mg/dL 
 
≥ 185.64 umol/L 
Glucose 
≤54 mg/dL 
 
>200 mg/dL 
(random) 
≤ 2.997 mmol/L 
 
> 11.1 mmol/L 
 
Potassium 
≤3.2 mEq/L  
≥5.5 mEq/L  
≤3.2 mmol/L 
≥5.5 mmol/L  
Protein Total 
<5 g/dL 
 
<50 g/L 
 
Sodium 
≤129 mEq/L 
≥148 mEq/L  
≤129 mmol/L 
≥148 mmol/L  
Urine 
Glucose 
 
2+ (≥100 mg/dL)  
 
2+ (≥5.55 mmol/L) 
Protein 
 
2+ (≥100 mg/dL) 
 
2+ (≥ 1.0 gm/L) 
Blood (microscopic) 
 
>50 rbc/hpf 
 
>50 rbc/hpf 
Source: FDA Guidance for Industry 2007, Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
 
 


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Appendix C. Criteria for Potentially Clinically Significant Vital Signs Values 
Parameter 
Unit 
Lower Criteria 
Upper Criteria 
Heart Rate 
bpm 
< 45 
>100 
>130 
Supine systolic blood pressure 
mm Hg 
< 80 
>155 
Supine diastolic blood pressure 
mmHg 
 
>100 
Standing systolic blood pressure 
mmHg 
<80 
>155 
Standing diastolic blood pressure 
mmHg 
 
>100 
Body temperature 
oC 
 
≥39.0 
 
 
 
 


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Appendix D. Conventions for Imputing Missing Dates 
1. Adverse event (AE) start (onset) date imputation 
AE start (onset) date is separated into 3 different data fields, including day, month, and year. 
Completely missing AE start date (i.e., missing day, missing month, and missing year) will not 
be imputed. Partial AE start date will be imputed according to treatment start date as follows in a 
sequential fashion. 
• If AE year is missing, then no imputation 
• If AE month and day are missing and 
‒ if AE year < Treatment year then AE month/day = ‘01JUL’ 
‒ if AE year = Treatment year then AE month/day = treatment start date+1 
‒ if AE year > Treatment year then AE month/day = ’01JAN’ 
• If AE day is missing and 
‒ if AE year < Treatment year then AE day = ‘15’ 
‒ if AE year = Treatment year and 
➢ if AE month < Treatment month then AE day = ‘15’ 
➢ if AE month = Treatment month then AE date = treatment start date+1 
➢ if AE month > Treatment month then AE day = ‘01’ 
‒ if AE year > Treatment year, then AE day = ‘01’ 
• If AE start date is still missing after the above imputation and AE end date is nonmissing 
then AE start date = AE end date. 
• If AE start date is still missing after the above imputation, then count this AE as a treatment-
emergent AE. 
2. Concomitant medication (CM) start and end date imputation 
The imputation of missing medication start and/or end dates is performed for the following 
reasons: 
• To determine if a medication is a prior medication or a concomitant medication. 
• To determine if treatment with the medication satisfies any of the medication-related 
exclusion criteria #18, #19, #20, #21, #22, #23, #24, #25, and #27 for subject eligibility.  
The medication start and end dates are separated into 3 different data fields, including day, 
month, and year. Completely missing medication start and/or end date (i.e., missing day, missing 
month, and missing year) will not be imputed. Partially missing medication start/end date will be 
imputed according to treatment start date. The rules on how to determine if a medication is a 
prior medication only or both prior and concomitant medication and to determine if subjects 
violated any protocol specified medication-related exclusion criteria are specified below.  
The prior and concomitant medications data listings will display all data as collected; imputed 
values will not be shown. 
• Medication Start Date Imputation 
a) If medication start year is missing, then no imputation 
b) If medication start year is reported while medication start month and day are missing, 
then medication start month/day = ‘01JAN’ 


Radius Health, Inc.  
25 August 2021 
Abaloparatide-SC  
Confidential 
 
Study BA058-05-019 SAP 
 
Page 50 of 51 
 
 
c) If medication start year and month are reported while medication start day is missing, 
then medication start day = ‘01’ 
• Medication End Date Imputation 
a) If medication start date and medication end date are completely missing; or medication 
end date is completely missing while medication start date is either a complete date or 
partially missing and the observed/imputed medication start date < treatment start date, 
then no imputation: 
• If Ongoing = Yes, the medication is considered to be both prior and concomitant 
medication 
• If Ongoing = No or missing, the medication is considered to be a prior medication 
only 
• Subject will be considered as violating the medication-related exclusion criteria if the 
medication is one of the prohibited medications according to the medication-related 
exclusion criteria. 
b) If medication start date is completely missing while medication end date is partially 
missing; or medication end date is partially missing while medication start date is either a 
complete date or partially missing and the observed/imputed medication start date < 
treatment start date, then the missing medication end date will be imputed as follows: 
 
MMM 
Missing 
MMM < TRT 
Month 
MMM = TRT 
Month 
MMM > TRT 
Month 
YYYY < TRT Year 
31DEC 
Last day of MMM 
Last day of MMM 
Last day of MMM 
YYYY = TRT Year 
TRTDT * 
Last day of MMM 
TRTDT * 
01MMM 
YYYY > TRT Year 
31JAN 
Last day of MMM 
Last day of MMM 
Last day of MMM 
              * If Ongoing = Yes, then no imputation.  
              Where: YYYY = Medication end year; MMM = Medication end month; TRT Year = Treatment start year; 
                          TRT Month = Treatment start month; and TRTDT = Treatment start date. 
• The observed and/or imputed medication end date will be used to determine if a 
medication is a prior medication only; or is both a prior and a concomitant 
medication. 
• If the medication is one of the prohibited medications according to the medication-
related exclusion criteria, the observed and/or imputed medication end date will also 
be used to determine if a subject meets any medication-related exclusion criteria. 
c) If the medication start date is either a complete date or partially missing with the 
observed/imputed medication start date >= treatment start date, then no imputation for 
medication end date, and: 
• The medication is considered to be a concomitant medication only.  
• Subject doesn’t meet any medication-related exclusion criteria.  
3. Other date imputations 
Any event with a partial date that requires imputation but has no specific imputation rule will be 
imputed as follows: 


Radius Health, Inc.  
25 August 2021 
Abaloparatide-SC  
Confidential 
 
Study BA058-05-019 SAP 
 
Page 51 of 51 
 
 
• If the day is missing, then impute the day as ‘01’ 
• If the month is missing, then impute the month as ‘JUL’ 
• If the imputation of a start date causes the start date to be post the non-missing end date, then 
the start date will be imputed as the end date. 
• If the imputation of a start date causes the start date to be prior to the start of treatment (but 
the event should happen post-baseline), then the start date will be imputed as “treatment start 
date + 1.” 
Any date cannot be imputed past the date of death. When this happens, the date will be imputed 
as the date of death. 
 


Signature Page for RAD-CLIN-002815 v1.0
Signature Page for RAD-CLIN-002815 v1.0
Approval
25-Aug-2021 13:52:49 GMT+0000
Approval
25-Aug-2021 14:24:02 GMT+0000
Approval
25-Aug-2021 14:28:48 GMT+0000