Clinical trial NCT03710889
Conditions: Osteoporosis, Postmenopausal Osteoporosis Osteoporosis Vertebral Osteoporosis Risk Osteoporosis Fracture Osteoporosis Localized to Spine Osteoporosis, Age-Related Osteoporosis Senile Osteoporosis of Vertebrae
Keywords: BA058 abaloparatide TYMLOS® Bone metabolism Osteoporosis Fracture Bone loss
Sponsor: Radius Health, Inc.
Start date: 2018-09-20; Completion date: 2020-07-15
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this study is to measure the early effects of abaloparatide on tissue-based bone formation using samples obtained by transiliac crest bone biopsy after quadruple fluorochrome labeling.

Detailed description:
This was an open-label, single-arm study of postmenopausal women with osteoporosis treated with 80 micrograms (μg) abaloparatide for 3 months. Transiliac bone biopsies were taken at 3 months after quadruple fluorochrome labeling. The treatment duration of 3 months was determined to be the optimal time when biochemical markers of bone turnover peak and are predictive of subsequent changes in bone mineral density (BMD).

The main study was conducted for a 3-month treatment period with a 1-month follow up. A sub-study was conducted at 1 site to collect peripheral quantitative computed tomography (pQCT) data. Study treatment for participants in the sub-study was extended for an additional 3 months of study drug administration for a total of 6 months of treatment.

Arms: arm 1: Participants self-administered a single daily dose of 80 micrograms (µg) of abaloparatide subcutaneously (SC) during the treatment period. Participants were instructed to use a new injection pen after each 30-day period.
Interventions: intervention 1: Abaloparatide
Intervention descriptions: intervention 1: Abaloparatide 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\[1-34\].

Protocol documents:
Prot_000.pdf: 
Radius Health, Inc. 
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Confidential 
Radius Health, Inc. (RADIUS) 
950 Winter Street, Waltham, MA 02451 USA 
Abaloparatide-SC 
CLINICAL STUDY PROTOCOL: BA058-05-020 
An Open-label, Single-arm, Multicenter Study to Evaluate the Early Effects of 
Abaloparatide on Tissue-based Indices of Bone Formation and Resorption 
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 
IND number 
73,176 
Version number: 
Amendment 2 - 05 November 2018 
Development phase: 
3 
Study Site: 
Multicenter 
Protocol Version History 
Version number 
Version date 
Original 
14 December 2017 
Amendment 1 
9 February 2018 
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 # NCT03710889


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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as 
required by the following: United States (US) Code of Federal Regulations (CFR) 
applicable to clinical studies (Title 21 CFR Part 11, 50, 54, 56, 312, and International 
Conference on Harmonization (ICH) GCP Guideline E6 (R2)): 
In addition, I have read the study protocol titled “An Open-label, Single-arm, Multicenter 
Study to Evaluate the Early Effects of Abaloparatide on Tissue-based Indices of Bone 
Formation and Resorption, amendment 2 dated 05 November2018, and agree to the 
following: 
• To conduct this study in accordance with the design and provisions of this 
protocol. 
• To await institutional review board (IRB) approval for the protocol and 
informed consent (IC) before initiating enrollment into the study. 
• 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 one 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 International Conference on 
Harmonisation (ICH), the Declaration of Helsinki, and applicable regulatory 
requirements. 
• To permit study-related monitoring, audits, IRB 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 for data collected during this 
study. 


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Signature of Principal Investigator 
Date 
 
 
 
 
 
 
 
 
 
Print Name 
Site Number 


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AMENDMENT 1 RATIONALE 
 
This amendment updates and supersedes BA058-05-020 Clinical Study Protocol dated 
14 December 2017 for all investigative sites. The key revisions are as follows: 
 
• Revised inclusion criteria for acceptable serum 25-hydroxyvitamin D values 
• Removed all references to the subject’s assessment of local tolerance after 
injection 
• Removed vitamin D and calcium dose requirement from Month 3 and Month 4 as 
shown in Table 1. 
• Added BMD assessment to Section 7.2.10 and to Table 1. 
• Removed references to and discussion of “incident” vertebral fractures in 
Section 7.7.2. This assessment tool will not be included in the protocol 
The protocol was updated to reflect these changes and to correct administrative and 
consistency errors. Full details of changes are presented in the “Protocol Amendment 1 
Summary of Changes”. 
 
AMENDMENT 2 RATIONALE 
This amendment updates and supersedes BA058-05-020 Amendment 1 Clinical Study 
Protocol dated 9 Feb 2018 for all investigative sites. The key revisions are as follows: 
• Calcium will be administered daily, with the exception of the days of 
administration of demeclocycline and tetracycline where calcium administration 
will be withheld. 
• 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 within 30 days of the original test date. If upon reanalysis, the values fall 
within the inclusion/exclusion criteria, the subject may enter the study. 
• Added calcium withholding days to Figure 1. 
The protocol was updated to reflect these changes and to correct administrative and 
consistency errors. Full details of changes are presented in the “Protocol Amendment 2 
Summary of Changes”. 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ................................................................................................. 2 
AMENDMENT 1 RATIONALE ..................................................................................................... 4 
AMENDMENT 2 RATIONALE ..................................................................................................... 4 
TABLE OF CONTENTS ................................................................................................................. 5 
LIST OF ABBREVIATIONS .......................................................................................................... 9 
1. 
PROTOCOL SYNOPSIS ........................................................................................... 12 
2. 
INTRODUCTION ...................................................................................................... 18 
2.1. 
Background ................................................................................................................. 18 
2.2. 
Disease and Study Background .................................................................................. 18 
2.3. 
Quadruple Label Technique ....................................................................................... 19 
2.4. 
Bone Histomorphometry Results from Study BA058-05-003 ................................... 20 
2.5. 
Study Rationale ........................................................................................................... 21 
2.6. 
Dose Rationale ............................................................................................................ 21 
3. 
STUDY OBJECTIVES AND ENDPOINTS.............................................................. 22 
3.1. 
Objectives ................................................................................................................... 22 
3.2. 
Endpoints .................................................................................................................... 22 
4. 
STUDY DESIGN ....................................................................................................... 23 
4.1. 
Description of the Study Design ................................................................................. 23 
5. 
SELECTION OF STUDY POPULATION ................................................................ 24 
5.1. 
Inclusion Criteria ........................................................................................................ 24 
5.2. 
Exclusion Criteria ....................................................................................................... 25 
5.3. 
Participant Withdrawal or Termination ...................................................................... 26 
5.3.1. 
Reasons for Withdrawal or Termination .................................................................... 26 
5.3.2. 
Handling of Participant Withdrawals or Terminations ............................................... 27 
5.4. 
Concomitant Medications ........................................................................................... 27 
5.5. 
Prohibited Medications ............................................................................................... 28 
5.6. 
Premature Termination or Suspension of Study ......................................................... 28 
5.7. 
Temporary Suspension of Treatment .......................................................................... 29 
5.7.1. 
Treatment Algorithm in Subjects Who Develop Hypercalcemia ............................... 29 
6. 
STUDY DRUG ADMINISTRATION AND MANAGEMENT................................ 30 


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6.1. 
Study Medication ........................................................................................................ 30 
6.1.1. 
Abaloparatide .............................................................................................................. 30 
6.2. 
Packaging, Labeling and Storage ............................................................................... 30 
6.2.1. 
Packaging and Labeling .............................................................................................. 30 
6.2.2. 
Storage ........................................................................................................................ 30 
6.3. 
Treatment Assignment ................................................................................................ 30 
6.4. 
Dosing and Administration ......................................................................................... 31 
6.5. 
Treatment Compliance ................................................................................................ 31 
6.6. 
Study Drug Accountability ......................................................................................... 32 
7. 
STUDY PROCEDURES AND SCHEDULE ............................................................ 33 
7.1. 
Study Procedures ........................................................................................................ 33 
7.2. 
Study Schedule ........................................................................................................... 33 
7.2.1. 
Schedule of Assessments and Procedures .................................................................. 33 
7.2.2. 
Informed Consent Process .......................................................................................... 37 
7.2.3. 
Assigning Subject Numbers ....................................................................................... 37 
7.2.4. 
Subject and Disease Characteristics ........................................................................... 37 
7.2.5. 
Screening (Visit 1) ...................................................................................................... 37 
7.2.6. 
Pretreatment (Visit 2) ................................................................................................. 38 
7.2.7. 
Treatment Period ........................................................................................................ 39 
7.2.8. 
Day 1 (Visit 3) ............................................................................................................ 39 
7.2.9. 
Month 1 (Visit 4) ........................................................................................................ 40 
7.2.10. 
Month 3/Early Termination (Visit 5) .......................................................................... 40 
7.2.11. 
Month 4 (Visit 6) ........................................................................................................ 41 
7.2.12. 
Unscheduled Visit ....................................................................................................... 41 
7.3. 
Vital Signs and Physical Examinations ...................................................................... 41 
7.4. 
12-Lead Electrocardiogram ........................................................................................ 42 
7.5. 
Laboratory Evaluations ............................................................................................... 42 
7.5.1. 
Clinical Laboratory Evaluations ................................................................................. 42 
7.5.2. 
Serum Markers of Bone Metabolism .......................................................................... 43 
7.5.3. 
Specimen Preparation, Handling and Storage ............................................................ 44 
7.6. 
Bone Biopsy Processing Procedure ............................................................................ 44 
7.7. 
Imaging Procedures .................................................................................................... 44 


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7.7.1. 
Dual Energy X-ray Absorptiometry (DXA) ............................................................... 44 
7.7.2. 
Clinical and Radiologic Evaluation of Fractures ........................................................ 44 
7.7.3. 
Treatment and Imaging at Selected Sites .................................................................... 45 
7.8. 
Discontinuation from the Study .................................................................................. 45 
7.8.1. 
Withdrawal of Consent ............................................................................................... 45 
7.8.2. 
Early Study Termination ............................................................................................. 46 
8. 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
DOCUMENTATION ................................................................................................. 47 
8.1. 
Evaluation of Safety ................................................................................................... 47 
8.1.1. 
Adverse Events ........................................................................................................... 47 
8.1.2. 
Serious Adverse Events .............................................................................................. 47 
8.1.3. 
Recording Adverse Events.......................................................................................... 48 
8.1.4. 
Serious Adverse Event (SAE) Reporting ................................................................... 50 
8.1.5. 
Follow-up of Adverse Events ..................................................................................... 50 
8.1.6. 
Abuse, Misuse, Overdose, or Medication Error ......................................................... 50 
8.1.7. 
Regulatory Agency, Institutional Review Board, Ethics Committee 
and Site Reporting ...................................................................................................... 51 
8.2. 
Study Completion and Post-Study Treatment ............................................................. 51 
8.3. 
Lost to Follow-up ....................................................................................................... 51 
9. 
STATISTICAL CONSIDERATIONS ....................................................................... 52 
9.1. 
Statistical Analysis Plan ............................................................................................. 52 
9.2. 
Statistical Hypothesis .................................................................................................. 52 
9.3. 
Analysis Datasets ........................................................................................................ 52 
9.3.1. 
Population for Analysis .............................................................................................. 52 
9.4. 
Description of Statistical Methods .............................................................................. 52 
9.4.1. 
General Approach ....................................................................................................... 52 
9.4.2. 
Analysis of the Primary Efficacy Endpoint(s) ............................................................ 52 
9.4.3. 
Analysis of Secondary Endpoint(s) ............................................................................ 52 
9.4.4. 
Safety Analyses........................................................................................................... 53 
9.4.5. 
Adherence and Retention Analyses ............................................................................ 53 
9.4.6. 
Baseline Descriptive Statistics .................................................................................... 54 
9.4.7. 
Interim Analyses ......................................................................................................... 54 
9.4.8. 
Tabulation of Individual Response Data .................................................................... 54 


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9.5. 
Sample Size Calculation ............................................................................................. 54 
9.6. 
Measures to Minimize Bias ........................................................................................ 54 
9.7. 
Enrollment/Randomization/Masking Procedures ....................................................... 54 
10. 
ADMINISTRATIVE REQUIREMENTS .................................................................. 55 
10.1. 
Ethical Considerations ................................................................................................ 55 
10.2. 
Subject Information and Informed Consent ............................................................... 55 
10.3. 
Investigator Compliance ............................................................................................. 55 
10.4. 
Access to Records ....................................................................................................... 56 
10.5. 
Subject Data Confidentiality ....................................................................................... 56 
10.6. 
Research Use of Stored Human Samples, Specimens, or Data .................................. 56 
10.7. 
Data Quality Assurance .............................................................................................. 57 
10.8. 
Monitoring .................................................................................................................. 57 
10.9. 
Data Collection and Management Responsibilities .................................................... 57 
10.10. 
Study Records Retention ............................................................................................ 58 
10.11. 
Publication and Data Sharing Policy .......................................................................... 58 
REFERENCES .............................................................................................................................. 59 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments and Procedures .................................................................. 34 
Table 2: 
Clinical Laboratory Tests............................................................................................ 43 
 
 
LIST OF FIGURES 
Figure 1: 
BA058-05-020 Study Design, Including Schematic of Bone Biopsy 
Labeling Procedure ..................................................................................................... 23 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
 
°C 
Degree Celsius 
°F 
Degree Fahrenheit 
µg 
Microgram 
µL 
Microliter 
µmol 
Micromole 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AP 
Anterior posterior 
AST 
Aspartate aminotransferase 
BFR/BS 
Bone formation rate 
BMD 
Bone mineral density 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
cAMP 
Cyclic adenosine monophosphate 
Cm 
Centimeter 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRO 
Contract research organization 
Ct.Po/Ct.Ar 
Cortical porosity 
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 
EDC 
Electronic data capture 
ES/BS 
Eroded surface 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GMP 
Good Manufacturing Practice 
HIV 
Human immunodeficiency virus infection 
IB 
Investigator's Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 


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Abbreviation 
Term 
 
IU 
International unit 
IV 
Intravenous 
kg 
Kilogram 
L 
Liter 
LDH 
Lactate dehydrogenase 
MAR 
Mineral apposition rate 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
MF/BS 
Modeling-based formation 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
MS/BS 
Mineralizing surface 
ng 
Nanogram 
oMF/BS 
Overflow modeling-based formation 
OS/BS 
Osteoid surface 
O.Th 
Osteoid thickness 
OV/BV 
Osteoid volume 
PA 
Posterior-anterior 
PI 
Principal Investigator 
s-PINP 
Serum procollagen type I N propeptide 
pQCT 
Peripheral quantitative computed tomography 
RANK 
Receptor activator of nuclear factor kappa-B 
RBC 
Red blood cell 
RmF/BS 
Remodeling-based formation 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SERMs 
Selective estrogen receptor modulators 
SOC 
System organ class 
SOP 
Standard operating procedure 
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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Abbreviation 
Term 
 
W.Th 
Wall thickness 


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1. 
PROTOCOL SYNOPSIS 
 
Name of Sponsor/Company: 
Radius Health, Inc. (RADIUS) 
Name of Investigational Product: 
Abaloparatide-SC 
Name of Active Ingredient: 
abaloparatide 
Title of Study: 
An Open-label, Single-arm, Multicenter Study to Evaluate the Early Effects of Abaloparatide 
on Tissue-based Indices of Bone Formation and Resorption 
Study center(s): Approximately 5 in the United States 
Studied period (years): 
Estimated date first subject enrolled: April 2018 
Estimated date last subject completed: January 2019 
Phase of development: 3 
Objectives: 
The objectives of this study are to: 
1. Demonstrate the early effects of abaloparatide on tissue-based bone formation and 
resorption indices 
2. Assess the degree to which increased bone formation is achieved by modeling, 
remodeling, and overflow bone formation 
3. Relate the early indices of tissue-based bone formation and bone resorption to those 
measured using biochemical markers of bone turnover. 
Endpoints: 
• 
Change from baseline to 3 months in dynamic indices of bone formation in the 
relevant bone envelopes (cancellous, endocortical, intracortical, and periosteal) 
− 
Mineralizing surface (MS/BS) 
− 
Mineral apposition rate (MAR) 
− 
Bone formation rate (BFR/BS) 
• 
Structural indices in the relevant bone envelopes at Month 3 
− 
Cortical porosity (Ct.Po/Ct.Ar) 
• 
Static indices in the relevant bone envelopes at Month 3 
− 
Osteoid volume (OV/BV) 
− 
Osteoid surface (OS/BS) 


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− 
Osteoid thickness (O.Th) 
− 
Wall thickness (W.Th) 
− 
Eroded surface (ES/BS) 
• 
Change from baseline to 3 months in special histomorphometric variables in the 
relevant bone envelopes 
− 
Remodeling, modeling, and overflow modeling-based formation (RmF/BS, 
MF/BS, oMF/BS) 
• 
Change in serum procollagen type I N-terminal propeptide (s-PINP) and carboxy- 
terminal cross-linking telopeptide of type I collagen (s-CTX) from baseline to 1 and 3 
months 
• 
Correlations of tissue-based indices of bone formation and bone resorption with s- 
PINP and s-CTX 
• 
Overall safety and tolerability of abaloparatide in postmenopausal women with 
osteoporosis. 
Methodology: 
This is an open-label, single-arm, multicenter study of postmenopausal women with 
osteoporosis. The study is designed to measure the early effects of abaloparatide on 
tissue-based bone formation using samples obtained by iliac crest bone biopsy after quadruple 
fluorochrome labeling. The study will consist of a Screening Period (up to 1 month), a 
Pretreatment Period (approximately 1 month), a Treatment Period (3 months), and a Month 4 
visit one month after the last dose of study medication. Biopsies are to be obtained at 3 
months of treatment for the following reasons: 
• 
This is the optimal time for changes in biochemical markers of bone turnover to 
predict changes in BMD after 18 months of treatment with abaloparatide (Radius, 
data on file). 
• 
Longer periods of time increase the risk that the initial set of labels will be 
resorbed, which would seriously confound the results. 
• 
Comparisons to the 3-month results for teriparatide from the AVA Osteoporosis 
Study will be possible. 
There will be a sub-study at selected sites to collect pQCT data and extend an additional 
3 months of study drug administration for a total of 6 months of treatment. 
Details of the schedule of measurements, endpoints and statistical analysis methods will be 
described in a separate document for the sub-study. 
Number of subjects (planned): 
Approximately 25 


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Diagnosis and main criteria for inclusion: 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible to participate in this study: 
1. The subject is a healthy ambulatory postmenopausal female from 50 to 85 years of 
age (inclusive) with osteoporosis. 
2. The subject has been postmenopausal for at least 5 years. Postmenopausal status will 
be established by a history of amenorrhea for at least 5 years and by an elevated 
follicle-stimulating hormone (FSH) value of > 30 IU/L. 
3. The subject has a BMD T-score ≤ -2.5 at the lumbar spine (L1-L4) or hip (femoral 
neck or total hip) by Dual energy X-ray absorptiometry (DXA) or lumbar spine or 
hip BMD T-score < -2.0 with a history of low trauma vertebral, forearm, humerus, 
sacral, pelvic, hip, femoral, or tibial fracture sustained within 5 years prior to 
enrollment. These fractures must be documented by radiograph or hospital report. 
4. The subject is in good general health as determined by medical history and physical 
examination (including vital signs), has a body mass index (BMI) of 18.5 to 33, 
inclusive, and is without evidence of clinically significant abnormality in the opinion 
of the Investigator. 
5. The subject has serum calcium (albumin-corrected), PTH (1-84), phosphorus, and 
alkaline phosphatase levels all within the normal range during the Screening Period. 
Any subject with an elevated alkaline phosphatase value, and who meets all other 
entry criteria, is required to have a normal bone-specific alkaline phosphatase result 
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 D3 and re-tested once. 
7. The subject’s resting 12-lead electrocardiogram (ECG) obtained during screening 
shows no clinically significant abnormality. 
8. The subject has read, understood, and signed the written informed consent form. 
Exclusion Criteria 
Subjects with any of the following characteristics are not eligible to participate in the study: 
General exclusion criteria. 
1. Presence of abnormalities of the lumbar spine that would prohibit assessment of 
lumbar spine BMD, defined as having at least 2 radiologically evaluable vertebrae 
within L1-L4. 
2. Unevaluable hip BMD or subjects who have undergone bilateral hip replacement 
(unilateral hip replacement is acceptable). 
3. History of bone disorders (eg, Paget’s disease) other than postmenopausal 
osteoporosis. 


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4. Clinically significant abnormality of serum hemoglobin, hematocrit, white blood 
cells (WBC) and platelets, coagulation, or usual serum chemistry: electrolytes, renal 
function, liver function and serum proteins 
5. Unexplained elevation of serum alkaline phosphatase. 
6. History of radiotherapy (radiation therapy), other than radioiodine. 
7. History of bleeding disorder that would preclude a bone biopsy, in the opinion of the 
Investigator. 
8. 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. 
9. History of Cushing’s disease, hyperthyroidism, hypo- or hyperparathyroidism, or 
malabsorptive syndromes within the past year. 
10. 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 ≥ 30 mL/min. 
11. History of any cancer within the past 5 years (other than basal cell or squamous 
cancer of the skin). 
12. History of osteosarcoma at any time, or a history of hereditary disorders which would 
predispose the subject to osteosarcoma. 
13. History of nephrolithiasis or urolithiasis within the past five years. 
14. Subjects known to be positive for hepatitis B, hepatitis C, human immunodeficiency 
virus infection (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 
15. Known history of hypersensitivity to any of the test materials, related compounds, or 
tetracyclines. 
16. Prior treatment with PTH or PTHrP drugs, including abaloparatide. 
17. Prior treatment with IV bisphosphonates at any time, or oral bisphosphonates within 
the past three 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. 
18. Treatment with fluoride or strontium in the five years prior to the Screening Period or 
prior treatment with gallium nitrate, or with any unapproved bone-acting 
investigational agents at any time. 
19. Treatment with calcitonin, SERMs (such as raloxifene or tamoxifen), or tibolone, in 
the past 6 months prior to the Screening Period. Estrogens administered as hormone 


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replacement therapy with or without progestins are not exclusionary. 
20. 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. 
21. Prior treatment with denosumab. 
22. Daily treatment with oral, intranasal or inhaled corticosteroids within the 12 months 
prior to the Screening Period. Occasional use of corticosteroids (for seasonal allergies 
or asthma) is not exclusionary. 
23. Prior treatment with anabolic steroids or calcineurin inhibitors (cyclosporin, 
tacrolimus). 
24. Exposure to an investigational drug within the 12 months prior to the Screening 
Period. 
Lifestyle-related exclusion criteria 
25. Abnormal nutritional status (abnormal diets, excessive or unusual vitamin or herbal 
intakes, malabsorption, significant recent weight change), vitamin D intake of 
≥ 4,000 IU/day or vitamin A intake of ≥ 10,000 IU/day. 
26. Subject is known to abuse alcohol or use illegal drugs within 12 months of the 
Screening Period. 
Investigational product, dosage and mode of administration: 
Abaloparatide 80 µg for subcutaneous injection 
Duration of treatment: 
3 months; 6 months at selected sites in the sub-study 
Reference therapy, dosage and mode of administration: 
Not applicable 
Duration of Subject Participation 
Participation will be up to 6 months (3 months total treatment duration; 6 months total 
treatment for subjects at selected sites in the sub-study). 
Statistical methods: 
Subject demographics and baseline characteristics will be summarized using descriptive 
statistics. 
Sample size 
A sample size of 21 completers will provide at least 90% power to detect a statistically 
significant change from baseline in cancellous MS/BS (%) for abaloparatide at 3 months of 
9.2%, assuming a standard deviation of 12.0%. The study is planned to enroll approximately 
25 subjects to accommodate a drop-out rate of 15%, including those with non-evaluable bone 
biopsy. Additional subjects may be enrolled if the number of evaluable biopsies is insufficient 
to achieve this power. 
Analysis population 
The primary population for all efficacy analyses will be the Bone-Biopsy Population, which 


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is defined as all enrolled subjects who received a biopsy. The primary population for all 
safety analyses will be the Safety Population, which will be defined as all enrolled subjects 
who received at least one dose of abaloparatide. 
Efficacy analysis 
The primary endpoint of this study is the change from baseline to 3 months in mineralizing 
surface (MS/BS) in the cancellous bone envelope. Paired t-tests will be used to compare the 
differences in dynamic indices between the two time-points derived from the two sets of 
double labels using the Bone-Biopsy Population. If the normality assumption of efficacy 
variable is not satisfied at the 0.01 significance level and if visual inspection of the data 
deems it necessary, an appropriate nonparametric test, such as the Wilcoxon signed-rank test, 
will be used to evaluate the primary endpoint. No adjustments for multiplicity will be made. 
A p-value < 0.05 will be considered statistically significant. 
The change and percent change in s-PINP and s-CTX from baseline will be summarized 
descriptively. The relationship between bone turnover markers and histomorphometric 
parameters will be explored using the linear regression method. 
Safety 
Safety analyses will be descriptive in nature and will include incidence and severity of 
adverse events and abnormalities in clinical laboratory tests, vital signs, ECGs, and 
Investigator assessment of local tolerance. All adverse events prior to the first dose of 
abaloparatide will be summarized separately. 


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2. 
INTRODUCTION 
2.1. 
Background 
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]. Abaloparatide is 
differentiated from PTH and PTHrP ligands based on its high affinity and > 1000-fold 
greater selectivity for the G protein-coupled (RG) vs the non-G protein-coupled (R0) 
conformation of PTHR1 (Hattersley, 2016). Differential PTHR1-RG binding with 
abaloparatide results in potent and transient intracellular cyclic AMP (cAMP) signaling. 
In nonclinical studies, the transient PTHR1 activation with abaloparatide strongly favors 
bone anabolism with a limited effect on bone resorption (Makino, 2015). 
Abaloparatide is approved in the United States for the treatment of postmenopausal 
women with osteoporosis at high risk for fracture. Abaloparatide was shown in Study 
BA058-05-003 (ACTIVE) to reduce the risk of vertebral and nonvertebral fractures 
compared to placebo, and to increase hip BMD more than teriparatide (Miller, 2016). 
 
2.2. 
Disease and Study 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, 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 United States (US), there are 
an estimated 2 million osteoporotic fractures annually (Litwic, 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). 
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, 2017), or the monoclonal antibody, denosumab, that inhibits the 
action of osteoclasts by binding to the 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. Teriparatide has delayed and modest effects on increasing 
BMD at the total hip and femoral neck, and on decreasing BMD at the distal 1/3 radius. 


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The increase in cortical porosity that can occur may result in maladaptive effects on 
cortical bone microarchitecture (Bilezikian, 2007). 
The short-term anabolic effects of teriparatide have been demonstrated in 
histomorphometric analyses of a single transiliac crest bone biopsy after administration 
of two sets of tetracycline labels (quadruple labeling) (Lindsay, 2006). One month of 
treatment stimulated bone formation on cancellous and endocortical surfaces by both 
modeling-based and remodeling-based formation. Likewise, the same technique 
demonstrated stimulation of bone formation after 3 months of treatment with teriparatide, 
but inhibition of bone formation in subjects treated with the antiresorptive agent, 
denosumab (Dempster, 2016, AVA Osteoporosis Study). In this study, early stimulation 
of bone formation by teriparatide was observed in cancellous, endocortical, intracortical 
and periosteal envelopes. The stimulation of bone formation was due to an increase in 
remodeling-based formation (27%), overflow modeling-based formation (9%), and 
modeling-based formation (6%) (Dempster, 2017). 
The effects of abaloparatide on bone histomorphometry were recently reported in a subset 
of subjects in the ACTIVE trial (Moreira, 2017). Biopsies were obtained at 12 to18 
months (average 15.5 months) from subjects treated with either abaloparatide, 
teriparatide, or placebo. Few differences were detected among the three treatments, likely 
due to the fact that only cancellous bone was studied, as well as the late timing of the 
biopsies when the effects of the anabolic agents were declining. 
2.3. 
Quadruple Label Technique 
The purpose of this study is to assess the early effects of abaloparatide in postmenopausal 
women with osteoporosis using tissue-based indices of bone metabolism and to relate 
these indices to biochemical markers of bone turnover. All four bone envelopes 
(cancellous, endocortical, intracortical, and periosteal) will be examined in iliac crest 
biopsies after fluorochrome labeling. The quadruple labeling technique has previously 
been described by Lindsay (Lindsay, 2006). 
As noted above, this novel labeling technique has been found to be highly effective in 
two studies demonstrating the early effects of anabolic therapy with PTH (1-34) on bone 
formation in subjects with osteoporosis. It has also been used successfully to investigate 
the early effects of PTH (1-84) replacement in subjects with hypoparathyroidism 
(Rubin, 2011). Recently, a quadruple label protocol proved to be particularly useful in 
elucidating the mechanism of action of the sclerostin antibody, romosozumab, in the 
treatment of osteoporosis (Chavassieux, 2017). In quadruple-labeled biopsies taken at 
two months, the bone formation rate was dramatically increased compared to 
pretreatment levels. However, in biopsies taken at 12 months with conventional 
double-labeling, bone formation rate was reduced compared to placebo treatment. If the 
quadruple-labeling protocol had not been employed, it would have been difficult to 
explain the large increments in bone mineral density, cancellous bone volume, trabecular 
connectivity, and cortical thickness achieved by romosozumab treatment. The principal 
advantage of the technique is that it allows measurement of dynamic bone formation 
variables before and after initiation of a drug treatment in a single biopsy. This eliminates 
the side-to-side variability in the traditional paired biopsy study design and, in any case, 


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such a design is not practical to study early effects (within 3 months) of drug 
administration. In the quadruple labeling technique, two different fluorochromes 
(demeclocycline HCl and tetracycline HCl) are used for the pre-treatment and 
on-treatment labels. The difference in color of each fluorochrome allows any label to be 
unambiguously identified as a pre-treatment or on-treatment label, even if only one set of 
labels is present in a particular forming osteon. 
To prepare for biopsy, subjects will be given two sets of fluorochrome labels in the 
following way. The first set of labels will be given to all subjects in standard format: 3 
days of demeclocycline HCl (150 mg, four times per day), a 12-day intermission, and 3 
more days of demeclocycline (same dose). After the first set of labels has been 
administered, daily administration of 80 µg abaloparatide will commence. This treatment 
will be continued during administration of the second set of labels and until the day of 
biopsy. Approximately 23-26 days before the Month 3 visit, a second set of double labels 
will be administered following the same schedule, but this time using tetracycline HCl 
(250 mg, four times daily for 3 days on, 12 days off, 3 days on). 
Standard transiliac crest bone biopsies will be performed 5 to 8 days after the last day of 
tetracycline administration following standard procedures (See Section 7.2.10). The 
biopsies will be embedded in methyl methacrylate and prepared in a standard fashion for 
histomorphometric analysis. Serial sections from each subject will be examined under 
UV light for evaluation of tetracycline labels and under polarized light after staining with 
toluidine blue for evaluation of reversal and cement lines. 
Using two sets of fluorochrome labels, which differ in their color under fluorescent light 
enables one to distinguish the first and second sets of labels, even when only single labels 
are present. Using standard histomorphometry, mineral apposition rate and mineralizing 
surface can be measured for the two separate labeling periods, and bone formation rates 
can be calculated. The technique has two key advantages over paired biopsies. First, only 
one biopsy is required. Second, each subject serves as his or her own pretreatment 
control, eliminating problems caused by the large intersubject variability in 
histomorphometric variables. 
2.4. 
Bone Histomorphometry Results from Study BA058-05-003 
In Study BA058-05-003, a subset of subjects at selected centers was asked to undergo a 
bone biopsy (Moreira, 2017). Biopsies were obtained after the subjects had received 
between 12 and 18 months of treatment and were obtained primarily to assess safety. 
Qualitative histological analysis of biopsies from abaloparatide-treated subjects revealed 
normal bone microarchitecture without evidence of adverse effects on mineralization or 
on the formation of normal lamellar bone. There were no bone marrow abnormalities or 
marrow fibrosis, nor was there presence of excess osteoid or woven bone. There were 
few significant differences among the three treatment groups in a standard panel of static 
and dynamic histomorphometric indices. The mineral apposition rate was higher in the 
teriparatide-treated group than in the placebo-treated group. The eroded surface was 
lower in the abaloparatide-treated group than in the placebo-treated group. Cortical 
porosity was higher in both the abaloparatide- and the teriparatide-treated groups than in 
the placebo-treated group. 


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2.5. 
Study Rationale 
The purpose of this study is to assess the early effects of abaloparatide in postmenopausal 
women with osteoporosis using tissue-based indices of bone metabolism obtained by iliac 
crest bone biopsy after quadruple tetracycline labeling and to relate these indices to 
biochemical markers of bone turnover. All four bone envelopes (cancellous, endocortical, 
intracortical, and periosteal) will be examined. 
2.6. 
Dose Rationale 
The approved dose of abaloparatide in the US for the treatment of postmenopausal 
women at a risk for fracture is 80 µg per day. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
1. Demonstrate the early effects of abaloparatide on tissue-based indices of bone 
formation and resorption 
2. Assess the degree to which increased bone formation is achieved by modeling, 
remodeling, and overflow bone formation 
3. Relate the early indices of tissue-based bone formation and bone resorption to 
those measured using biochemical markers of bone turnover 
 
3.2. 
Endpoints 
• Change from baseline to 3 months in dynamic indices of bone formation in 
the relevant bone envelopes (cancellous, endocortical, intracortical, and 
periosteal) 
− Mineralizing surface (MS/BS) 
− Mineral apposition rate (MAR) 
− Bone formation rate (BFR/BS) 
• Structural indices in the relevant bone envelopes at Month 3 
− Cortical porosity (Ct.Po/Ct.Ar) 
• Static indices in the relevant bone envelopes at Month 3 
− Osteoid volume (OV/BV) 
− Osteoid surface (OS/BS) 
− Osteoid thickness (O.Th) 
− Wall thickness (W.Th) 
− Eroded surface (ES/BS) 
• Change from baseline to 3 months in special histomorphometric variables in 
the relevant bone envelopes 
− Remodeling, modeling, and overflow modeling-based formation 
(RmF/BS, MF/BS, oMF/BS) 
• Change in serum procollagen type I N-terminal propeptide (s-PINP) and 
carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX) from 
baseline to 1 and 3 months 
• Correlations of tissue-based indices of bone formation and bone resorption 
with s-PINP and s-CTX 
• Overall safety and tolerability of abaloparatide in postmenopausal women 
with osteoporosis. 


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4. 
STUDY DESIGN 
4.1. 
Description of the Study Design 
This is an open-label, single-arm, multicenter study enrolling approximately 25 
postmenopausal women with osteoporosis at approximately 5 study centers. The study is 
designed to measure the early effects of abaloparatide on tissue-based bone formation and 
resorption variables based on samples obtained by iliac crest bone biopsy after 
fluorochrome labeling. The study will consist of a Screening Period (up to 1 month), a 
Pretreatment Period (approximately 1 month), a Treatment Period (3 months), and a 
Month 4 visit one month after the last dose of study medication. Biopsies are to be 
obtained at 3 months of treatment for the following reasons: 
• This is the optimal time for changes in biochemical markers of bone turnover 
to predict changes in BMD after 18 months of treatment with abaloparatide 
(Radius, Data on file) 
• Longer periods of time increase the risk that the initial set of labels will be 
resorbed, which would seriously confound the results 
• Comparisons to the 3-month results for teriparatide from the AVA 
Osteoporosis Study will be possible (Dempster, 2016) 
Figure 1: 
BA058-05-020 Study Design, Including Schematic of Bone Biopsy 
Labeling Procedure 
 


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Full details of the protocol required assessments can be found in the Schedule of 
Assessments and Procedures (Section 7.2.1). 
There will be a sub-study at selected sites to collect pQCT data and extend an additional 
3 months of study drug administration for a total of 6 months of treatment. 
Details of the schedule of measurements, endpoints and statistical analysis methods for 
the sub-study will be described in a separate document. 
 
5. 
SELECTION OF STUDY POPULATION 
5.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible to participate in this study: 
1. The subject is a healthy ambulatory postmenopausal female from 50 to 85 years 
of age (inclusive) with osteoporosis. 
2. The subject has been postmenopausal for at least 5 years. Postmenopausal status 
will be established by a history of amenorrhea for at least 5 years and by an 
elevated follicle-stimulating hormone (FSH) value of ≥ 30 IU/L. 
3. The subject has a BMD T-score ≤ -2.5 at the lumbar spine (L1-L4) or hip 
(femoral neck or total hip) by DXA or lumbar spine or hip BMD T-score ≤ -2.0 
with a history of low trauma vertebral, forearm, humerus, sacral, pelvic, hip, 
femoral, or tibial fracture sustained within 5 years prior to enrollment. These 
fractures must be documented by radiograph or hospital report. 
4. The subject is in good general health as determined by medical history and 
physical examination (including vital signs), has a body mass index (BMI) of 18.5 
to 33, inclusive, and is without evidence of clinically significant abnormality in 
the opinion of the Investigator. 
5. The subject has serum calcium (albumin-corrected), PTH (1-84), phosphorus, and 
alkaline phosphatase levels all within the normal range during the Screening 
Period. Any subject with an elevated alkaline phosphatase value, and who meets 
all other entry criteria, is required to have a normal bone-specific alkaline 
phosphatase result 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 D3 and re-tested once. 
7. The subject’s resting 12-lead electrocardiogram (ECG) obtained during screening 
shows no clinically significant abnormality. 
8. The subject has read, understood, and signed the written informed consent form. 


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5.2. 
Exclusion Criteria 
Subjects with any of the following characteristics are not eligible to participate in the 
study: 
General exclusion criteria 
1. Presence of abnormalities of the lumbar spine that would prohibit assessment of 
lumbar spine BMD, defined as having at least 2 radiologically evaluable vertebrae 
within L1-L4. 
2. Unevaluable hip BMD or subjects who have undergone bilateral hip replacement 
(unilateral hip replacement is acceptable). 
3. History of bone disorders (eg, Paget’s disease) other than postmenopausal 
osteoporosis. 
4. Clinically significant abnormality of serum hemoglobin, hematocrit, white blood 
cells (WBC) and platelets, coagulation, or usual serum chemistry: electrolytes, 
renal function, liver function and serum proteins. 
5. Unexplained elevation of serum alkaline phosphatase. 
6. History of radiotherapy (radiation therapy), other than radioiodine. 
7. History of bleeding disorder that would preclude a bone biopsy, in the opinion of 
the Investigator. 
8. 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. 
9. History of Cushing’s disease, hyperthyroidism, hypo- or hyperparathyroidism, or 
malabsorptive syndromes within the past year. 
10. 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 ≥ 30 mL/min. 
11. History of any cancer within the past 5 years (other than basal cell or squamous 
cell cancer of the skin). 
12. History of osteosarcoma at any time or a history of hereditary disorders which 
could predispose the subject to osteosarcoma. 
13. History of nephrolithiasis or urolithiasis within the past five years. 
14. Subjects known to be positive for hepatitis B, hepatitis C, human 
immunodeficiency virus infection (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 


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15. Known history of hypersensitivity to any of the test materials, related compounds, 
or tetracyclines. 
16. Prior treatment with PTH or PTHrP drugs, including abaloparatide. 
17. Prior treatment with IV bisphosphonates at any time or oral bisphosphonates 
within the past three 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. 
18. Treatment with fluoride or strontium in the five years prior to the Screening 
Period, or prior treatment with gallium nitrate, or with any unapproved 
bone-acting investigational agents at any time. 
19. Treatment with calcitonin, SERMs (such as raloxifene or tamoxifen), or tibolone, 
within the 6 months prior to the Screening Period. Estrogens administered as 
hormone replacement therapy with or without progestins are not exclusionary. 
20. 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. 
21. Prior treatment with denosumab. 
22. Daily treatment with oral, intranasal or inhaled corticosteroids within the 12 
months prior to the Screening Period. Occasional use of corticosteroids (for 
seasonal allergies or asthma) is not exclusionary. 
23. Prior treatment with anabolic steroids or calcineurin inhibitors (cyclosporin, 
tacrolimus). 
24. Exposure to an investigational drug within the 12 months prior to the Screening 
Period. 
Lifestyle-related exclusion criteria 
25. Abnormal nutritional status (abnormal diets, excessive or unusual vitamin or 
herbal intakes, malabsorption, significant recent weight change), vitamin D intake 
of ≥ 4,000 IU/day or vitamin A intake of ≥ 10,000 IU/day. 
26. Subject is known to abuse alcohol or use illegal drugs within 12 months of the 
Screening Period. 
 
5.3. 
Participant Withdrawal or Termination 
5.3.1. 
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: 
• Hypercalcemia as described in Section 5.7.1; 
• Severe hypersensitivity to abaloparatide; 


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• 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 adverse events (as described in Section 8.1.2); 
• A complex of adverse events which, in the judgment of the Investigator, 
justifies treatment cessation; 
• Serious intercurrent illness; 
• Non-compliance; 
• Protocol violations; 
• 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 
Should a subject who experiences a clinical vertebral or nonvertebral fragility fracture 
choose to remain in the study, she will be asked to sign an additional Informed Consent 
Form further explaining the potential risks and benefits of remaining in the study. 
 
5.3.2. 
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 case report form. All 
subjects withdrawn prior to completing the study should be encouraged to complete study 
procedures scheduled for the Month 3/Early Termination visit and to return in one month 
for a follow-up visit. The Sponsor Medical Monitor will decide if the tetracycline 
labeling procedure and bone biopsy will be performed as part of the Early Termination 
visit. All adverse events should be followed as described in Section 8. Subjects who 
discontinue or are withdrawn from the study may be replaced. 
 
5.4. 
Concomitant Medications 
Vitamin D supplements are required to be administered daily from the Pretreatment 
Period until the end of the Treatment Period. Calcium will also be administered daily, 
with the exception of the days of administration of demeclocycline and tetracycline 
where calcium administration will be withheld. The doses and schedule of calcium and 
vitamin D supplements (Section 7.2.5) 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. Calcium (500–1000 mg) and 
vitamin D (400–800 IU) supplements will be sourced locally by the site and provided to 
the subjects at the expense of the Sponsor. 


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Two different fluorochromes (demeclocycline HCl and tetracycline HCl) are used for the 
pre-treatment and on-treatment labels. Instructions for administration of fluorochromes is 
detailed in Section 7.2.6 and Section 7.2.9. 
For any required concomitant medication, such as statins or antihypertensives, the subject 
must be on a stable dose at study entry and every effort should be made to maintain a 
stable dose during study participation. 
The occasional use of over-the-counter medications at approved doses (eg, ibuprofen or 
acetaminophen) for headache or minor discomfort is allowed. These are to be recorded on 
the appropriate eCRF. 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 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. 
 
5.5. 
Prohibited Medications 
Please refer to Section 5.2 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 5.4, 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 (≤ 1 week) use of inhaled 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. 
 
5.6. 
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) 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 


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The study may resume once concerns about safety, protocol compliance, or data quality 
are addressed and satisfy the Sponsor, IRB, and/or Regulatory Agencies, if applicable. 
 
5.7. 
Temporary Suspension of Treatment 
The Investigator has the right to suspend treatment with study medication for up to 7 
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 (eg, a planned procedure), or important social or administrative events. The reason 
for the suspension of treatment is to be documented in the eCRF and in source 
documents. 
When treatment is restarted, the subject should resume treatment with the next scheduled 
dose and continue until the scheduled End-of-Treatment. 
Subjects who develop hypercalcemia during the study are to have treatment with calcium 
and vitamin D temporarily suspended as described below. 
 
5.7.1. 
Treatment Algorithm in Subjects Who Develop Hypercalcemia 
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 upper limit of normal (ULN) 
(inclusive), the Investigator will confirm hypercalcemia by drawing a new serum sample 
as soon as possible after the result is received. 
If a subject’s predose serum calcium is elevated on repeated testing, calcium and vitamin 
D supplementation should be withheld. If the subject’s serum calcium remains elevated 1 
to 2 weeks after calcium and vitamin D supplementation is withheld, dosing of study 
medication should be stopped. Treatment can be restarted if other causes of 
hypercalcemia are excluded after consultation with the Sponsor. Treatment with study 
medication should not be suspended for greater than 7 days. 


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6. 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
6.1. 
Study Medication 
6.1.1. 
Abaloparatide 
Abaloparatide 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 mcg/1.56 mL. 
Additional information will be provided to clinical sites in a separate Pharmacy Manual 
including instructions on how to use the injection pen. 
 
6.2. 
Packaging, Labeling and Storage 
6.2.1. 
Packaging and Labeling 
Abaloparatide will be supplied and packaged as injection pens. All packaging operations 
will be performed in accordance with Good Manufacturing Practices (GMP). 
All Investigational Product (IP) will be supplied to study sites packaged and labeled 
according to local regulations with a statement that all IP is limited to investigational use 
only. A detailed study drug dispensation plan will be provided in the Pharmacy Manual. 
 
6.2.2. 
Storage 
While at the clinical site, abaloparatide injection pens must be stored in a secure, limited 
access, temperature monitored refrigerator at 2°C to 8°C (36°F to 46°F) until dispensed 
for use to a study subject or until returned to the Sponsor. 
After the abaloparatide injection pen is used for the first time, the pen may be stored for 
30 days at room temperature, 20°C to 25°C (68°F to 77°F). Unused pens should be 
refrigerated until use. Instructions regarding the storage and handling of the study drug 
after dispensation to subjects will be provided to sites in the Pharmacy manual. 
6.3. 
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 on the 
eCRFs. Subject numbers will be assigned as follows: 
XXX YYY, where: 
• XXX represents the study site number; 
• YYY represents the subject ID number 


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6.4. 
Dosing and Administration 
Subjects will self-administer a single daily dose of 80 µg of study medication 
(abaloparatide) 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 
procedures. Study personnel may administer the study medication during clinic visits. 
Subjects will be trained by study personnel during the Pretreatment Period how to 
self-inject study medication with the abaloparatide injection pen. If a subject requires 
assistance with study medication administration, an individual (eg, 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 
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 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 of the abdomen, rotating the site of 
injection each day, and administered at approximately the same time every 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 position for approximately 5 
minutes. The subject is to remain under observation for a minimum of 60 minutes after 
the initial injection. A blood pressure measurement will be taken 60 minutes after the 
injection. Subjects are to be instructed to self-inject at home in a location where they have 
the ability to sit or lie down. 
Subjects will be instructed to use a new pen after each 30-day period. At each clinic visit 
during the Treatment Period, the used abaloparatide injection pens should be returned. 
Compliance, adverse events, and use of concomitant medications should be reviewed 
upon drug re-supply and documented accordingly in the drug accountability log and 
eCRF. 
 
6.5. 
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 two 
methods: subject diaries and measuring residual drug in the cartridge. 


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Discrepancies between expected and actual dosing will be assessed and discussed with 
the subject. All discrepancies, causes and subject retraining will be documented in the 
medical charts, and recorded in the eCRF as appropriate. If a subject does not take all 
study medication (abaloparatide) as required, the reason for the missed dose is to be 
discussed with the subject during the visit. 
Although calcium and vitamin D are considered concomitant medications for this study, 
missed doses of calcium and vitamin D will be determined by performing a pill count. If 
a subject demonstrates continued noncompliance with required abaloparatide dosing 
despite educational efforts, the Investigator should contact the Sponsor Medical Monitor 
to discuss discontinuation of the subject from the Study. 
6.6. 
Study 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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7. 
STUDY PROCEDURES AND SCHEDULE 
7.1. 
Study Procedures 
The study-specific assessments are detailed in this section and outlined in Table 1. Any 
results falling outside of the reference ranges may be repeated one time at the discretion 
of the Investigator. 
 
7.2. 
Study Schedule 
This study is comprised of six clinic visits. Study assessments are to be performed 
according to the Schedule of Events (Table 1). There is a ± 4-day window for each clinic 
visit, other than the Day 1 for which there is a +4-day window and Month 4 visit for 
which there is a ± 7-day window. 
The study will consist of a Screening Period (up to 1 month), a Pretreatment Period 
(approximately 1 month), a Treatment Period (3 months), and a Month 4 Visit 
(one month). During the Treatment Period, subjects will have clinic visits for study- 
related protocol procedures at Day 1, Month 1, and Month 3. For the purpose of this 
study, one month is equal to 30 days. 
 
7.2.1. 
Schedule of Assessments and Procedures 
A comprehensive Schedule of Assessments and Procedures is presented in Table 1. 


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Table 1: 
Schedule of Assessments and Procedures 
 
Procedure 
Visit 1 
Visit 2 
(±4 days) 
Visit 3 
(+4 days) 
Visit 4 
(±4 days) 
Visit 5 
(±4 days) 
Visit 6 
(±7 days) 
Screening 
(30 Days) 
Pre- 
treatment 
Day 1 
Month 1 
Month 3 
Month 4 
Informed consent 
X 
Verification of entry criteria 
X 
X 
Review of medical history
a
 
X 
X 
X 
X 
X 
X 
Physical examination
b
 
X 
Symptom directed physical examination 
X 
X 
X 
X 
X 
Vital signs
c
 
X 
X 
X 
X 
X 
X 
Weight and height measurements
d
 
X 
X 
X 
X 
X 
12-lead Electrocardiogram
e
 
X 
X 
X 
X 
Urinalysis (dipstick)
f
 
X 
X 
X 
X 
Chemistry blood collection
g
 
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 
1,25-dihydroxy vitamin D level 
X 
FSH 
X 
Thyroid stimulating hormone 
X 
Injection training for subjects 
X 
Dispense calcium and vitamin D supplementsn 
X 
X 
X 
X 


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Procedure 
Visit 1 
Visit 2 
(±4 days) 
Visit 3 
(+4 days) 
Visit 4 
(±4 days) 
Visit 5 
(±4 days) 
Visit 6 
(±7 days) 
Screening 
(30 Days) 
Pre- 
treatment 
Day 1 
Month 1 
Month 3 
Month 4 
Study medication (abaloparatide) administration 
Daily abaloparatide administration until 
and including the day of bone biopsy 
Demeclocycline (dispense and administration) 
X
h 
Tetracycline (dispense and administration) 
X
i 
Transiliac crest bone biopsy
j
 
X 
Serum markers of bone metabolism (PINP and 
CTX) 
X 
X 
X 
AP and lateral lumbar and thoracic spine 
radiographs 
X 
Clinical assessment of new fractures
k
 
X 
X 
X 
X 
X 
Collect blood for immunogenicity testing 
X 
X 
BMD of lumbar spine, total hip, and femoral 
neck 
X 
X 
Investigator assessment of local tolerance 
(dermal reactions assessment) 
X 
X 
X 
Subject diary review
l
 
X 
X 
X 
Document AEs and concomitant medications
m
 
At any time, question subject at each visit 
Drug supply/resupply/accountability 
X 
X 
X 
X 
a Including alcohol and tobacco use assessment. 
b 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 not present at screening should be reported as AEs. 


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c Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse 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. Only blood pressure, pulse rate, and respiration rate are to be recorded one hour post-dose. Supine and standing blood pressure 
measurements will be performed at each visit during the Treatment Period. 
d Height is to be measured in the standing position with shoes off using a medical stadiometer. 
e An ECG will be recorded immediately prior to dosing and one hour post-dose during the Treatment Period. 
f 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. 
g Serum chemistry will be measured predose at Visits 3, 4, and 5. 
h Eighteen days before Day 1 of the Treatment Period (Visit 3), subjects who remain eligible for study participation will begin the first bone biopsy labeling 
procedure with administration of 150 mg demeclocycline 4 times daily for 3 days followed by a 12-day intermission, and then demeclocycline for 3 additional 
days at the same dose. 
i Approximately 23 to 26 days before Month 3 (Visit 5), subjects will begin the second bone biopsy labeling procedure with administration of 250 mg 
tetracycline 4 times daily for 3 days followed by a 12-day intermission, and then tetracycline for 3 additional days at the same dose. 
j Transiliac crest bone biopsy 5-8 days after last tetracycline dose. Sponsor Medical Monitor will decide if included in Early Termination Visit. 
k 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. 
l. Subject will be instructed on completion of diary in the Pretreatment Period to include administration of medications for bone biopsy labeling procedure. The 
subject medication diary will be reviewed by study personnel at each study visit during the Treatment Period to ensure subject compliance. 
m 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. 
n Vitamin D supplements are required to be administered daily from the Pretreatment Period until the end of the Treatment Period. Calcium will also be 
administered daily, with the exception of the days of administration of demeclocycline and tetracycline where calcium administration will be withheld. 


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7.2.2. 
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 institutional review board (IRB) must be used. The Investigator or 
designee must record the date when the ICF was signed in the subject’s source document. 
7.2.3. 
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. 
 
7.2.4. 
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. 
 
7.2.5. 
Screening (Visit 1) 
Signed informed consent will be obtained and eligibility for study entry assessed. 
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 calcium and vitamin D 
supplements. This should be continued through the Treatment Period according to the 
subject’s need, so that they have an intake of at least 1200 mg/day of calcium and 
800-1000 IU/day of vitamin D. Vitamin D supplements are required to be administered 
daily from the Pretreatment Period until the end of the Treatment Period. Calcium will 
also be administered daily, with the exception of the days of administration of 
demeclocycline and tetracycline, where calcium administration will be withheld. The 
following baseline screening evaluations will be performed: 
• Obtain Informed Consent 
• Verification of study entry criteria 
• Review of medical history 
• Physical examination 
• Blood pressure and vital signs (see Section 7.3) 
• Weight and height (see Section 7.3) 


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• 12-lead ECG 
• Laboratory testing of serum chemistry, hematology, urine dipstick, and 
coagulation 
• PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels 
• FSH and TSH levels 
• Lumbar and thoracic spine radiographs (anteroposterior and lateral) 
• BMD assessments of lumbar spine, total hip and femoral neck by dual X-ray 
absorptiometry (DXA) 
• AE and concomitant medication review from signing of the informed consent 
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 within 
30 days of the original test date. If upon reanalysis, the values fall within the 
inclusion/exclusion criteria, the subject may enter the study. Subjects who do not meet 
the 25-hydroxyvitamin D entry criterion may receive vitamin D supplementation and be 
retested one time. Similarly, subjects with minor elevations of PTH may be retested one 
time after vitamin D supplementation. All subjects enrolled following retesting must have 
safety laboratory results reported within 30 days prior to enrollment. 
All AEs, including serious adverse events (SAEs), will be recorded from the time of 
signing of the informed consent and through the 30 days after the last dose of study 
medication. 
 
7.2.6. 
Pretreatment (Visit 2) 
All subjects will receive calcium and vitamin D until the end of the Treatment Period, 
according to the subject’s need so that they have an intake of at least 1200 mg/day of 
calcium and 800-1000 IU/day of vitamin D. Subjects should be on a stable dose of 
calcium and vitamin D for 30 days prior to initiating the double labeling procedure. 
Subjects will undergo training for medication self-administration and for completion of 
diary, to include administration of medications for bone biopsy labeling procedure. 
Vitamin D supplements are required to be administered daily from the Pretreatment 
Period until the end of the Treatment Period. Calcium will also be administered daily, 
with the exception of the days of administration of demeclocycline and tetracycline 
where calcium administration will be withheld. The following procedures will be 
performed: 
• Verification of study entry criteria 
• Review of medical history 
• Symptom directed physical exam (see Section 7.3) 
• Blood pressure and vital signs (see Section 7.3) 
• Clinical assessment of new fractures 


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• AE and concomitant medication review 
• Dispense demeclocycline, vitamin D and calcium 
• Drug accountability 
• Subject injection training 
Eighteen (18) days before Day 1 of the Treatment Period (Visit 3), subjects who remain 
eligible for study participation will begin the first bone biopsy labeling procedure with 
administration of 150 mg demeclocycline 4 times daily for 3 days followed by a 12-day 
intermission, and then demeclocycline for 3 additional days at the same dose. 
Demeclocycline should be taken on an empty stomach, at least 1 hour before meals and 2 
hours after a meal with a full glass of water. 
 
7.2.7. 
Treatment Period 
At each clinic visit during the Treatment Period, recent health status will be obtained, the 
diary reviewed, adverse events and concomitant medications collected, drug supply / 
resupply and accountability, and blood pressure and vital signs performed. Laboratory 
assessments of serum chemistry, hematology and urinalyses will be obtained at Day 1, 
Month 1, and 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. 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. 
Bone turnover marker assessments (s-PINP and s-CTX) will be performed on the Day 1, 
Month 1 and Month 3 visits (Visits 3, 4, and 5, respectively). 
 
7.2.8. 
Day 1 (Visit 3) 
• Review of medical history 
• Symptom directed physical exam (see Section 7.3) 
• Blood pressure and vital signs (see Section 7.3) 
• Weight and height measurement (see Section 7.3) 
• 12-lead ECG 
• Laboratory testing of serum chemistry (predose), hematology, and urine 
dipstick 
• Bone turnover markers (s-PINP and s-CTX) 
• Clinical assessments of new fractures 
• Collect blood for immunogenicity testing 
• Subject diary review 


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• AE and concomitant medication review 
• Dispense abaloparatide, vitamin D and calcium 
• First dose of abaloparatide will be administered by the subject in clinic 
• Investigator assessment of local tolerance after injection 
• Drug accountability 
7.2.9. 
Month 1 (Visit 4) 
• Review of medical history 
• Symptom directed physical exam (see Section 7.3) 
• Blood pressure and vital signs (see Section 7.3) 
• Weight and height measurements (see Section 7.3) 
• Laboratory testing of serum chemistry (predose), hematology, and urine 
dipstick 
• Bone turnover markers (s-PINP and s-CTX) 
• Clinical assessment of new fractures 
• Review subject diary 
• AE and concomitant medication review 
• Dispense abaloparatide, vitamin D and calcium 
• Self-administration of study medication when directed by site staff after 
completion of predose activities 
• Investigator assessment of local tolerance after injection 
• Drug accountability 
Approximately twenty-three (23) to twenty-six (26) days prior to Visit 5, subjects 
will begin the second bone biopsy labeling procedure with administration of 250 
mg tetracycline 4 times daily for 3 days followed by a 12-day intermission, and 
then tetracycline for 3 additional days at the same dose. Tetracycline should be 
taken on an empty stomach, at least 1 hour before meals and 2 hours after a meal 
with a full glass of water. 
7.2.10. 
Month 3/Early Termination (Visit 5) 
• Review of medical history 
• Symptom directed physical exam (see Section 7.3) 
• Blood pressure and vital signs (see Section 7.3) 
• Weight and height measurements (see Section 7.3) 
• 12-lead ECG 


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• Laboratory testing of serum chemistry (predose), hematology, and urine 
dipstick 
• Coagulation blood testing 
• PTH level 
• Bone turnover markers (s-PINP and s-CTX) 
• Clinical assessment of new fractures 
• Collect blood for immunogenicity testing 
• Review subject diary 
• AE and concomitant medication review 
• Self-administration of last dose of study medication when directed by site 
staff after completion of predose activities 
• Investigator assessment of local tolerance after injection 
• BMD assessments of lumbar spine, total hip and femoral neck by dual X-ray 
absorptiometry (DXA) 
• Transiliac crest bone biopsy 5-8 days after last tetracycline dose (Sponsor 
together with the Medical Monitor should determine if included in Early 
Termination Visit) 
• Drug accountability 
7.2.11. 
Month 4 (Visit 6) 
• Review of medical history 
• Symptom directed physical examination (see Section 7.3) 
• Blood pressure and vital signs (see Section 7.3) 
• Weight and height measurements (see Section 7.3) 
• 12-lead ECG 
• Clinical assessment of new fractures 
• All AEs and concomitant medications review 
7.2.12. 
Unscheduled Visit 
If the subject returns to the clinic for an unscheduled visit (eg, to follow-up on an 
abnormal laboratory test), the procedures performed at this visit will be recorded in the 
eCRF and source documentation. 
 
7.3. 
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. 


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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. 
Height and weight will be measured with shoes off. Height is to be measured using a wall 
mounted stadiometer. 
Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse 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. Only blood 
pressure, pulse rate, and respiration rate are to be recorded one hour post-dose. Supine 
and standing blood pressure measurements will be performed at each visit during the 
Treatment Period. After screening, any clinically significant abnormal findings in vital 
signs should be reported as AEs. 
 
7.4. 
12-Lead Electrocardiogram 
A standard, 12-lead ECG 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 one hour post-dose during the Treatment Period. After screening, any clinically 
significant abnormal findings in ECGs should be reported as AEs. 
7.5. 
Laboratory Evaluations 
7.5.1. 
Clinical Laboratory Evaluations 
Hematology, serum chemistry, and urinalysis will be collected at time points indicated in 
the Schedule of Assessments and Procedures in Table 1. All clinical laboratory blood 
samples will be sent to a central laboratory for analysis and testing. A list of study 
clinical laboratory tests is in Table 2. 
• 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 within 30 days of the original test date. If upon reanalysis, 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 
as may subjects with minor elevations of PTH. All subjects enrolled following 
retesting must have safety labs within 30 days of randomization (Day 1). 


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Table 2: 
Clinical Laboratory Tests 
 
Hematology 
Serum Chemistry 
Urinalysis 
(dipstick) a 
Additional Tests 
Hemoglobin 
Hematocrit 
Sodium 
Potassium 
pH 
Glucose 
PTH (1–84)b 
25-hydroxyvitamin Dc 
1,25-dihydroxy vitamin Dc 
WBC count with 
differential in absolute 
counts 
RBC count 
Mean corpuscular volume 
(MCV) 
Chloride 
Inorganic phosphorus 
Albumin 
Protein 
Ketones 
Bilirubin 
Coagulationb 
FSHc 
TSHc 
Mean corpuscular 
hemoglobin 
concentration (MCHC) 
Total protein 
Blood 
Mean corpuscular 
hemoglobin (MCH) 
Glucose 
Urobilinogen 
Platelet count 
Blood urea nitrogen (BUN) 
Specific gravity 
Creatinine 
Nitrite 
Uric acid 
Leukocytes 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Gamma-glutamyltranspeptidase 
(GGT) 
Creatine phosphokinase (CPK) 
Alkaline phosphatase 
Total bilirubin 
Lactate dehydrogenase (LDH) 
Total Cholesterol 
Triglycerides 
Total calcium 
a Local laboratory, send to a central lab for microscopy if test is positive for micro-organisms 
b Only required at Screening and Visit 5 (Month 3/Early Termination) 
c Only required at Screening 
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. After 
screening, clinically significant changes in laboratory tests that occur during the course of 
the study are to be reported as adverse events. 
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. 
 
7.5.2. 
Serum Markers of Bone Metabolism 
Blood samples will be taken to measure efficacy related markers of bone metabolism at 
Day 1, Month 1, and Month 3 or early termination. Serum procollagen type I N-terminal 
propeptide (s-PINP) and serum carboxy-terminal cross-linking telopeptide of type I 
collagen (s-CTX) will be measured in all subjects. 


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7.5.3. 
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. 
 
7.6. 
Bone Biopsy Processing Procedure 
The bone cores will be processed without decalcification and embedded in methyl 
methacrylate. Three levels of transverse sections from each biopsy block will be cut 100 
micron apart using a Leica SM 2500E Polycut microtome. In each level, two adjacent 
sections at 7-microns and one adjacent 20-micron thick sections will be collected. The 
two 7-micron adjacent sections will be stained with toluidine-blue (ethanol base) and 
Goldner’s trichrome, respectively. The toluidine-blue stained section will be used to 
demonstrate bone cells, osteons, and cement lines. The trichrome stained section will be 
used to demonstrate osteoid. The 20-micron section will be left unstained for 
visualization of tetracycline labels. Each section will be subjected to histomorphometric 
analysis using computerized image analysis as previously described (Dempster, 2001; 
Dempster 2017). All variables will be calculated and expressed according to the 
guidelines of the ASBMR’s Bone Histomorphometry Committee (Dempster, 2013). 
7.7. 
Imaging Procedures 
All imaging measurements (spine radiographs and BMD by DXA) will be performed 
according to the procedures outlined in the Imaging Charter and Imaging Manuals which 
will be provided as a separate document. 
 
7.7.1. 
Dual Energy X-ray Absorptiometry (DXA) 
All subjects will have areal bone density (aBMD) measurements taken via DXA of the 
lumbar spine, total hip, femoral neck, at Screening (Visit 1). Lumbar spine scans must 
include L1 through L4. Hip scans will include the entire proximal femur to about 2 cm 
below the lesser trochanter. 
 
7.7.2. 
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 vertebral fractures using the Genant Semi-quantitative (SQ) 
Scoring method (Genant, 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) 


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• 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). 
Subjects will 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 eCRFs and source documents. 
 
7.7.3. 
Treatment and Imaging at Selected Sites 
Selected sites will follow expanded treatment and imaging procedures. Sites following 
expanded procedures will be provided instructions and details in a separate document for 
the sub-study. 
Additional treatment and imaging procedures at selected sites includes: 
• Abaloparatide treatment for total of 6 months 
• pQCT of the forearm and tibiae performed at the pretreatment visit (Visit 2), 
at Month 3 (Visit 5), and at Month 6 (Visit 7). 
 
7.8. 
Discontinuation from the Study 
Subjects may voluntarily discontinue from the study for any reason at any time. 
Subjects sustaining a radiologically confirmed incident vertebral 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. 
Subjects who decide they do not wish to participate in the study further should return for 
the assessments indicated for the Month 3/Early Termination and 30 days later for the 
Month 4 Visit in the Schedule of Assessments and Procedures (Table 1). If they fail to 
return for these assessments for unknown reasons, every effort (eg, by telephone, email, 
and letter for a minimum of three attempts) should be made and documented in the 
subject’s study file. 
 
7.8.1. 
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. 


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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. 
 
7.8.2. 
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 of the early termination of the 
study. 


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8. 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
DOCUMENTATION 
8.1. 
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 and determine reporting 
requirements to the Sponsor as well as the IRB. 
8.1.1. 
Adverse Events 
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. 
 
8.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is any AE that results in any of the following: 


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• 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 event/reaction; it does not refer to an event/reaction which 
hypothetically might have caused death if it were more severe 
• Required inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity (ie, 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 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
All adverse events 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 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). 
 
8.1.3. 
Recording Adverse Events 
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 case report 
form and by collection of source documents. 
For both serious and non-serious adverse events, the Investigator must determine the 
intensity of the event and the relationship of the event to study drug administration. 
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. 


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Relationship 
Definition 
 
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. 
 
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. 
 
8.1.4. 
Serious Adverse Event (SAE) 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 to RADIUS Pharmacovigilance. These events will be followed 
until resolution or stabilization. The reference safety information for this study is 
included in the Investigator Brochure, 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 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. 
 
8.1.5. 
Follow-up of Adverse Events 
All AEs will be followed with appropriate medical management until resolved or 
stabilized. 
 
8.1.6. 
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 (eg, 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. 


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• 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. 
 
8.1.7. 
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 Institutional Review Boards 
(IRBs)/EU central ethics committees (ECs) of related, unexpected SAEs. 
The Investigator is responsible for notifying the Sponsor, CRO, and local IRB, local EC, 
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 3/Early Termination visit 
(Visit 5), and it is determined to be related either to a study procedure or study drug, the 
Investigator or his/her designee must notify the Sponsor and will communicate that 
information to the IRB within one business day of knowledge of the event. The contact 
may be by phone or e-mail. 
8.2. 
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. 
 
8.3. 
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, eg, 
dates of telephone calls, registered letters, etc. A subject should not be formally 
considered lost to follow-up until his/her scheduled end of study visit would have 
occurred. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Analysis Plan 
A comprehensive Statistical Analysis Plan (SAP) will be completed and approved prior 
to database lock. All statistical tests will be two-sided with a significance level of 5%, 
unless otherwise specified. 
 
9.2. 
Statistical Hypothesis 
9.3. 
Analysis Datasets 
9.3.1. 
Population for Analysis 
The primary population for all efficacy analyses will be the Bone-Biopsy Population, 
which is defined as all enrolled subjects who received a biopsy. The primary population 
for all safety analyses will be the Safety Population, which will be defined as all enrolled 
subjects who received at least one dose of abaloparatide. 
9.4. 
Description of Statistical Methods 
9.4.1. 
General Approach 
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. 
 
9.4.2. 
Analysis of the Primary Efficacy Endpoint(s) 
The primary endpoint of this study is the change from baseline to 3 months in 
mineralizing surface (MS/BS) in the cancellous bone envelope. Paired t-tests will be used 
to compare the differences in dynamic indices between the two time-points derived from 
the two sets of double labels using the Bone-Biopsy Population. If the normality 
assumption of the efficacy data is not satisfied at the 0.01 significance level and if visual 
inspection of the data deems it necessary, an appropriate nonparametric test, such as the 
Wilcoxon signed-rank test, will be used to assess changes from baseline. No adjustments 
for multiplicity will be made. A p-value < 0.05 will be considered statistically significant. 
9.4.3. 
Analysis of Secondary Endpoint(s) 
Secondary efficacy endpoints of tissue-based indices of bone formation and bone 
resorption will be analyzed in the same manner as the analysis of the primary efficacy 
endpoint using the Bone Biopsy Population. 


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The change and percent change from baseline in bone turnover makers (s-PINP and 
s-CTX) will be summarized descriptively at each visit (1 and 3 months) using the 
Bone-Biopsy and the Safety Populations. 
Linear regression analyses will be used to assess the relationships between efficacy 
endpoints of tissue-based indices of bone formation and bone resorption and changes in 
bone turnover markers at each visit, including changes in MS/BS and BFR/BS in each 
envelope to changes in s-PINP, changes in intracortical MS/BS and BFR/BS to changes 
in s-CTX, MS/BS and BFR/BS in each envelope at Month 3 to s-PINP at Months 1 and 
3, intracortical MS and BFR/BS at Month 3 to s-CTX at Month 3, and ES/BS in each 
envelope and cortical porosity at Month 3 to s-CTX at Month 3. The analyses include 
scatter plots, Pearson’s correlation coefficient, and slopes of simple regression models 
using the Bone-Biopsy Population. 
 
9.4.4. 
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. 
All AEs will be coded using MedDRA. The number and percent of subjects who 
experienced treatment-emergent AEs (TEAEs) will be summarized by MedDRA system 
organ class (SOC), and preferred term (PT). Summaries will also be provided for severe 
TEAEs, serious TEAEs (SAEs), TEAEs leading to 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. 
All AEs collected prior to the first dose of study drug will be summarized separately. 
Descriptive statistics for clinical laboratory data (including serum calcium and albumin), 
vital signs (including blood pressure), ECGs, and Investigator assessment of local 
tolerance will be provided by 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). 
Concomitant medications will be coded using the WHO Drug Dictionary and 
summarized by number and percentage of subjects using each class and preferred drug 
term. 
 
9.4.5. 
Adherence and Retention Analyses 
The number and percentage of subjects who withdraw from the study, with primary 
reason, will be summarized. 


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9.4.6. 
Baseline Descriptive Statistics 
Medical history, physical examination, demographics and baseline characteristics will be 
summarized and presented. Medical history will be presented by MedDRA SOC and PT, 
summarizing the proportion of subjects who have a condition noted. Results from the 
baseline physical examination will be summarized by body system as recorded in the 
eCRF. 
9.4.7. 
Interim Analyses 
There are no interim analyses planned for this study. 
 
9.4.8. 
Tabulation of Individual Response Data 
Individual efficacy and safety data will be tabulated as appropriate. 
 
9.5. 
Sample Size Calculation 
In the AVA study of teriparatide and denosumab (Dempster, 2016), the mean (± SD) 
change from baseline in cancellous MS/BS (%) for teriparatide was 13.90 (± 9.38) at 
3 months. In the ACTIVE study, the median % change from baseline in s-PINP at 
3 months was 60% for abaloparatide and 94% for teriparatide. The ratio between the 2 
groups is approximately 2/3 (= 60%/94%). 
Using the same ratio and the results for teriparatide obtained from the AVA study, we can 
assume that the mean change from baseline in cancellous MS/BS (%) for abaloparatide at 
3 months will be 9.2% (= 13.90*2/3). Assuming a standard deviation (SD) of 12.0%, a 
sample size of 21 completers will provide at least 90% power to detect a statistically 
significant change from baseline in cancellous MS/BS (%) for abaloparatide at 3 months 
of 9.2%. The study is planned to enroll approximately 25 subjects to accommodate a 
drop-out rate of 15%, including those with non-evaluable bone biopsy. Additional 
subjects may be enrolled if the number of evaluable biopsies is insufficient to achieve this 
power. 
 
9.6. 
Measures to Minimize Bias 
Not applicable. 
 
9.7. 
Enrollment/Randomization/Masking Procedures 
Not applicable. 


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10. 
ADMINISTRATIVE REQUIREMENTS 
10.1. 
Ethical Considerations 
This clinical study will be conducted in accordance with the current version of ICH 
Harmonized Tripartite Guidelines 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 
Regulations for the Protection of Human Subjects of Research codified in 21 CFR Part 
50, 21 CFR Part 54, 21 CFR Part 56, 21 CFR Part 312, 21 CFR Part 314, and ICH GCP 
E6. 
The IRB 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 
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 by the Investigator or RADIUS 
or designee, as allowable by local applicable laws and regulations. 
10.2. 
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. 
10.3. 
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 (ie, efficacy assessments) 
will require IRB 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. 


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10.4. 
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 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 must comply with applicable privacy and security laws for use and 
disclosure of information related to the research set forth in this protocol. 
 
10.5. 
Subject 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. 
 
10.6. 
Research Use of Stored Human Samples, Specimens, or Data 
With the subject’s approval, and as approved by the site’s IRB, 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. The 
storage facility will be provided with a code-link that will allow linking the biological 
specimens with the phenotypic data from each subject, maintaining 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. 


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10.7. 
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. 
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. 
10.8. 
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. 
 
10.9. 
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. 


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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. 
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. 
 
10.10. 
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. 
10.11. 
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 centers. 
Subsequently, individual Investigators may publish results from the study in compliance 
with their agreement with RADIUS. 


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Bone HG, Cosman F. Miller PD, Williams GC, Hattersley G, Hu M-y, Fitzpatrick LA. 
Papapoulos S. Sustained fracture risk reduction with sequential 
abaloparatide/alendronate: results of ACTIVExtend. ASBMR 2017 Annual Meeting. 
1074. Abstract. 
 
Cosman F, Miller PD, Williams GC, Hattersley G, Hu MY, Valter I, Fitzpatrick LA, Riis 
BJ, Christiansen C, Bilezikian JP, Black D. Eighteen months of treatment with 
subcutaneous abaloparatide followed by 6 months of treatment with alendronate in 
postmenopausal women with osteoporosis: results of the ACTIVExtend Trial. Mayo Clin 
Proc. 2017;92:200-210. 
 
Dempster DW, Cosman F, Kurland ES, Zhou H, Nieves J, Woelfert L, Shane E, Plavetic 
K, Muller R, Bilezikian J, Lindsay R. Effects of daily treatment with parathyroid 
hormone on bone architecture and turnover in subjects with osteoporosis: a paired biopsy 
study. J Bone Miner Res. 2001;16:1846-1853. 
 
Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, 
Meunier PJ, Ott SM, Recker RR, Parfitt AM. Standardized nomenclature, symbols, and 
units for bone histomorphometry: a 2012 update of the report of the ASBMR 
Histomorphometry Nomenclature Committee. J Bone Miner Res. 2013;28:2-17. 
 
Dempster DW, Zhou H, Recker RR, Brown JP, Recknor CP, Lewiecki EM, Miller PD, 
Rao SD, Kendler DL, Lindsay R, Krege JH, Alam J, Taylor KA, Janos B, Ruff VA. 
Differential effects of teriparatide and denosumab on intact PTH and bone formation 
indices: the AVA osteoporosis study. J Bone Miner Res. 2016;101:1353-1363. 
 
Dempster D, Zhou H, Recker R, Brown J, Recknor C, Lewiecki EM, Miller P, Rao S, 
Kendler D, Lindsay R, Krege J, Alam J, Taylor K, Ruff V. Longitudinal changes in 
modeling- and remodeling-based bone formation with an anabolic vs. antiresorptive 
agent in the AVA Osteoporosis Study. ASBMR 2016 Annual Meeting. S51. Abstract. 
 
Dempster DW, Zhou H, Recker RR, Brown JP, Recknor CP, Lewiecki EM, Miller PD, 
Rao SD, Kendler DL, Lindsay R, Krege JH, Alam J, Taylor KA, Melby TE, Ruff VA. 
Remodeling- and Modeling-Based Bone Formation With Teriparatide Versus 
Denosumab: A Longitudinal Analysis From Baseline to 3 Months in the AVA Study. J 
Bone Miner Res. 2017 Oct 12. doi: 10.1002/jbmr.3309. 
 
Genant HK, Wu CY, van Kuijk KC, Nevitt MC. Vertebral fracture assessment using a 
semiquantitative technique. J Bone Miner Res. 1993;8:1137-1148. 


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Study BA058-05-020, Amendment 2 
Page 60 of 60 
 
 
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;157:141-149. 
 
Lindsay R, Cosman F, Zhou H, Bostrom MP, Shen VW, Cruz JD, Nieves JW, Dempster 
DW. A novel tetracycline labeling schedule for longitudinal evaluation of the short-term 
effects of anabolic therapy with a single iliac crest bone biopsy: early actions of 
teriparatide. J Bone Miner Res. 2006;21:366-373. 
 
Litwic A, Lekarz, Warwick D, Denniston E. Distal radius fracture: Cinderella of the 
osteoporotic fractures. Orthop Muscul Syst. 2014; 3:162-168. 
Makino, A., Takagi, H., Sugiyama, H. Effects of Abaloparatide on the Expression of 
Bone Resorption-and Formation-related Factors in Osteoblastic Cells; a Comparison with 
Teriparatide. J Bone Miner Res, 30 (Suppl 1). 
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. JAMA. 2016;316:722-733. 
Moreira CA, Fitzpatrick LA, Wang Y, Recker RR. Effects of abaloparatide-SC (BA058) 
on bone histology and histomorphometry: the ACTIVE phase 3 trial. Bone. 
2017;97:314-319. 
 
Rizzoli R. Osteoporosis, genetics and hormones. J Mol Endocrinol. 2001;26:79-94. 
 
Rosen CJ. Clinical practice. Postmenopausal osteoporosis. N Engl J Med. 2005;353:59 
 
Rubin MR, Dempster DW, Sliney J Jr, Zhou H, Nickolas TL, Stein EM, Dworakowski 
E, Dellabadia M, Ives R, McMahon DJ, Zhang C, Silverberg SJ, Shane E, Cremers S, 
Bilezikian JP. PTH(1-84) administration reverses abnormal bone-remodeling 
dynamics and structure in hypoparathyroidism. J Bone Miner Res. 2011 
Nov;26(11):2727-36. 
 
World Health Organization (2007) 


 
 
08-Nov-2018 16:59:33 GMT+0000 
Approval 
 
09-Nov-2018 13:00:59 GMT+0000 
Approval 
 
 
Signature Page for RAD-CLIN-000924 v4.0 
 
 
 
Signature Page for RAD-CLIN-000924 v4.0 


Radius Health, Inc. 
Abaloparatide-SC 
Confidential 
 
 
Radius Health, Inc. (RADIUS) 
950 Winter Street, Waltham, MA 02451 
USA 
 
 
 
Abaloparatide-SC 
 
Addendum to 
CLINICAL STUDY PROTOCOL: BA058-05-020 
 
An Open-label, Single-arm, Multicenter Study to Evaluate the Early Effects of 
Abaloparatide on Tissue-based Indices of Bone Formation and Resorption 
 
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 Addendum 
 
IND number 
73,176 
 
Version number: 
Version 3.0 (14 November 2018) 
Development phase: 
3 
 
Study Site: 
 
 
 
 
 
 
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. 
 
 
 
Study BA058-05-020 Addendum 


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Study BA058-05-020 Addendum 
 
 
 
TABLE OF CONTENTS 
Radius Health, Inc. (RADIUS) ........................................................................................................1 
Addendum to ....................................................................................................................................1 
An Open-label, Single-arm, Multicenter Study to Evaluate the Early Effects of 
Abaloparatide on Tissue-based Indices of Bone Formation and Resorption................1 
Confidentiality Statement ................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
PURPOSE OF THIS ADDENDUM ................................................................................................3 
STUDY SCHEDULE ......................................................................................................................4 
Screening (Visit 1) ...........................................................................................................................4 
Pretreatment (Visit 2) .......................................................................................................................5 
Treatment Period ..............................................................................................................................6 
Day 1 (Visit 3) .................................................................................................................................6 
Month 1 (Visit 4) .............................................................................................................................7 
Month 3 (Visit 5) .............................................................................................................................7 
Month 4 (Visit 6) .............................................................................................................................8 
Month 6/Early Termination (Visit 7) ...............................................................................................8 
Month 7 (Visit 8) .............................................................................................................................9 
Unscheduled Visit ............................................................................................................................9 
DISCONTINUATION FROM THE STUDY ...............................................................................10 
LIST OF TABLES 
Table 1: 
Schedule of Assessments and Procedures .................................................................. 12 


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Study BA058-05-020 Addendum 
 
 
 
 
1. 
PURPOSE OF THIS ADDENDUM 
This is a single-site Addendum that applies to 
, based on Clinical 
Study Protocol BA058-05-020 Version 3.0, dated 14 November 2018. 
Study assessments and procedures have been modified as follows and are presented in the 
Schedule of Assessments and Procedures (Table 1). 
The treatment period is extended to six (6) months 
1. Additional visits at Month 6 (Visit 7) and Month 7 (Visit 8) are added 
2. Peripheral quantitative computed tomography (pQCT) of the forearm and tibiae is 
added at Pretreatment (Visit 2), Month 3 (Visit 5), and Month 6 (Visit 7) 
3. “Discontinuation from the Study” has been updated to reflect the modified visit 
schedule 
4. Early termination procedures have been updated to reflect the extended treatment 
period. 


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Study BA058-05-020 Addendum 
 
 
 
 
 
2. 
STUDY SCHEDULE 
This study addendum is comprised of seven clinic visits. Study assessments are to be 
performed according to the Schedule of Events (Table 1). There is a ± 4-day window for 
each clinic visit, other than Day 1 for which there is a +4-day window and Month 7 (Visit 
8) for which there is a ± 7-day window. 
The study will consist of a Screening Period (up to 1 month), a Pretreatment Period 
(approximately 1 month), a Treatment Period (6 months), and a Month 7 Visit (one 
month). During the Treatment Period, subjects will have clinic visits for study-related 
protocol procedures at Day 1, Month 1, Month 3, Month 4, and Month 6. For the 
purpose of this study, one month is equal to 30 days. 
Subjects consenting under the addendum will have data collected according to the length 
of their participation. An addendum subject who terminates at or before the Month 3 
Visit will return for assessments as indicated in the Addendum Schedule of Assessments 
and Procedures for the Month 3 Visit and complete the study 30 days later at the Month 4 
Visit (See Section 2.6 of the main protocol). Subjects who decide they do not wish to 
participate in the study following the Month 3 Visit should return for assessments as 
indicated in the Addendum, Schedule of Assessments and Procedures for Month 6/Early 
Termination Visit and 30 days later for the Month 7 Visit (see Section 2.9 of the main 
protocol). 
 
2.1. 
Screening (Visit 1) 
Signed informed consent will be obtained and eligibility for study entry assessed. 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 calcium and vitamin D 
supplements. This should be continued through the Treatment Period according to the 
subject’s need, so that they have an intake of at least 1200 mg/day of calcium and 800- 
1000 IU/day of vitamin D. Vitamin D supplements are required to be administered daily 
from the Pretreatment Period until the end of the Treatment Period. Calcium will also be 
administered daily, with the exception of the days of administration of demeclocycline and 
tetracycline, where calcium administration will be withheld. The following baseline 
screening evaluations will be performed: 
• 
Obtain Informed Consent 
• 
Verification of study entry criteria 
• 
Review of medical history 
• 
Physical examination 
• 
Blood pressure and vital signs (see Section 7.3 of main protocol) 
• 
Weight and height (see Section 7.3 of main protocol) 
• 
12-lead ECG 
• 
Laboratory testing of serum chemistry, hematology, urine dipstick, and coagulation 


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• 
Drug accountability 
Study BA058-05-020 Addendum 
 
 
 
• 
PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels 
• 
FSH and TSH levels 
• 
Lumbar and thoracic spine radiographs (anteroposterior and lateral) 
• 
BMD assessments of lumbar spine, total hip and femoral neck by dual X-ray 
absorptiometry (DXA) 
• 
AE and concomitant medication review from signing of the informed consent 
• 
Dispense vitamin D and calcium 
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 within 30 
days of the original test date. If upon reanalysis, the values fall within the 
inclusion/exclusion criteria, the subject may enter the study. Subjects who do not meet the 
25-hydroxyvitamin D entry criterion may receive vitamin D supplementation and be 
retested one time. Similarly, subjects with minor elevations of PTH may be retested one 
time after vitamin D supplementation. All subjects enrolled following retesting must have 
safety laboratory results reported within 30 days prior to enrollment. 
All AEs, including serious adverse events (SAEs), will be recorded from the time of 
signing of the informed consent and through the 30 days after the last dose of study 
medication. 
 
2.2. 
Pretreatment (Visit 2) 
All subjects will receive calcium and vitamin D until the end of the Treatment Period, 
according to the subject’s need so that they have an intake of at least 1200 mg/day of 
calcium and 800-1000 IU/day of vitamin D. Subjects should be on a stable dose of 
calcium and vitamin D for 30 days prior to initiating the double labeling procedure. 
Subjects will undergo training for medication self-administration and for completion of 
diary, to include administration of medications for bone biopsy labeling procedure. 
Vitamin D supplements are required to be administered daily from the Pretreatment 
Period until the end of the Treatment Period. Calcium will also be administered daily, 
with the exception of the days of administration of demeclocycline and tetracycline where 
calcium administration will be withheld. The following procedures will be performed: 
• 
Verification of study entry criteria 
• 
Review of medical history 
• 
Symptom directed physical exam (see Section 7.3 of main protocol) 
• 
Blood pressure and vital signs (see Section 7.3 of main protocol) 
• 
Peripheral quantitative computed tomography (pQCT) of the forearm and tibiae 
• 
Clinical assessment of new fractures 
• 
AE and concomitant medication review 
• 
Dispense demeclocycline, vitamin D and calcium 


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• 
Drug accountability 
Study BA058-05-020 Addendum 
 
 
 
• 
Subject injection training 
Eighteen (18) days before Day 1 of the Treatment Period (Visit 3), subjects who remain 
eligible for study participation will begin the first bone biopsy labeling procedure with 
administration of 150 mg demeclocycline 4 times daily for 3 days followed by a 12-day 
intermission, and then demeclocycline for 3 additional days at the same dose. 
Demeclocycline should be taken on an empty stomach, at least 1 hour before meals and 2 
hours after a meal with a full glass of water. 
 
2.3. 
Treatment Period 
At each clinic visit during the Treatment Period, recent health status will be obtained, the 
diary reviewed, adverse events and concomitant medications collected, drug supply / 
resupply and accountability, and blood pressure and vital signs performed. Laboratory 
assessments of serum chemistry, hematology and urinalyses will be obtained at Day 1, 
Month 1, Month 3, and Month 6. 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. 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. 
Bone turnover marker assessments (s-PINP and s-CTX) will be performed on the Day 1, 
Month 1 and Month 3 visits (Visits 3, 4, and 5, respectively). 
 
2.4. 
Day 1 (Visit 3) 
• 
Review of medical history 
• 
Symptom directed physical exam (see Section 7.3 of main protocol) 
• 
Blood pressure and vital signs (see Section 7.3 of main protocol) 
• 
Weight and height measurement (see Section 7.3 of main protocol) 
• 
12-lead ECG 
• 
Laboratory testing of serum chemistry (pre-dose), hematology, and urine dipstick 
• 
Bone turnover markers (s-PINP and s-CTX) 
• 
Clinical assessments of new fractures 
• 
Collect blood for immunogenicity testing 
• 
Subject diary review 
• 
AE and concomitant medication review 
• 
Dispense abaloparatide, vitamin D and calcium 
• 
First dose of abaloparatide will be administered by the subject in clinic 
• 
Investigator assessment of local tolerance after injection 


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Study BA058-05-020 Addendum 
 
 
 
2.5. 
Month 1 (Visit 4) 
• 
Review of medical history 
• 
Symptom directed physical exam (see Section 7.3 of main protocol) 
• 
Blood pressure and vital signs (see Section 7.3 of main protocol) 
• 
Weight and height measurements (see Section 7.3 of main protocol) 
• 
Laboratory testing of serum chemistry (predose), hematology, and urine dipstick 
• 
Bone turnover markers (s-PINP and s-CTX) 
• 
Clinical assessment of new fractures 
• 
Review subject diary 
• 
AE and concomitant medication review 
• 
Dispense abaloparatide, vitamin D, calcium and tetracycline 
• 
Self-administration of study medication when directed by site staff after completion of 
predose activities 
• 
Investigator assessment of local tolerance after injection 
• 
Drug accountability 
Approximately twenty-three (23) to twenty-six (26) days prior to Visit 5, subjects will begin the 
second bone biopsy labeling procedure with administration of 250 mg tetracycline 4 times daily 
for 3 days followed by a 12-day intermission, and then tetracycline for 3 additional days at the 
same dose. Tetracycline should be taken on an empty stomach, at least 1 hour before meals and 2 
hours after a meal with a full glass of water. 
 
Note: Subjects consenting under the addendum will have data collected according to the length 
of their participation. An addendum subject who terminates at or before the Month 3 Visit will 
return for assessments as indicated in the Addendum Schedule of Assessments and Procedures 
for the Month 3 Visit and complete the study 30 days later at the Month 4 Visit (Table 1). 
 
2.6. 
Month 3 (Visit 5) 
• 
Review of medical history 
• 
Symptom directed physical exam (see Section 7.3 of main protocol) 
• 
Blood pressure and vital signs (see Section 7.3 of main protocol) 
• 
Weight and height measurements (see Section 7.3 of main protocol) 
• 
12-lead ECG 
• 
Laboratory testing of serum chemistry (pre-dose), hematology, and urine dipstick 
• 
Coagulation blood testing 
• 
PTH level 
• 
Bone turnover markers (s-PINP and s-CTX) 
• 
Peripheral quantitative computed tomography (pQCT) of the forearm and tibiae 


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Study BA058-05-020 Addendum 
 
 
 
• 
Clinical assessment of new fractures 
• 
Collect blood for immunogenicity testing 
• 
Review subject diary 
• 
AE and concomitant medication review 
• 
Self-administration of study medication when directed by site staff after completion of 
predose activities 
• 
Investigator assessment of local tolerance after injection 
• 
BMD assessments of lumbar spine, total hip and femoral neck by dual X-ray 
absorptiometry (DXA) 
• 
Transiliac crest bone biopsy 5-8 days after last tetracycline dose (Sponsor together with 
Medical Monitor should determine if included should an addendum subject terminate 
study participation after initiating tetracycline labeling) 
• 
Dispense abaloparatide, vitamin D and calcium 
• 
Drug accountability 
 
Note: Subjects who decide they do not wish to participate in the study following the 
Month 3 Visit should return for assessments as indicated in the Addendum, Schedule of 
Assessments and Procedures for Month 6/Early Termination Visit and 30 days later for 
the Month 7 Visit (Table 1). 
 
2.7. 
Month 4 (Visit 6) 
• 
Review of medical history 
• 
Symptom directed physical examination (see Section 7.3 of main protocol) 
• 
Blood pressure and vital signs (see Section 7.3 of main protocol) 
• 
Weight and height measurements (see Section 7.3 of main protocol) 
• 
12-lead ECG 
• 
Clinical assessment of new fractures 
• 
Review subject diary 
• 
AE and concomitant medication review 
• 
Dispense abaloparatide, vitamin D and calcium 
• 
Self-administration of study medication when directed by site staff after completion of 
pre-dose activities 
• 
Drug accountability 
• 
Investigator assessment of local tolerance after injection 
 
2.8. 
Month 6/Early Termination (Visit 7) 
• 
Review of medical history 
• 
Symptom directed physical exam (see Section 7.3 of main protocol) 


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Study BA058-05-020 Addendum 
 
 
 
• 
Blood pressure and vital signs (see Section 7.3 of main protocol) 
• 
12-lead electrocardiogram (ECG) 
• 
Laboratory testing of serum chemistry (pre-dose), hematology, and urine dipstick 
• 
PTH level 
• 
Peripheral quantitative computed tomography (pQCT) of the forearm and tibiae 
• 
Clinical assessment of new fractures 
• 
BMD assessments of lumbar spine, total hip and femoral neck by dual X-ray 
absorptiometry (DXA) 
• 
Review subject diary 
• 
AE and concomitant medication review 
• 
Self-administration of last dose of study medication when directed by site staff after 
completion of pre-dose activities 
• 
Drug accountability 
• 
Investigator assessment of local tolerance after injection 
 
2.9. 
Month 7 (Visit 8) 
• 
Review of medical history 
• 
Symptom directed physical examination (see Section 7.3 of main protocol) 
• 
Blood pressure and vital signs (see Section 7.3 of main protocol) 
• 
Weight and height measurements (see Section 7.3 of main protocol) 
• 12-lead electrocardiogram (ECG) 
• Clinical assessment of new fractures 
• 
AE and concomitant medications review 
 
2.10. 
Unscheduled Visit 
If the subject returns to the clinic for an unscheduled visit (eg, to follow-up on an abnormal 
laboratory test), the procedures performed at this visit will be recorded in the eCRF and source 
documentation. 


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Study BA058-05-020 Addendum 
 
 
 
3. 
DISCONTINUATION FROM THE STUDY 
Subjects may voluntarily discontinue from the study for any reason at any time. 
Subjects sustaining a radiologically confirmed incident vertebral 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.  Refer to Section 5.3.1 of the main protocol for details. 
Subjects who decide they do not wish to participate in the study at or before the Month 3 Visit 
will return for assessments as indicated in the Addendum Schedule of Assessments and 
Procedures for Month 3 Visit and complete the study 30 days later at the Month 4 Visit. 
Subjects who decide they do not wish to participate in the study following the Month 3 
Visit should return for assessments as indicated in the Addendum, Schedule of Assessments and 
Procedures for Month 6/Early Termination and 30 days later for the Month 7 Visit (Table 1). 
If they fail to return for these assessments for unknown reasons, every effort to contact them (eg, 
by telephone, email, and letter for a minimum of three attempts) should be made and 
documented in the subject’s study file. 


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Study BA058-05-020 Addendum 
 
 
 
Table 1: 
Schedule of Assessments and Procedures 
 
Procedure 
Visit 1 
Visit 2 (±4 
days) 
Visit 3 
(+4 days) 
Visit 4 
(±4 days) 
Visit 5 
(±4 days) 
Visit 6 
(±4 days) 
Visit 7 
(±4 days) 
Visit 8 
(±7 days) 
Screening 
(30 Days) 
Pretreatment 
Day 1 
Month 1 
Month 3 
Month 4 
Month 6 
Month 7 
Informed consent 
X 
Verification of entry criteria 
X 
X 
Review of medical historya 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationb 
X 
Symptom directed physical examination 
X 
X 
X 
X 
X 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and height measurementsd 
X 
X 
X 
X 
X 
X 
12-lead Electrocardiograme 
X 
X 
X 
X 
X 
X 
Urinalysis (dipstick)f 
X 
X 
X 
X 
X 
Chemistry blood collectiong 
X 
X 
X 
X 
X 
Hematology blood collection 
X 
X 
X 
X 
X 
Coagulation (PT and PTT) blood collection 
X 
X 
PTH (1-84) 
X 
X 
X 
25-hydroxyvitamin D level 
X 
1,25-dihydroxy vitamin D level 
X 
FSH 
X 
Thyroid stimulating hormone 
X 
Injection training for subjects 
X 
Dispense calcium and vitamin D 
supplementsn 
X 
X 
X 
X 
X 
X 
Study medication (abaloparatide) 
administration 
Daily abaloparatide administration 


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Study BA058-05-020 Addendum 
 
 
 
Procedure 
Visit 1 
Visit 2 (±4 
days) 
Visit 3 
(+4 days) 
Visit 4 
(±4 days) 
Visit 5 
(±4 days) 
Visit 6 
(±4 days) 
Visit 7 
(±4 days) 
Visit 8 
(±7 days) 
Screening 
(30 Days) 
Pretreatment 
Day 1 
Month 1 
Month 3 
Month 4 
Month 6 
Month 7 
Demeclocycline (dispense and 
administration) 
Xh 
Tetracycline (dispense and administration) 
Xi 
Transiliac crest bone biopsyj 
X 
Serum markers of bone metabolism (PINP 
and CTX) 
X 
X 
X 
AP and lateral lumbar and thoracic spine 
radiographs 
X 
Peripheral quantitative computed 
tomography (pQCT) of the forearm and tibiae 
X 
X 
X 
Clinical assessment of new fracturesk 
X 
X 
X 
X 
X 
X 
X 
Collect blood for immunogenicity testing 
X 
X 
BMD of lumbar spine, total hip, and femoral 
neck 
X 
X 
X 
Investigator assessment of local tolerance 
(dermal reactions assessment) 
X 
X 
X 
X 
X 
Subject diary reviewl 
X 
X 
X 
X 
X 
Document AEs and concomitant 
medicationsm 
At any time, question subject at each visit 
Drug supply/resupply/accountability 
X 
X 
X 
X 
X 
X 
a Including alcohol and tobacco use assessment. 
b 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 not present at screening should be reported as AEs. 


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Study BA058-05-020 Addendum 
 
 
 
c Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse 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. Only blood pressure, pulse rate, and respiration rate are to be recorded one hour post-dose. Supine and standing blood 
pressure measurements will be performed at each visit during the Treatment Period. 
d Height is to be measured in the standing position with shoes off using a medical stadiometer. 
e An ECG will be recorded immediately prior to dosing and one hour post-dose during the Treatment Period. 
f 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 
microorganisms via dipstick. 
g Serum chemistry will be measured pre-dose at Visits 3, 4, 5 and 7. 
h Eighteen days before Day 1 of the Treatment Period (Visit 3), subjects who remain eligible for study participation will begin the first bone biopsy labeling 
procedure with administration of 150 mg demeclocycline 4 times daily for 3 days followed by a 12-day intermission, and then demeclocycline for 3 
additional days at the same dose. 
i Approximately 23 to 26 days before Month 3 (Visit 5), subjects will begin the second bone biopsy labeling procedure with administration of 250 mg 
tetracycline 4 times daily for 3 days followed by a 12-day intermission, and then tetracycline for 3 additional days at the same dose. 
j Transiliac crest bone biopsy 5-8 days after last tetracycline dose. If an addendum subject terminates at or before Month 3, data will be collected 
according to the Addendum schedule for Month 3 (Visit 5) and study completion will occur at Month 4 (Visit 6). The Sponsor Medical Monitor will 
decide if the bone biopsy will be included at Month 3 (Visit 5). 
k 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. 
l The subject will maintain a diary of her assessment of local tolerance after each injection for one week beginning on Day1, Month 1 and Month 3. 
Subject will be instructed on completion of diary in the Pretreatment Period to include administration of medications for bone biopsy labeling 
procedure. The subject medication diary will be reviewed by study personnel at each study visit during the Treatment Period to ensure subject 
compliance. 
m 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. 
n Vitamin D supplements are required to be administered daily from the Pretreatment Period until the end of the Treatment Period. Calcium will also be 
administered daily, with the exception of the days of administration of demeclocycline and tetracycline where calcium administration will be withheld. 


 
 
13-Oct-2020 23:45:13 GMT+0000 
Approval 
 
14-Oct-2020 12:40:35 GMT+0000 
Approval 
 
 
30-Oct-2020 03:06:19 GMT+0000 
Approval 
 
 
Signature Page for RAD-CLIN-002212 v1.0 
 
 
 
 
Signature Page for RAD-CLIN-002212 v1.0 

SAP_001.pdf: 
Confidentiality Statement 
The 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. 
STATISTICAL ANALYSIS PLAN 
An Open-label, Single-arm, Multicenter Study to Evaluate the Early Effects 
of Abaloparatide on Tissue-based Indices of Bone Formation and Resorption 
Protocol BA058-05-020 
Protocol Version and Date: 
Amendment 2 (5 November 2018) 
Name of Test Drug: 
Abaloparatide-SC 
Phase: 
Phase 3 
Methodology: 
Prospective, Single Arm, Open-Label 
Sponsor: 
Radius Health, Inc. 
950 Winter Street 
Waltham, MA 02451 USA 
Tel: 
 
Fax: 
 
Analysis Plan Date: 
05 Mar 2020 
Analysis Plan Version: 
Version 1.0 (final) 
NCT # NCT03710889


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Protocol Title: 
An Open-label, Single-arm, Multicenter Study to Evaluate the 
Early Effects of Abaloparatide on Tissue-based Indices of 
Bone Formation and Resorption 
Protocol Number: 
BA058-05-020, Amendment 2 (5 November 2018) 
Study Drug: 
Abaloparatide-SC 
SAP Version: 
Version 1.0 (final) (05 Mar 2020) 
Prepared By: 
 
 
 
 
 
 
Date 
 
Radius Health, Inc. 
 
REVIEWED AND APPROVED BY: 
 
 
 
 
 
 
Date 
 
Radius Health, Inc. 
 
Date 
 
Radius Health, Inc. 
 
 
 
 
 
 
 
Date 
 
Radius Health, Inc. 
 
Date 
 
Radius Health, Inc. 
 
 
 
 
 
 
 
Date 
 
Radius Health, Inc. 
 
Date 
 
Radius Health, Inc. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................................... 5 
1 
BACKGROUND .................................................................................................................................. 7 
1.1 
Study Objectives............................................................................................................................ 7 
1.2 
Study Design .................................................................................................................................. 7 
1.2.1 
Synopsis of Study Design ....................................................................................................... 7 
1.2.2 
Randomization Methodology ............................................................................................. 13 
1.2.3 
Unblinding ........................................................................................................................... 13 
1.2.4 
Study Procedures ................................................................................................................ 13 
1.2.5 
Study Endpoints .................................................................................................................. 13 
2 
SUBJECT ANALYSIS POPULATIONS ...................................................................................................... 14 
2.1 
Population Definitions ................................................................................................................ 14 
2.2 
Protocol Deviations ..................................................................................................................... 14 
3 
GENERAL STATISTICAL METHODS ....................................................................................................... 14 
3.1 
Sample Size Planned and Specified in the Protocol .................................................................... 14 
3.2 
General Methods ........................................................................................................................ 14 
3.3 
Computing Environment ............................................................................................................. 15 
3.4 
Baseline Definitions..................................................................................................................... 15 
3.5 
Data Pooling ................................................................................................................................ 15 
3.6 
Adjustments for Covariates......................................................................................................... 15 
3.7 
Multiple Comparisons ................................................................................................................. 15 
3.8 
Subgroups ................................................................................................................................... 16 
3.9 
Withdrawals, Dropouts, Loss to Follow-up ................................................................................. 16 
3.10 
Missing, Unused, and Spurious Data........................................................................................... 16 
3.11 
Visit Windows ............................................................................................................................. 16 
3.12 
Interim Analyses .......................................................................................................................... 16 
4 
STUDY ANALYSES ................................................................................................................................ 16 
4.1 
Subject Disposition ...................................................................................................................... 16 
4.2 
Demographics and Baseline Characteristics ............................................................................... 17 
4.3 
Extent of Exposure and Compliance ........................................................................................... 17 


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4.4 
Concomitant Medication ............................................................................................................ 18 
4.5 
Analyses of the Primary Endpoint ............................................................................................... 18 
4.6 
Analyses of Secondary Endpoints ............................................................................................... 18 
4.6.1 
Change from baseline to 3 months in MS/BS in the endocortical, intracortical, and 
periosteal envelopes ........................................................................................................................... 18 
4.6.2 
Change from baseline to 3 months in MAR in the cancellous, endocortical, intracortical, 
and periosteal envelopes .................................................................................................................... 18 
4.6.3 
Change from baseline to 3 months in BFR/BS in the cancellous, endocortical, intracortical, 
and periosteal envelopes .................................................................................................................... 18 
4.6.4 
Structural index (Ct.Po/Ct.Ar) in the intracortical envelope at Month 3 ............................ 18 
4.6.5 
Static indices in the relevant bone envelopes (cancellous, endocortical, intracortical, and 
periosteal) at Month 3 ........................................................................................................................ 19 
4.6.6 
Change from baseline to 3 months in special histomorphometric variables in the relevant 
bone envelopes (cancellous, endocortical, intracortical, and periosteal) .......................................... 19 
4.6.7 
Change in s-PINP and s-CTX from baseline to 1 and 3 months ........................................... 19 
4.6.8 
Correlations of tissue-based indices of bone formation and bone resorption with s-PINP 
and s-CTX19 
4.7 
Safety Analyses ........................................................................................................................... 20 
4.7.1 
Adverse Events .................................................................................................................... 20 
4.7.2 
Investigator Assessment of Local Tolerance ....................................................................... 21 
4.7.3 
Laboratory Data .................................................................................................................. 21 
4.7.4 
Vital Signs ............................................................................................................................ 21 
4.7.5 
Electrocardiogram ............................................................................................................... 23 
4.7.6 
Clinical Fractures ................................................................................................................. 23 
4.7.7 
Anti-abaloparatide Antibodies ............................................................................................ 23 
5 
CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ..................................................................... 23 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
BFR/BS 
Bone formation rate 
BMD 
Bone mineral density 
BMI 
Body Mass Index 
BP 
Blood pressure 
bpm 
Beats per minute 
CI 
Confidence interval 
CSR 
Clinical study report 
Ct.Po/Ct.Ar 
Cortical porosity 
CTMS 
Clinical trial management system 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ES/BS 
Eroded surface 
FSH 
Follicle-stimulating hormone 
IRB 
Institutional Review Board 
MAR 
Mineral apposition rate 
MedDRA 
Medical dictionary for regulatory activities 
MF/BS 
Modeling-based formation 
MS/BS 
Mineralizing surface 
msec 
Millisecond 
oMF/BS 
Overflow modeling-based formation 
OS/BS 
Osteoid surface 
O.Th 
Osteoid thickness 
OV/BV 
Osteoid volume 
PCS 
Potentially clinically significant 
pQCT 
Peripheral quantitative computed tomography 
PR 
Time from beginning of P wave (onset of atrial depolarization) 
to beginning of QRS complex (onset of ventricular 
depolarization) 
PT 
Preferred Term 
PTH 
Parathyroid hormone 
PTT 
Partial thromboplastin time 


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Abbreviation 
Term 
Q1, Q3 
Lower and upper quartiles, respectively, of the interquartile 
range 
QT 
Total depolarization and repolarization time 
QTc 
Total depolarization and repolarization time corrected with 
heart rate 
QTcF 
Total depolarization and repolarization time corrected with 
heart rate – Fridericia correction 
RmF/BS 
Remodeling-based formation 
RR 
Time elapsed between two successive R-waves of the QRS 
signal on the electrocardiogram 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard error 
SI 
Standard international 
SOC 
System organ class 
s-CTX 
Carboxy-terminal cross-linking telopeptide of type I collagen 
s-PINP 
Serum procollagen type 1 N propeptide 
TEAE 
Treatment emergent adverse event 
WHO 
World Health Organization 
W.Th 
Wall thickness 


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1 
BACKGROUND 
This statistical analysis plan (SAP) enhances the statistical considerations specified in the 
protocol for Study BA058-05-020. If considerations are substantially different, they will be 
identified. Any post-hoc or unplanned analyses, or any significant changes from the planned 
analysis in this SAP will be clearly identified and described in the clinical study report (CSR). 
 
1.1 Study Objectives 
Study objectives are to 
1. Demonstrate the early effects of abaloparatide on tissue-based indices of bone formation 
and resorption 
2. Assess the degree to which increased bone formation is achieved by modeling, 
remodeling, and overflow bone formation 
3. Relate the early indices of tissue-based bone formation and bone resorption to those 
measured using biochemical markers of bone turnover 
1.2 Study Design 
1.2.1 Synopsis of Study Design 
This is an open-label, single-arm, multicenter study enrolling postmenopausal women with 
osteoporosis . The study is designed to measure the early effects of abaloparatide on tissue-based 
bone formation and resorption variables based on samples obtained by iliac crest bone biopsy 
after fluorochrome labeling. The study will consist of a Screening Period (up to 1 month), a 
Pretreatment Period (approximately 1 month), a Treatment Period (3 months), and a Month 4 
visit one month after the last dose of study medication. 
There is a sub study at one site to collect pQCT data and extend an additional 3 months of study 
drug administration for a total of 6 months of treatment. 
The study design is presented in Figure 1. Full details of the protocol required assessments can 
be found in the Schedule of Assessments and Procedures (Table 1). 


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Figure 1: BA058-05-020 Study Design, Including Schematic of Bone Biopsy Labeling 
Procedure 


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Table 1: 
Schedule of Assessments 
 
Procedure 
Visit 1 
Visit 2 
(±4 days) 
Visit 3 
(+4 days) 
Visit 4 
(±4 days) 
Visit 5 
(±4 days) 
Visit 6 
(±7 days) 
Screening 
(30 Days) 
Pre- 
treatment 
Day 1 
Month 1 
Month 3 
Month 4 
Informed consent 
X 
Verification of entry criteria 
X 
X 
Review of medical historya 
X 
X 
X 
X 
X 
X 
Physical examinationb 
X 
Symptom directed physical examination 
X 
X 
X 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
Weight and height measurementsd 
X 
X 
X 
X 
X 
12-lead Electrocardiograme 
X 
X 
X 
X 
Urinalysis (dipstick)f 
X 
X 
X 
X 
Chemistry blood collectiong 
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 


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Procedure 
Visit 1 
Visit 2 
(±4 days) 
Visit 3 
(+4 days) 
Visit 4 
(±4 days) 
Visit 5 
(±4 days) 
Visit 6 
(±7 days) 
Screening 
(30 Days) 
Pre- 
treatment 
Day 1 
Month 1 
Month 3 
Month 4 
1,25-dihydroxy vitamin D level 
X 
FSH 
X 
Thyroid stimulating hormone 
X 
Injection training for subjects 
X 
Dispense calcium and vitamin D supplementsn 
X 
X 
X 
X 
Study medication (abaloparatide) administration 
Daily abaloparatide administration until 
and including the day of bone biopsy 
Demeclocycline (dispense and administration) 
Xh 
Tetracycline (dispense and administration) 
Xi 
Transiliac crest bone biopsyj 
X 
Serum markers of bone metabolism (PINP and 
CTX) 
X 
X 
X 
AP and lateral lumbar and thoracic spine 
radiographs 
X 
Clinical assessment of new fracturesk 
X 
X 
X 
X 
X 
Collect blood for immunogenicity testing 
X 
X 
BMD of lumbar spine, total hip, and femoral 
neck 
X 
X 


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Procedure 
Visit 1 
Visit 2 
(±4 days) 
Visit 3 
(+4 days) 
Visit 4 
(±4 days) 
Visit 5 
(±4 days) 
Visit 6 
(±7 days) 
Screening 
(30 Days) 
Pre- 
treatment 
Day 1 
Month 1 
Month 3 
Month 4 
Investigator assessment of local tolerance 
(dermal reactions assessment) 
X 
X 
X 
Subject diary reviewl 
X 
X 
X 
Document AEs and concomitant medicationsm 
At any time, question subject at each visit 
Drug supply/resupply/accountability 
X 
X 
X 
X 
a Including alcohol and tobacco use assessment. 
Error! Reference source not found. 
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 not present at screening 
should be reported as AEs. 
Error! Reference source not found. 
Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse 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. Only blood pressure, pulse rate, and respiration rate are to be recorded one hour post-dose. Supine 
and standing blood pressure measurements will be performed at each visit during the Treatment Period. 
Error! Reference source not found. 
Height is to be measured in the standing position with shoes off using a medical stadiometer. 
Error! Reference source not found. 
An ECG will be recorded immediately prior to dosing and one hour post-dose during the Treatment Period. 
Error! Reference source not found. 
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. 
Error! Reference source not found. 
Serum chemistry will be measured predose at Visits 3, 4, and 5. 
Error! Reference source not found. 
Eighteen days before Day 1 of the Treatment Period (Visit 3), subjects who remain eligible for study participation 
will begin the first bone biopsy labeling procedure with administration of 150 mg demeclocycline 4 times daily for 3 days followed by a 12-day intermission, 
and then demeclocycline for 3 additional days at the same dose. 
Error! Reference source not found. 
Approximately 23 to 26 days before Month 3 (Visit 5), subjects will begin the second bone biopsy labeling 
procedure with administration of 250 mg tetracycline 4 times daily for 3 days followed by a 12-day intermission, and then tetracycline for 3 additional days at 
the same dose. 
Error! Reference source not found. 
Transiliac crest bone biopsy 5-8 days after last tetracycline dose. Sponsor Medical Monitor will decide if included in 
Early Termination Visit. 


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Error! Reference source not found. 
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. 
l. Subject will be instructed on completion of diary in the Pretreatment Period to include administration of medications for bone biopsy labeling procedure. The 
subject medication diary will be reviewed by study personnel at each study visit during the Treatment Period to ensure subject compliance. 
m 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. 
n Vitamin D supplements are required to be administered daily from the Pretreatment Period until the end of the Treatment Period. Calcium will also be 
administered daily, with the exception of the days of administration of demeclocycline and tetracycline where calcium administration will be withheld. 


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1.2.2 Randomization Methodology 
This is a single arm study, and randomization is not used. i.e., not applicable. 
1.2.3 Unblinding 
This is an open-label study, and there is no blinding of study medication. i.e., not applicable. 
1.2.4 Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1. 
1.2.5 Study Endpoints 
• Change from baseline to 3 months in dynamic indices of bone formation in the 
relevant bone envelopes (cancellous, endocortical, intracortical, and periosteal) 
− Mineralizing surface (MS/BS) 
− Mineral apposition rate (MAR) 
− Bone formation rate (BFR/BS) 
• Structural indices in the intracortical envelope at Month 3 
− Cortical porosity (Ct.Po/Ct.Ar) 
• Static indices in the relevant bone envelopes (cancellous, endocortical, intracortical, 
and periosteal) at Month 3 
− Osteoid volume (OV/BV) 
− Osteoid surface (OS/BS) 
− Osteoid thickness (O.Th) 
− Wall thickness (W.Th) 
− Eroded surface (ES/BS) 
• Change from baseline to 3 months in special histomorphometric variables in the 
relevant bone envelopes (cancellous, endocortical, intracortical, and periosteal) 
− Remodeling, modeling, and overflow modeling-based formation (RmF/BS, 
MF/BS, oMF/BS) 
• Change in serum procollagen type I N-terminal propeptide (s-PINP) and carboxy- 
terminal cross-linking telopeptide of type I collagen (s-CTX) from baseline to 1 and 3 
months 
• Correlations of tissue-based indices of bone formation and bone resorption with s- 
PINP and s-CTX 
• Overall safety and tolerability of abaloparatide in postmenopausal women with 
osteoporosis. 


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2 SUBJECT ANALYSIS POPULATIONS 
2.1 Population Definitions 
The primary population for all efficacy analyses will be the Bone-Biopsy Population, which is 
defined as all enrolled subjects who received an evaluable biopsy, defined as a biopsy sample 
that can be analyzed in the laboratory. The primary population for all safety analyses will be the 
Safety Population, which will be defined as all enrolled subjects who received at least one dose 
of abaloparatide. 
2.2 Protocol Deviations 
As documented in the BA058-05-020 Medical Monitoring Plan, the definitions/classifications of 
protocol deviations are as defined in 
 document CTM002-SOP (Managing Protocol 
Deviations; Effective Date: 05 Sep 2017). A protocol devation is any intentional, unintentional 
change or non-compliance with the current IRB/IEC and Competent Authority approved 
protocol procedures or requirements per ICH/GCP guidelines. A deviation may result from the 
action or inaction of the subject, Investigator or site staff. 
Subjects with protocol deviations will be identified and recorded by the clinical trial vendor 
 using their Clinical Trial Management System (CTMS). The list of protocol deviations 
and protocol violations will be reviewed by the clinical team on a regular basis throughout the 
study. At the end of the study, a list of the protocol deviations/violations will be generated from 
the CTMS and included in the clinical study report (CSR). 
 
3 GENERAL STATISTICAL METHODS 
3.1 Sample Size Planned and Specified in the Protocol 
In the AVA study of teriparatide and denosumab (Dempster, 2016), the mean (± SD) change 
from baseline in cancellous MS/BS (%) for teriparatide was 13.90 (± 9.38) at 3 months. In the 
ACTIVE study, the median % change from baseline in s-PINP at 3 months was 60% for 
abaloparatide and 94% for teriparatide. The ratio between the 2 groups is approximately 2/3 (= 
60%/94%). 
Using the same ratio and the results for teriparatide obtained from the AVA study, we can 
assume that the mean change from baseline in cancellous MS/BS (%) for abaloparatide at 3 
months will be 9.2% (= 13.90*2/3). Assuming a standard deviation (SD) of 12.0%, a sample size 
of 21 completers will provide at least 90% power to detect a statistically significant change from 
baseline in cancellous MS/BS (%) for abaloparatide at 3 months of 9.2%. The study is planned to 
enroll approximately 25 subjects to accommodate a drop-out rate of 15%, including those with 
non-evaluable bone biopsy. Additional subjects may be enrolled if the number of evaluable 
biopsies is insufficient to achieve this power. 
3.2 General Methods 
Continuous variables will be summarized with the following descriptive statistics: number of 
observations, (arithmetic) mean, standard deviation (SD), median, interquartile range (Q1 and 
Q3), minimum, and maximum. If the number of subjects is 1, the standard deviation will be left 
blank. Categorical data will be summarized with frequencies for each category and 
corresponding percentages. 


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All data listings that contain an evaluation date will contain a relative study day. Screening, pre- 
treatment and on-treatment study days are numbered relative to the day of the first dose of study 
medication which is designated as Day 1. The preceding day is Day -1, the day before that is Day 
-2, etc. 
In listings, data will be presented with the same precision as the original data. Derived data may 
be rounded to 1 decimal place greater than the original data for presentation purposes. 
Frequency percentages will be presented with 1 decimal. 
For all summaries, the mean and median will be presented to 1 decimal place greater than the 
original data, standard deviation (SD) to 2 greater than the original data, and the minimum and 
maximum will be presented to the same number of decimal places as the original data. 
The summaries will include: 
• data from subjects participating in the main study (i.e., subjects with planned treatment 
duration of 3 months, plus 1 month after the last dose of study medication); and 
• data up to Month 4 for subjects participating in the sub-study (i.e., subjects with planned 
treatment duration of 6 months, plus 1 month after the last dose of study medication). 
All subject data (from the main study and the sub-study) will be presented in listings. 
 
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 21.0. Concomitant medications will be coded using 
the World Health Organization Drug Dictionary (WHODrug Global March 2018 B3). 
 
3.4 Baseline Definitions 
Unless otherwise specified, the baseline value is defined as the last value obtained prior to the 
first dose of study medication. 
 
3.5 Data Pooling 
Data from all sites will be pooled together for all analyses unless otherwise 
specified. 
 
3.6 Adjustments for Covariates 
No adjustment for covariates will be made in any of the planned analyses for study endpoints. 
 
3.7 Multiple Comparisons 
Not applicable. 


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3.8 Subgroups 
Not applicable. 
 
3.9 Withdrawals, Dropouts, Loss to Follow-up 
Data from subjects who do not complete the study, or who are lost to follow-up will be included 
in data listings and in summary tables, as appropriate. 
 
3.10 Missing, Unused, and Spurious Data 
Unless otherwise specified, there will be no imputation of data. 
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. 
 
3.11 Visit Windows 
Unless otherwise specified, data will not be analyzed using visit windows; instead, the nominal 
visit will be used. 
 
3.12 Interim Analyses 
There are no interim analyses planned for this study. 
 
 
4 STUDY ANALYSES 
Unless otherwise specified, all summary tables described in this section will be presented for the 
Safety Population. 
 
4.1 Subject Disposition 
Subject disposition will include the number of subjects enrolled, included in the safety 
population and reasons for exclusion from the safety population, included in the bone-biopsy 
population and reasons for exclusion from the bone-biopsy population, completed treatment, 
discontinued treatment with reasons for treatment discontinuation, completed the study, 
discontinued study with primary reasons for not completing the study. 


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A by-subject data listing of treatment completion and study completion information, including 
the primary reasons for treatment discontinuation and for study withdrawal, as recorded in the 
eCRF, will be presented. 
 
4.2 Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized. Age, height, weight, body mass 
index (BMI), total hip T-score, total hip BMD, femoral neck T-score, femoral neck BMD, 
lumbar spine T-score, and lumbar spine BMD will be summarized using descriptive statistics 
(number of subjects, mean, SD, median, interquartile range, minimum and maximum). The 
number and percentage of subjects in each age (<65 years, 65 to <75, >=75), gender, ethnicity, 
race and total hip/lumbar spine/femoral neck T-score category (> -2.5 to <= -2.0; > -3.0 to 
<= -2.5; and <= -3.0) will also be presented. 
The number and percentage of subjects in each substance use category (tobacco history, alcohol 
use, use of other substances) and with prevalent clinical fracture will also be presented. 
Medical history will be presented by MedDRA system organ class (SOC) and preferred term 
(PT) summarizing the proportion of subjects who have a condition noted. 
All subject data collected for demographics and baseline characteristics will be presented in data 
listings. 
 
4.3 Extent of Exposure and Compliance 
Study drug exposure and compliance will be calculated using the data recorded on the Visit Day 
Study Medication Injection, the Injected Medication Accountability Log, and the End of 
Treatment eCRF pages as follows: 
• Duration of Exposure (days) 
= date of last study medication – date of first study medication + 1 
Note: The date of last study medication will be obtained from the End of Treatment 
eCRF. If the date of last study medication is missing, the last available date of study 
medication on the Visit Day Study Medication Injection eCRF will be used. 
• Number of Doses Delivered 
= duration of exposure - number of missed doses per subject diary 
• Compliance (%) 
= (Number of doses delivered / Duration of exposure) x 100% 
For demeclocycline and tetracycline, the number of doses delivered will be calculated as 
• Number of Tablets Dispensed - Number of Tablets Returned. 
 
Descriptive statistics (number of subjects, mean, SD, median, interquartile range, minimum and 
maximum) will be used to summarize duration of exposure, number of doses delivered, and 
compliance. 


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4.4 Concomitant Medication 
Concomitant medications will be coded using the WHO Drug Dictionary. The number (and 
percentage) of subjects taking medications will be tabulated by Anatomical Therapeutic 
Chemical (ATC) class and preferred term (PT). 
The tabulations will include concomitant 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 and PT. 
All recorded prior and concomitant medications will be presented in a by-subject listing. 
 
4.5 Analyses of the Primary Endpoint 
The primary endpoint is the change from baseline to 3 months in MS/BS in the cancellous 
envelope. Paired t-tests will be used to compare the differences in dynamic indices between the 
two time-points using the Bone-Biopsy Population. If the normality assumption of the efficacy 
data is not satisfied at the 0.01 significance level with Shapiro–Wilk test and if visual inspection 
of the data deems it necessary, the Wilcoxon signed-rank test will be used to assess changes from 
baseline. No adjustments for multiplicity will be made. A two-sided p-value < 0.05 will be 
considered statistically significant. The actual values and change from baseline values will be 
summarized with descriptive statistics (number of subjects, mean, SD, median, interquartile 
range, minimum and maximum) by visit, together with 95% CI for the mean. 
 
4.6 Analyses of Secondary Endpoints 
4.6.1 Change from baseline to 3 months in MS/BS in the endocortical, intracortical, and 
periosteal envelopes 
The same analyses described in Section 4.5 will be used. 
4.6.2 Change from baseline to 3 months in MAR in the cancellous, endocortical, intracortical, 
and periosteal envelopes 
The same analyses described in Section 4.5 will be used. 
4.6.3 Change from baseline to 3 months in BFR/BS in the cancellous, endocortical, 
intracortical, and periosteal envelopes 
The same analyses described in Section 4.5 will be used. 
4.6.4 Structural index (Ct.Po/Ct.Ar) in the intracortical envelope at Month 3 
The actual values will be summarized with descriptive statistics (number of subjects, mean, SD, 
median, interquartile range, minimum and maximum), together with 95% CI for the mean. 


Radius Health, Inc. 
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Final V1.0 
Page 19 of 25 
 
 
 
4.6.5 Static indices in the relevant bone envelopes (cancellous, endocortical, intracortical, and 
periosteal) at Month 3 
The following study endpoints will be summarized with descriptive statistics (number of 
subjects, mean, SD, median, interquartile range, minimum and maximum), together with 95% CI 
for the mean. 
• OV/BV 
• OS/BS 
• O.Th 
• W.Th 
• ES/BS 
4.6.6 Change from baseline to 3 months in special histomorphometric variables in the relevant 
bone envelopes (cancellous, endocortical, intracortical, and periosteal) 
Decriptive statistics (number of subjects, mean, SD, median, interquartiale range (Q1, Q3), 
minimum and maximum) will be provided for the following endpoints. 
• RmF/BS 
• MF/BS 
• oMF/BS 
4.6.7 Change in s-PINP and s-CTX from baseline to 1 and 3 months 
The actual values, change from baseline values, percentage change from baseline values, 
geometric mean, geometric mean (SE) of ratio (post-baseline value to baseline value) in s-PINP 
and s-CTX will be summarized descriptively by visit, together with the 95% CI of the mean, for 
both the Bone-Biopsy and the Safety populations. 
4.6.8 Correlations of tissue-based indices of bone formation and bone resorption with s-PINP 
and s-CTX 
Linear regression analyses will be used to assess the relationships between tissue-based indices 
of bone formation and bone resorption and changes in bone turnover markers at each visit, 
including 
• Changes in MS/BS in each envelope (cancellous, endocortical, intracortical, and 
periosteal) at Month 3 to changes in s-PINP at Months 1 and 3 
• Changes in BFR/BS in each envelope (cancellous, endocortical, intracortical, and 
periosteal) at Month 3 to changes in s-PINP at Months 1 and 3 
• Changes in intracortical MS/BS at Month 3 to changes in s-CTX at Months 1 and 3, 
• Changes in intracortical BFR/BS at Month 3 to changes in s-CTX at Months 1 and 3, 
• MS/BS in each envelope (cancellous, endocortical, intracortical, and periosteal) at Month 
3 to s-PINP at Months 1 and 3 


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• BFR/BS in each envelope (cancellous, endocortical, intracortical, and periosteal) at 
Month 3 to s-PINP at Months 1 and 3 
• Intracortical MS/BS at Month 3 to s-CTX at Months 1 and 3 
• Intracortical BFR/BS at Month 3 to s-CTX at Months 1 and 3 
• ES/BS in each envelope (cancellous, endocortical, intracortical, and periosteal) at Month 
3 to s-CTX at Months 1 and 3 
• Cortical porosity at Month 3 to s-CTX at Months 1 and 3 
The analyses include scatter plots, Spearman’s rank correlation coefficient, and slopes of simple 
regression models, together with corresponding 95% CI of Spearman's correlation coefficient 
using the Bone-Biopsy population. 
 
4.7 Safety Analyses 
All safety analyses will be conducted using the Safety population. Unless otherwise specified, 
no formal statistical hypothesis testing will be performed for safety endpoints, and the 
presentations will be based on descriptive summaries. 
4.7.1 Adverse Events 
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) 
prior to the start of study drug and which occurs 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 during the study 
period(s) prior to the start of study drug and worsened in severity after the start of study drug 
within 30 days of the last dose of study drug. 
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. 
The number (%) of subjects with TEAEs will be summarized by SOC and PT. This analysis will 
also be performed for the following types of AEs: most common (≥5%) TEAEs, severe TEAEs, 
serious TEAEs (SAEs), TEAEs leading to study drug withdrawal, drug-related TEAEs (with 
probable or possible relationship to study drug), and AEs that are not treatment-emergent. 
The number (%) of subjects with TEAEs will also be summarized by PT in order of decreasing 
frequency. 
The number (%) of subjects with TEAEs by SOC and PT will also be tabulated by maximum 
severity (mild, moderate, or severe). A similar tabulation will be presented by relationship 
(related or not related) to study drug. 
Subject listings will be provided for all AEs by SOC and PT. Listings will also be produced for 
AEs with outcome of deaths, severe AEs, SAEs, and AEs leading to study drug withdrawal. 


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4.7.2 Investigator Assessment of Local Tolerance 
For each symptom (redness, swelling, pain, tenderness), descriptive statistics (number of 
subjects, mean, SD, median, interquartile range, minimum and maximum) will be used to 
summarize 4-point scale scores (0=None, 1=Mild, 2=Moderate,3=Severe) by visit and timepoint. 
The maximum severity of each symptom of local skin reaction per subject will be summarized 
with the number (%) of subjects in each response category by 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 timepoint (including any post dose timepoint). 
In addition, for each symptom, the number (%) of subjects in each response category (none, 
mild, moderate, and severe) will be provided per visit and timepoint. The maximum severity of 
symptom scores will be similarly summarized for each response category by visit and by 
timepoint, respectively. 
All local tolerance assessment scores will be presented in a listing. 
4.7.3 Laboratory Data 
Clinical laboratory values will be provided in standard international (SI) units by the central 
laboratory. 
Summaries of laboratory data using descriptive statistics by study visit will be presented based 
on the SI units, including absolute results and changes from baseline. This includes serum 
chemistry, hematology, coagulation, urinalysis, and additional tests. In the event of repeat or 
unscheduled assessments prior to Day 1, the last non-missing value prior to Day 1 will be used to 
represent the Screening laboratory assessment. Results from other repeat or unscheduled visits 
will not be included in this summary. 
Shift analyses of laboratory data from baseline to each post-baseline visit will be performed. 
Results for laboratory data will be presented by category (above normal limit, within normal 
limit, below normal limit). For shift tables, subjects who are missing either assessment will not 
be included in the percentage calculation (numerator or denominator). In addition, shift analyses 
of laboratory data from baseline to the worst post-baseline value will be provided. Results from 
repeat or unscheduled visits will be included in the shift analyses as applicable. 
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. 
4.7.4 Vital Signs 
Vital signs data will be summarized by visit (and timepoint if applicable). Descriptive statistics 
will be provided for the observed value and the change from baseline values.Results from repeat 
or unscheduled visits will not be included in this summary. 
All vital signs data will be presented for each subject in a data listing. 
Criteria for determining vital signs values that are considered potentially clinically significant 
(PCS) are listed below: 


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Vital Sign 
Criterion 
Body Temperature (⁰C) 
≥ 39.0 
Heart Rate (bpm) 
> 100 
> 130 
< 45 
Supine Systolic BP (mmHg) 
> 155 
< 80 
Supine Diastolic BP (mmHg) 
> 100 
Standing Systolic BP (mmHg) 
> 155 
< 80 
Standing Diastolic BP (mmHg) 
> 100 
 
 
The number (and percentage) of subjects who have PCS values after the first dose of study drug, 
but did not have PCS values at baseline, will be presented. 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. 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 vital sign parameter of interest. All vital 
signs data, including repeat and unscheduled assessments, will be included in determining the 
incidence of PCS vital sign values. A listing of subjects with any PCS vital sign values will be 
provided. 
4.7.4.1 Orthostatic Hypotension 
The number (%) of subjects experiencing orthostatic hypotension will be summarized by visit 
and time point. Orthostatic hypotension will be defined as a decrease in systolic blood pressure 
(SBP) of ≥ 20 mmHg from seated or supine to standing or in diastolic blood pressure (DBP) of ≥ 
10 mmHg from seated or supine to standing. All blood pressure data, including repeat and 
unscheduled assessments, will be included in determining the incidence of orthostatic 
hypotension. If a subject has multiple results on the vital signs at a particular visit and time point, 
the last non-missing value at that visit/time point will be used for this summary. 
A listing of subjects who experienced orthostatic hypotension will be provided. 
4.7.4.2 Heart Rate 
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 


Radius Health, Inc. 
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Page 23 of 25 
 
 
 
occurrences will be summarized using the median, minimum and maximum values. All heart rate 
data, including repeat and unscheduled assessments, will be included in determining the increase 
from pre-dose in this summary. 
4.7.5 Electrocardiogram 
Descriptive statistics will be provided to summarize ECG parameters and changes from baseline 
by visit and time point. The ECG parameters include heart rate (bpm), RR interval (msec), PR 
interval (msec), QRS duration (msec), QT interval (msec), and QTcF (Fridericia) (msec). Results 
from repeat or unscheduled visits will not be included in this summary. 
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 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. 
Incidence of change from baseline in QTcF >=30 msec and >=60 msec by visit and time point 
will be provided. The number and percentage of subjects with post-baseline QTcF > 500 msec 
and change from baseline >= 60 msec in QTcF by visit and time point will be presented. 
Shifts from baseline (<=450 msec and >450 msec, <=480 msec and >480 msec; <=500 msec and 
>500 msec) in QTcF by visit and time point will be provided. 
Listings of subjects satisfying each of the above criteria will be provided. 
4.7.6 Clinical Fractures 
The number and percentage of subjects with any post-baseline clinical fracture will be presented, 
together with the fracture location. 
4.7.7 Anti-abaloparatide Antibodies 
As per Radius deviation report QE-003032 approved 27-Feb-2020, the collected immunogenicity 
samples will not be tested as part of this study. 
 
 
5 CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES 
The following changes from the protocol-specified analyses are included in this SAP: 
1. Sectioin 4.6.8 states that correlations between the tissue-based indices of bone formation 
and bone resorption with the bone turnover markers (s-PINP and s-CTX) will be 
evaluated using Spearman’s rank correlation coefficient, instead of Pearson’s correlation 
coefficient, due to the expected non-linear relationship between variables. 
2. Section 4.7.4 provides criteria for potentially clinically significant (PCS) vital signs 
values with corresponding analyses. 
3. Section 4.7.4.1 gives the definition for othostatic hypotension and the analysis of this 
parameter. 


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4. Section 4.7.5 describes summaries for QTcF notable values, change from baseline values, 
and shifts from baseline values. 
5. Section 4.7.7 states that the collected immunogenicity samples will not be tested as part 
of this study. 
All other statements in this SAP are enhancements to the statistical considerations described in 
the protocol. 


Radius Health, Inc. 
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References 
Dempster DW, Zhou H, Recker RR, Brown JP, Recknor CP, Lewiecki EM, Miller PD, Rao SD, 
Kendler DL, Lindsay R, Krege JH, Alam J, Taylor KA, Janos B, Ruff VA. Differential effects of 
teriparatide and denosumab on intact PTH and bone formation indices: the AVA osteoporosis 
study. J Bone Miner Res. 2016;101:1353-1363. 


 
 
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Signature Page for RAD-CLIN-001709 v1.0 
 
 
 
 
 
 
 
 
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