Clinical trial NCT01631214
Conditions: Postmenopausal Women With Osteoporosis
Keywords: Osteoporosis, Osteoporosis-postmenopausal, Bone Diseases-Metabolic, Bone Diseases, Musculoskeletal Diseases
Sponsor: Amgen
Start date: 2012-05-04; Completion date: 2017-06-29
Enrollment: 4093 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if treatment is effective in preventing fractures in women with postmenopausal osteoporosis.

Detailed description:
In this trial, women were randomly assigned in a 1:1 ratio to receive monthly subcutaneous romosozumab or weekly oral alendronate for 12 months. Randomization was stratified according to age (\<75 vs. ≥75 years). After completion of the double-blind treatment period, all the participants were to receive open-label weekly oral alendronate until the end of the trial, with blinding to the initial treatment assignment maintained.

The primary analysis was performed when clinical fracture events had been confirmed in at least 330 participants and all the participants had completed the month 24 visit. The study was to continue in an event-driven manner until at least 440 participants experienced a nonvertebral fracture or if the superiority of romosozumab was proven for nonvertebral fractures at the primary analysis.

Arms: arm 1: Participants received 70 mg alendronate once a week and placebo to romosozumab subcutaneously once a month for the first 12 months. After completion of the 12-month double-blind treatment period participants continued to receive 70 mg alendronate once a week until the end of the study. arm 2: Participants received 210 mg romosozumab subcutaneously once a month and placebo to alendronate orally once a week for the first 12 months. After completion of the 12-month double-blind treatment period participants received 70 mg alendronate once a week until the end of the study.
Interventions: intervention 1: Romosozumab intervention 2: Alendronate intervention 3: Placebo to Romosozumab intervention 4: Placebo to Alendronate
Intervention descriptions: intervention 1: Romosozumab 210 mg administered by subcutaneous injection once a month during the double-blind treatment phase. intervention 2: Alendronate 70 mg tablet taken once a week intervention 3: Administered by subcutaneous injection once a month during the double-blind treatment phase. intervention 4: Matching placebo tablet taken once a week during the double-blind treatment phase.

Protocol documents:
SAP_002.pdf: 
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Product:  Romosozumab 
Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
Page 2 
 
Table of Contents 
Table of Abbreviations ...................................................................................................... 7 
1. 
Introduction .............................................................................................................. 9 
2. 
Objectives ................................................................................................................ 9 
2.1 
Primary ......................................................................................................... 9 
2.2 
Secondary .................................................................................................... 9 
2.3 
Exploratory ................................................................................................. 10 
2.4 
Safety ......................................................................................................... 11 
2.5 
Imaging and Pharmacokinetics (PK) / Bone Turnover Marker 
(BTM) / Biomarker Sub-study ..................................................................... 11 
3. 
Study overview ....................................................................................................... 12 
3.1 
Study Design .............................................................................................. 12 
3.2 
Sample Size ............................................................................................... 14 
3.2.1 
Sample Size Considerations ...................................................... 14 
3.2.2 
Assumptions ............................................................................... 14 
3.2.3 
Simulation and Power ................................................................. 16 
4. 
Study Endpoints and Covariates ............................................................................ 18 
4.1 
Primary Endpoints ...................................................................................... 18 
4.2 
Secondary Endpoints ................................................................................. 18 
4.3 
Safety Endpoints ........................................................................................ 19 
4.4 
Exploratory Endpoints ................................................................................ 20 
4.5 
Imaging and PK/BTM/Biomarker Sub-study Endpoints .............................. 21 
4.6 
Planned Covariates .................................................................................... 22 
5. 
Hypotheses and/or Estimation ............................................................................... 22 
6. 
Definitions .............................................................................................................. 23 
6.1 
Basic Definitions ......................................................................................... 23 
6.1.1 
Study Points of Reference .......................................................... 23 
6.1.2 
Study Dates ................................................................................ 24 
6.1.3 
Study Time Intervals ................................................................... 26 
6.1.4 
Fracture Risk Assessment Tool: 10-year Probability of 
Major Osteoporotic Fracture (FRAX) .......................................... 27 
6.2 
Subject Disposition ..................................................................................... 27 
6.3 
Arithmetic Calculations ............................................................................... 28 
6.4 
Fracture-related Study Endpoints ............................................................... 30 
6.4.1 
Trauma Severity Definitions ....................................................... 30 
6.4.2 
Vertebral Fracture ....................................................................... 30 
6.4.3 
Nonvertebral Fracture (Osteoporotic) ......................................... 32 
6.4.4 
Clinical Fracture .......................................................................... 34 


Product:  Romosozumab 
Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
Page 3 
 
6.4.5 
All Fracture (Osteoporotic) ......................................................... 34 
6.4.6 
Major Osteoporotic Fracture ....................................................... 34 
6.4.7 
Historical Fracture ...................................................................... 34 
6.5 
PRO Measurements ................................................................................... 35 
7. 
Analysis Subsets .................................................................................................... 36 
7.1 
Primary Efficacy Analysis Set For Vertebral Fractures ............................... 36 
7.2 
Full Analysis Set ......................................................................................... 36 
7.3 
Per Protocol Analysis Set for 12-month of Double-blind Period ................. 36 
7.4 
Per Protocol Analysis Set for 24-Month Study Period, Primary 
Analysis Period, and Overall Study Period ................................................. 37 
7.5 
Safety Analysis Set ..................................................................................... 38 
7.6 
Primary Efficacy Analysis Set for BMD, Height, and PRO/ClinRO 
Endpoints for the Double-blind ALN-controlled Study Period and 
Primary Analysis Period ............................................................................. 39 
7.7 
Analysis Set for Post Fracture PRO/ClinRO Endpoints .............................. 39 
7.8 
Analysis Subsets for Imaging and Pharmacokinetics (PK) / Bone 
Turnover Marker (BTM) / Biomarker Sub-study ......................................... 39 
7.8.1 
Sub-study Imaging Efficacy Analysis Set ................................... 39 
7.8.2 
Sub-study BTM  Efficacy Analysis Set ....................................... 39 
7.8.3 
Sub-study BTM  Safety Analysis Set .......................................... 40 
7.8.4 
Sub-study PK Analysis Set ......................................................... 40 
7.9 
Subgroup Analyses .................................................................................... 40 
7.10 
Efficacy Analysis Set in Month 12 to 24 Study Period ................................ 41 
7.11 
Efficacy Analysis Set for Vertebral Fracture in Month 12 to 24 
Study Period ............................................................................................... 41 
8. 
Interim Analysis and Early Stopping Guidelines ..................................................... 42 
9. 
Data Screening and Acceptance ............................................................................ 43 
9.1 
Data Handling and Electronic Transfer of Data .......................................... 43 
9.2 
Handling of Missing and Incomplete Data .................................................. 43 
9.2.1 
Genant Semiquantitative Grades ............................................... 43 
9.2.2 
Vertebral Fracture Assessment .................................................. 43 
9.2.3 
DXA or QCT Endpoints .............................................................. 44 
9.2.4 
Bone Turnover Markers/Biomarkers and PK .............................. 44 
9.2.5 
PRO Measurements ................................................................... 44 
9.2.5.1 
OPAQ-SV ................................................................. 44 
9.2.5.2 
EQ-5D-5L ................................................................. 44 
9.2.5.3 
BPI Worst Pain ......................................................... 44 
9.2.5.4 
LAD .......................................................................... 44 
9.2.6 
Dates .......................................................................................... 45 
9.2.7 
Lab Parameters .......................................................................... 46 
9.2.8 
Height ......................................................................................... 46 
9.2.9 
Oral IP Alendronate .................................................................... 47 


Product:  Romosozumab 
Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
Page 4 
 
9.3 
Outliers ....................................................................................................... 47 
9.4 
Distributional Characteristics ...................................................................... 47 
9.5 
Validation and Configuration Management ................................................ 47 
10. 
Statistical Methods of Analysis ............................................................................... 48 
10.1 
General Principles ...................................................................................... 48 
10.2 
Subject Accountability ................................................................................ 49 
10.3 
Important Protocol Deviations .................................................................... 50 
10.4 
Demographic and Baseline Characteristics ................................................ 50 
10.4.1 
Vitamin D Loading Dose Administration ..................................... 51 
10.5 
Efficacy Analyses ....................................................................................... 53 
10.5.1 
Descriptions of Standard Summaries and Statistical 
Models ........................................................................................ 53 
10.5.1.1 
Standard Analyses for Binary Endpoints ................. 53 
10.5.1.2 
Standard Analyses for Ordinal Endpoints ................ 54 
10.5.1.3 
Standard Analyses for Time-to-event 
Endpoints ................................................................. 54 
10.5.1.4 
Standard Analyses for Continuous 
Endpoints ................................................................. 55 
10.5.1.5 
ANCOVA Model ....................................................... 55 
10.5.1.6 
Repeated Measures Model ...................................... 55 
10.5.1.7 
Wilcoxon Rank-sum Test ......................................... 56 
10.5.1.8 
Van Elteren Stratified Rank Test .............................. 56 
10.5.2 
Analyses of Primary Efficacy Endpoints ..................................... 56 
10.5.2.1 
Primary Analytical Approach .................................... 56 
10.5.2.2 
Supportive Analyses ................................................ 57 
10.5.2.3 
Covariate Analysis ................................................... 57 
10.5.2.4 
Subgroup Analysis ................................................... 58 
10.5.3 
Analyses of Secondary and Exploratory Efficacy 
Endpoints ................................................................................... 58 
10.5.3.1 
Nonvertebral Fracture, Clinical Fracture, 
Clinical Vertebral Fracture, All Fracture, 
Major Nonvertebral Fracture, Major 
Osteoporotic Fracture and Hip Fracture .................. 58 
10.5.3.2 
New Vertebral Fracture, New or 
Worsening Vertebral Fracture, and 
Multiple New or Worsening Vertebral 
Fracture .................................................................... 60 
10.5.3.3 
Percent Changes in Lumbar Spine, Total 
Hip and Femoral Neck BMD by DXA ....................... 60 
10.5.3.4 
Change from Baseline in Height .............................. 61 
10.5.4 
PRO/ClinRO Exploratory Endpoints ........................................... 61 
10.6 
Safety Analyses .......................................................................................... 64 
10.6.1 
Adverse Events .......................................................................... 65 
10.6.2 
Osteonecrosis of the Jaw Adjudication ....................................... 66 


Product:  Romosozumab 
Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
Page 5 
 
10.6.3 
Adjudicated Positive Cardiovascular Events .............................. 66 
10.6.4 
Atypical Femoral Fracture Adjudication ...................................... 67 
10.6.5 
On Study Cancer ........................................................................ 67 
10.6.6 
Injection Site Reaction ................................................................ 67 
10.6.7 
Hypersensitivity .......................................................................... 67 
10.6.8 
Tumor Necrosis Factor Mediated Inflammatory 
Diseases .................................................................................... 68 
10.6.9 
Laboratory Test Results ............................................................. 68 
10.6.10 
Vital Signs, Height, Body Weight, and BMI ................................ 69 
10.6.11 
Anti-Romosozumab Antibody ..................................................... 69 
10.6.12 
Exposure to Investigational Product ........................................... 70 
10.6.13 
Exposure to Concomitant Medication ......................................... 70 
10.7 
Endpoints From Sub-study ......................................................................... 70 
10.7.1 
Bone Turnover Marker and Biomarker ....................................... 70 
10.7.2 
BMD by DXA .............................................................................. 70 
10.7.3 
vBMD by QCT and Lumber Spine Strength by FEA ................... 71 
10.7.4 
PK ............................................................................................... 71 
11. 
Changes From Protocol-Specified Analyses .......................................................... 71 
12. 
Literature Citations  References ............................................................................ 72 
13. 
Appendices ............................................................................................................ 74 
13.1 
Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs ......................................................... 74 
13.1.1 
Visit Windows ............................................................................. 74 
13.1.1.1 
Spine X-ray .............................................................. 74 
13.1.1.2 
DXA (lumbar spine and proximal femur) 
for All Subjects ......................................................... 75 
13.1.1.3 
DXA (lumbar spine and proximal femur) 
for imaging component of Sub-study ....................... 75 
13.1.1.4 
QCT for imaging component of Sub-study ............... 75 
13.1.1.5 
OC and BSAP for Sub-study .................................... 76 
13.1.1.6 
BTM (Excluding OC and BSAP) or 
Biomarker for Sub-study .......................................... 76 
13.1.1.7 
Laboratory ................................................................ 77 
13.1.1.8 
Antibody (AB) ........................................................... 77 
13.1.1.9 
Weight and Height ................................................... 78 
13.1.1.10 OPAQ-SV, LAD, BPI and EQ-5D ............................. 78 
13.1.1.11 Post-fracture OPAQ-SV and EQ-5D-5L, 
LAD and BPI ............................................................ 79 
13.1.1.12 Vital Signs ................................................................ 79 
13.2 
Genant Semiquantitative Scoring Method .................................................. 80 
13.3 
Reliability, Validity, and Scoring Algorithm for PRO 
Measurements ............................................................................................ 80 


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Product:  Romosozumab 
Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
Page 7 
 
Table of Abbreviations 
Abbreviation 
Definition 
AB 
Antibody 
AE 
Adverse Event 
ALN 
Alendronate 
ANCOVA 
Analysis of Covariance 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
BPI 
Brief Pain Index 
BTM 
Bone Turnover Marker 
BSAP 
Bone Specific Alkaline Phosphatase 
ClinRO 
Clinician Reported Outcome; questionnaires completed by physician or 
site staff using information provided by the subject 
CPEVENT 
Clinical planned event 
CTCAE 
Common Terminology Criteria of Adverse Events 
CT 
Computerized Tomography 
CV  
Cardiovascular  
DMC 
Data Monitoring Committee 
DXA 
Dual X-ray Absorptiometry 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EDC 
Electronic Data Capture 
EQ-5D-5L 
EuroQol-5 Dimensions-5 Levels Health Survey 
FEA 
Finite Element Analysis 
FRAX 
10-year Probability of Major Osteoporotic and Hip Fractures Based on 
WHO Risk Factor Criteria 
ICF 
Informed Consent Form 
IP 
Investigational Product 
IPD 
Important Protocol Deviation 
iPTH 
Intact Parathyroid Hormone 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
LAD 
Limited Activity Days  
Page 1 of 2 


Product:  Romosozumab 
Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
Page 8 
 
Abbreviation 
Definition 
LOCF 
Last Observation Carried Forward 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
OPAQ SV 
Osteoporosis Assessment Questionnaire Short Version 
OC 
Osteocalcin 
P1NP 
Procollagen Type I N-terminal Peptide  
PK 
Pharmacokinetic 
PKDM 
Pharmacokinetic and Drug Metabolism 
PO 
Orally 
PRO 
Patient Reported Outcomes  
PTH 
Parathyroid Hormone 
QCT 
Quantitative Computerized Tomography 
QM 
Every month 
sCTx 
Serum Type I Collagen C-telopeptide 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SERM 
Selective Estrogen Receptor Modulator 
SMQ 
Standardised MedDRA Query 
VAS 
Visual Analog Scale 
vBMD 
Volumetric Bone Mineral Density 
WHO 
World Health Organization 
Page 2 of 2 


Product:  Romosozumab 
Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
Page 9 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for romosozumab, 
Protocol 20110142 dated 14 September 2016. The scope of this plan includes analyses 
that are planned and will be executed by the Biostatistics department or designee unless 
otherwise specified (eg, pharmacokinetic [PK] modeling will be provided by 
Pharmacokinetic and Drug Metabolism [PKDM] group). 
2. 
Objectives 
2.1 
Primary 
For the primary analysis period (randomization to primary analysis): 
To assess the effect of romosozumab treatment for 12 months followed by alendronate 
(ALN) treatment compared with ALN treatment alone on: 
 
 Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral 
fracture) in postmenopausal women with osteoporosis  
 
Subject incidence of new vertebral fracture in postmenopausal women with 
osteoporosis 
2.2 
Secondary  
For the primary analysis period: 
To assess the effect of romosozumab treatment for 12 months followed by ALN 
treatment compared with ALN treatment alone on:  
 
Subject incidence of fractures (all fractures [nonvertebral fractures and new or 
worsening vertebral fractures], new or worsening vertebral fracture, nonvertebral 
fracture, major nonvertebral fracture [pelvis, distal femur, proximal tibia, ribs, 
proximal humerus, forearm, and hip], hip fracture, multiple new or worsening 
vertebral fracture, and clinical vertebral fracture) 
 
Percent changes in Dual energy X-ray Absorptiometry (DXA) bone mineral density 
(BMD) at the lumbar spine, total hip, and femoral neck 
For the 12-month double-blind ALN-controlled study period: 
To assess the effect of romosozumab treatment for 12 months compared with ALN 
treatment on:  
 
Subject incidence of fractures (clinical fracture [nonvertebral fracture and clinical 
vertebral fracture], new vertebral fracture, all fractures [nonvertebral fractures and 
new or worsening vertebral fractures], nonvertebral fracture, hip fracture, clinical 
vertebral fracture, major osteoporotic fracture [hip, forearm, humerus, and clinical 
vertebral])  


Product:  Romosozumab 
Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
Page 10 
 
 
Percent changes from baseline in DXA BMD at the lumbar spine, total hip and 
femoral neck 
For the overall study (randomization to end of study): 
 
To assess the effect of romosozumab treatment for 12 months followed by ALN 
treatment compared with ALN treatment alone on subject incidence of hip fracture, 
major nonvertebral fracture [pelvis, distal femur, proximal tibia, ribs, proximal 
humerus, forearm, and hip], and nonvertebral fractures  
2.3 
Exploratory   
For the 12-month double-blind ALN-controlled study period: 
 
To assess the effect of romosozumab treatment for 12 months compared with ALN 
treatment on subject incidence of fractures (new or worsening vertebral fracture,  
major nonvertebral fracture [pelvis, distal femur, proximal tibia, ribs, proximal 
humerus, forearm, and hip], and multiple new or worsening vertebral fracture) 
 
To describe subjects’ experience of pain and its impact on subjects’ activities and 
health-related quality of life at 6-month intervals for postmenopausal women with 
osteoporosis using Patient Reported Outcome (PRO) and Clinician Reported 
Outcome (ClinRO) questionnaires (Osteoporosis Assessment Questionnaire Short 
Version [OPAQ SV], EuroQoL-5 Dimensions-5 Levels Health Survey [EQ-5D-5L], 
Limited Activity Days [LAD] survey, and one item extracted from the Brief Pain 
Inventory [BPI] assessing the worst pain experienced in the past 24 hours [BPI worst 
pain]) 
 
To describe subjects’ experience of pain and its impact on subjects’ activities and 
health-related quality of life for 3 months at 1-month intervals after experiencing a 
nonvertebral or clinical vertebral fracture (OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain) 
 
To describe the effect of romosozumab treatment for 12 months compared with ALN 
treatment on the percent of subjects with a clinically meaningful improvement in 
worst pain for 3 months at 1-month intervals after experiencing a nonvertebral or 
clinical vertebral fracture (defined as a 2-point improvement in the BPI worst pain 
scale compared with the fracture reporting visit)  
 
To assess the effect of romosozumab treatment for 12 months compared with ALN 
treatment on changes in height 
For the primary analysis period: 
 
To assess the effect of romosozumab treatment for 12 months followed by ALN 
treatment compared with ALN treatment alone on subject incidence of major 
osteoporotic fracture (hip, forearm, humerus, and clinical vertebral) 
 
To describe subjects’ experience of pain and its impact on subjects’ activities and 
health-related quality of life at 6-month intervals for postmenopausal women with 
osteoporosis using PRO and ClinRO questionnaires (OPAQ SV, EQ-5D-5L, LAD, 
and BPI worst pain) 
 
To assess the effect of romosozumab treatment for 12 months followed by ALN 
treatment compared with ALN treatment alone on changes in height 


Product:  Romosozumab 
Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
Page 11 
 
During the Month 12 to 24 ALN study period 
 
To assess the effect of one year of romosozumab treatment compared with ALN 
treatment alone on subject incidence of new vertebral fractures, clinical fracture 
(nonvertebral fracture and clinical vertebral fracture), nonvertebral fracture, hip 
fracture, and clinical vertebral fracture during the subsequent year during which all 
subjects receive ALN treatment. 
2.4 
Safety 
For the 12-month double-blind ALN-controlled study period: 
 
To characterize the safety and tolerability of romosozumab treatment for 12 months 
as determined by a review of reported adverse events, laboratory data, vital signs, 
and formation of anti-romosozumab antibodies 
For primary analysis period: 
 
To characterize the safety and tolerability of romosozumab treatment for 12 months 
followed by ALN treatment as determined by a review of reported adverse events, 
laboratory data, vital signs, and formation of anti-romosozumab antibodies 
For the overall study: 
 
To characterize the safety and tolerability of romosozumab treatment for 12 months 
followed by ALN treatment as determined by a review of reported adverse events 
and vital signs 
2.5 
Imaging and Pharmacokinetics (PK) / Bone Turnover Marker (BTM) 
/ Biomarker Sub-study   
For the 12-month double-blind ALN-controlled study period: 
 
To characterize the serum romosozumab concentration 
 
To assess the effect of romosozumab treatment for 12 months compared with ALN 
treatment on: 
 Percent changes in bone formation markers Procollagen Type 1 N-telopeptide 
(P1NP), Bone Specific Alkaline Phosphatase (BSAP), and Osteocalcin (OC), 
and in bone resorption marker serum Type I collagen C-telopeptide (sCTX) 
 Percent changes in sclerostin and intact Parathyroid Hormone (iPTH) 
 For subjects also participating in the imaging components: Percent changes in 
integral (total) and trabecular volumetric BMD (vBMD) at the lumbar spine by 
Quantitative Computed Tomography (QCT) 
 For subjects also participating in the imaging components: Percent changes in 
lumbar spine strength as assessed by Finite Element Analysis (FEA) 
 
For subjects participating in the imaging components: To assess the effect of 
romosozumab treatment for 6 months compared with ALN treatment for 6 months on 
percent changes in DXA BMD at the lumbar spine, total hip, and femoral neck 


Product:  Romosozumab 
Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
Page 12 
 
 
To enable exploratory assessments of novel biomarkers through prospective 
collection of blood samples 
For the primary analysis period: 
 
To assess the effect of romosozumab treatment for 12 months followed by ALN 
treatment compared with ALN treatment alone on: 
 Percent changes in bone formation marker P1NP and bone resorption marker 
sCTX 
 Percent changes in sclerostin and iPTH 
 For subjects participating in the imaging components: Percent changes in 
integral (total) and trabecular vBMD at the lumbar spine by QCT 
 For subjects participating in the imaging components: Percent changes in 
lumbar spine strength as assessed by FEA 
 
For subjects participating in the imaging components: To assess the effect of 
romosozumab treatment for 12 months followed by ALN treatment for 6 months 
compared with ALN treatment alone on percent changes in DXA BMD at the lumbar 
spine, total hip, and femoral neck. 
 
To enable exploratory assessments of novel biomarkers through prospective 
collection of blood samples 
3. 
Study overview 
3.1 
Study Design 
This is a phase 3 multicenter, international, randomized, double-blind, ALN-controlled 
study of romosozumab in postmenopausal women with osteoporosis.  The study is 
designed to evaluate if romosozumab treatment for 12 months followed by ALN 
treatment, compared with ALN treatment alone, is effective in reducing the incidence of 
clinical fracture (nonvertebral fracture and clinical vertebral fracture) and/or new 
vertebral fracture. 
After signing the informed consent form (ICF), subjects will undergo a screening phase 
to complete eligibility assessments.  Upon confirmation of eligibility, approximately 
4,000 subjects will be randomized 1:1 (approximately 2,000 subjects per arm) to receive 
either 210 mg romosozumab subcutaneous (SC) every month (QM) or 70 mg ALN orally 
(PO) every week (QW) in a blinded fashion for the duration of the 12–month double-blind 
ALN-controlled study period.  Randomization will be stratified by age ( 75 years, 
 75 years).  Subjects will also receive matched placebo for either ALN or 
romosozumab.  After the initial 12-month study period, subjects will receive ALN while 


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remaining blinded to their initial treatment assignment (romosozumab or ALN).  The 
primary analysis period will end and the primary analysis will be performed when:  
 
clinical fracture events (nonvertebral fracture or clinical vertebral fracture) have 
been confirmed for at least 330 subjects 
AND 
 
all subjects have had the opportunity to complete their Month 24 study visit. 
If more than 330 subjects have confirmed clinical fractures at the time each subject has 
completed her Month 24 visit, the primary analysis will be based on all available data, 
which may include more than 330 events.  
Upon completion of the primary analysis period, subjects will continue to be followed for 
the secondary endpoint of nonvertebral fractures.  Subjects and site personnel will 
remain blinded to initial treatment assignments.  The study will proceed in an event-
driven manner.  The final analysis (end of study) will be performed when nonvertebral 
fracture events have been confirmed for at least 440 subjects across the lifetime of the 
study.  The study may be terminated earlier if the primary analysis demonstrates 
superiority of romosozumab treatment for nonvertebral fracture risk reduction (see 
Section 3.2.3 for details on testing strategy). Study completion constitutes either 
completion of primary analysis if superiority is proven for nonvertebral fractures or until 
440 subjects experience a nonvertebral fracture. 
Approximately 200 subjects at participating centers will be enrolled in an Imaging and 
PK/BTM/Biomarker sub-study. Within this sub-study, a subset of approximately 
100 subjects will participate in the imaging (DXA, QCT) portion of the sub-study.   
If there is insufficient enrollment into the blood only portion of the sub-study, additional 
sub-study sites will be intiatied.  Subjects already on trial will be invited to participate and 
consent will be obtained for the use of blood samples from earlier time points for 
sub-study analyses. 
From study start until primary analysis, an external, independent Data Monitoring 
Committee (DMC) will monitor unblinded safety data on an ongoing basis throughout the 
study and, if a potential safety signal is identified, may consider efficacy data in order to 
assess the risk/benefit profile of romosozumab.  


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3.2 
Sample Size  
3.2.1 
Sample Size Considerations 
The study is designed to evaluate the effectiveness of romosozumab treatment for 
12 months followed by ALN (romosozumab /ALN) treatment compared with ALN 
treatment alone in reducing the subject incidence of clinical fracture (nonvertebral 
fracture or clinical vertebral fracture), subject incidence of vertebral fracture through 
Month 24, and subject incidence of nonvertebral fracture in postmenopausal women with 
osteoporosis. The total sample size of approximately 4,000 subjects 
(2,000:2,000 equally allocated between the treatment groups) is determined based on 
the clinical fracture and new vertebral fracture endpoints.   
The dropout rate is assumed 10 for the first year and 8 per year thereafter.  The 
enrollment is expected to complete in 34 months. Because study design requires all 
subjects to complete the Month 24 visit for the ascertainment of the new vertebral 
fracture endpoint, the minimum follow-up on an individual subject is at least 24 months.  
Additionally, all subjects will be followed until 440 subjects have confirmed nonvertebral 
fracture events for the final analysis, unless superiority of the nonvertebral fracture 
endpoint is achieved at the primary analysis. The minimum follow-up time (24 months) 
and event-driven components of this study add complexity to the sample size calculation 
and power estimates.  To address this complexity and the added complexity of using 
Hochberg’s method (Hochberg, 1988) to adjust for the multiplicity of the primary 
endpoints, a simulation was performed to derive the sample size and power for the 
clinical fracture and nonvertebral fracture endpoints. 
3.2.2 
Assumptions 
New vertebral fracture assumptions 
The one-year incidence of new vertebral fractures in untreated subjects in the population 
defined in this study is expected to be 5.5 (Black et al, 1996; Cummings et al, 2009).  
Assuming ALN treatment decreases this incidence by 60, the new vertebral fracture 
incidence in the ALN group is expected to be 2.2 in one year and 4.4 in two years.  
romosozumab /ALN treatment is expected to decrease the incidence of new vertebral 
fractures by 80.  This represents a risk reduction of 50 compared to ALN treatment 
alone.   


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Nonvertebral fracture assumptions 
The one-year incidence rate of nonvertebral in the population defined in this study is 
expected to be 5.5% (Black et al, 2000).  Based on the ALN treatment assumption, 
25% risk reduction, the one-year nonvertebral incidence rate is expected to be 
approximately 4% when treated by ALN.  Romosozumab /ALN is assumed to reduce the 
risk by 45% when compared to no treatment.  The combination of the 25% assumed 
reduction for ALN and the 45% assumed reduction for romosozumab /ALN leads to the 
assumption of a 27% reduction in fracture risk when comparing romosozumab /ALN to 
ALN.  
Clinical fracture assumptions 
Clinical fracture is the combination of nonvertebral fractures and clinical vertebral 
fractures.  Clinical vertebral fractures are expected to account for 1/3 (Black et al, 2000) 
of new vertebral fractures.  In the FREEDOM study, in the untreated population, the 
one-year incidence rate was 0.5% for clinical vertebral fracture and 3.5% for clinical 
fracture (Amgen, data on file).  Therefore, it is expected that clinical fractures are 
composed of approximately 85% nonvertebral fractures and 15% clinical vertebral 
fractures.  By pooling the treatment effects of nonvertebral and clinical vertebral 
fractures in the natural log-scale, with 85% and 15% as weights, then taking the 
exponential, romosozumab /ALN treatment compared with ALN alone reduces the risk of 
clinical fractures by approximately 30% (ie, exp(0.15*ln(1-50%) + 0.85*ln(1-27%)) = 69%, 
approximately 30% risk reduction). This estimation of risk reduction was further 
supported in the simulation.  Under the assumption that romosozumab /ALN will reduce 
the risk by 30% compared to ALN, we would need to follow subjects until the 330th 
subject had a confirmed clinical fracture to achieve a 90% power to detect the treatment 
effect using a 2-sided log-rank test at an overall significance level of 0.05.  The power 
calculation was performed using software EAST 5.4. 
DXA BMD assumptions 
The assumptions of mean percent change in DXA BMD and standard deviation for ALN 
at Month 12 and Month 24 are summarized in Table 1 (Schnitzer et al, 2000; 
Greenspan et al, 2002).  Using the FRAME study, the assumptions of mean percent 
change in DXA BMD and standard deviation for romosozumab at Month 12 are 
 


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summarized in Table 2 (Amgen, data on file).  The mean of percent change from 
baseline at hip trochanter is used as the assumption for total hip.  It is further assumed 
that at Month 24, romosozumab/ALN will maintain the BMD increase achieved at 
Month 12. 
Table 1.  Mean Percent Change From Baseline in BMD for Alendronate 
 
Mean  Change from 
Baseline 
Standard Deviation 
Lumbar spine at Month 12 
5.1 
3.5 
Total hip at Month 12 
2.9 
3.5 
Femoral neck at Month 12 
2.3 
4.6 
Lumbar spine at Month 24 
6.3 
4.9 
Total hip at Month 24a 
4.7 
6.3 
Femoral neck at Month 24 
3.1 
4.8 
a The mean of percent change from baseline at hip trochanter is used as the assumption for total hip.  
Table 2.  Mean Percent Change From Baseline in BMD at Month 12 for 
Romosozumab 
 
Mean  Change from 
Baseline 
Standard Deviation 
Lumbar spine at Month 12 
13.1 
6.0 
Total hip at Month 12 
6.0 
4.2 
Femoral neck at Month 12 
5.5 
4.6 
3.2.3 
Simulation and Power 
Simulation parameters 
The assumed distributions for nonvertebral fractures and new vertebral fractures are 
exponential with the yearly rates specified previously.  A binomial distribution with 
probability of 1/3 is assumed for the likelihood of a new vertebral fractures being a 
clinical vertebral fracture.  Additionally, the censoring distribution is assumed exponential 
with a rate of 10 for the first year and a yearly rate of 8 thereafter.  Enrollment is 
assumed to be completed in 34 months.  As stated previously, the minimum follow-up is 
24 months and all subjects will be followed until the 330th subject has a clinical fracture.  
A log-rank test is used for the clinical and nonvertebral fracture endpoints and a Χ2 (no 
continuity correction) test is used for the new vertebral fracture endpoint.  All tests are 
2-sided and results are based on 10,000 iterations. 


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Power 
The power for the clinical fracture and new vertebral fracture endpoint after accounting 
for the multiplicity adjustment are 94 and 95.  There is 91 power that both primary 
endpoints will be significant at the 5 level (2-sided) after accounting for multiplicity.  
Based on the simulation, the median time of the primary analysis in the simulation is 
after the last enrolled subject completes the Month 24 visit.  The median number of 
subjects having clinical fractures in the simulation at the time of the primary analysis is 
396. Note that the number of clinical fractures at the time of the primary analysis will 
exceed 330 when 330 subjects with confirmed clinical fractures occur before the Month 
24 analysis. 
If both of the primary endpoints are significant under the Hochberg procedure, each of 
the following secondary DXA BMD endpoints will be tested hierarchically at 
0.05 according to the following sequence: percent change from baseline in BMD at 
lumbar spine at Month 24, percent change from baseline in BMD at total hip at Month 
24, percent change from baseline in BMD at femoral neck at Month 24, percent change 
from baseline in BMD at lumbar spine at Month 12, percent change from baseline in 
BMD at total hip at Month 12, and percent change from baseline in BMD at femoral neck 
at Month 12. The power for each DXA BMD endpoints is  99 using the 2-sample 
t-test.  
If all preceding endpoints are significant, the nonvertebral fracture endpoint will be tested 
using a group sequential approach at the primary analysis and the final analysis based 
on a 1-sided test (  0.025).  The Lan-DeMets alpha spending function (Lan and 
DeMets,1983) that approximates a Pocock boundary (Pocock, 1977), 
(0.025*LN(1(EXP(1) -1)*information fraction)), will be used to determine the 
significance level at the time of the primary analysis.  Based on the number of subjects 
with nonvertebral fractures at the time of the primary analysis out of the total 
440 planned, which represents the information fraction in the alpha spending function, 
the significance level will be calculated at the time of primary analysis.  For example, if 
the information fraction is 80 at time of the primary analysis, the significance level is 
0.0216.  Based on the simulation, the power for nonvertebral fracture, both primary 
endpoints, and DXA BMD endpoints at Month 12 and Month 24 all being significant is 
approximately 78 at the primary analysis.  


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If the significance of nonvertebral fracture is not demonstrated at the time of the primary 
analysis, the nonvertebral fracture endpoint will be tested again using a 1-sided test at 
the time of the final analysis.  Based on the alpha level spent at the primary analysis, the 
significance level at final will be determined.  For example, if the information fraction is 
80 at the primary analysis (ie, the significance level is 0.0216 at primary), the 
significance level at the final analysis will be 0.0119 using software EAST 5.4 or 
R gsDesign package.  Based on the simulation, the power for nonvertebral fracture 
being significant at the primary or final analysis, and both primary endpoints and DXA 
BMD endpoints at Month 12 and Month 24 being significant at primary analysis is 
approximately 84. 
Monitoring of Blinded Fracture Rates 
The sponsor will monitor the pooled, blinded clinical fracture rate; if it is lower than 
expected, the sample size may be modified. 
4. 
Study Endpoints and Covariates 
4.1 
Primary Endpoints 
During the primary analysis period: 
 
Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral 
fracture) at primary analysis 
 
Subject incidence of new vertebral fracture through Month 24 
4.2 
Secondary Endpoints 
The secondary efficacy endpoints include the following:  
During the primary analysis period: 
 
Subject incidence of nonvertebral fracture at primary analysis  
 
Subject incidence of all fractures (nonvertebral fracture and new or worsening 
vertebral fracture) at primary analysis 
 
Subject incidence of new or worsening vertebral fracture through Month 24 
 
Subject incidence of major nonvertebral fracture (pelvis, distal femur, proximal tibia, 
ribs, proximal humerus, forearm, and hip) at primary analysis 
 
Subject incidence of hip fracture at primary analysis  
 
Subject incidence of multiple new or worsening vertebral fractures through Month 24 
 
Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral 
fracture) through Month 24 


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 
Subject incidence of nonvertebral fracture through Month 24 
 
Subject incidence of hip fracture through Month 24 
 
Subject incidence of clinical vertebral fracture through Month 24 
 
Percent change from baseline in BMD at the lumbar spine, total hip, and femoral 
neck at Months 24, and 36 
During the 12-month double-blind ALN-controlled study period: 
 
Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral 
fracture) through Month 12 
 
Subject incidence of new vertebral fracture through Month 12 
 
Subject incidence of all fractures (nonvertebral fracture and new or worsening 
vertebral fracture) through Month 12 
 
Subject incidence of nonvertebral fracture through Month 12 
 
Subject incidence of hip fracture through Month 12 
 
Subject incidence of major osteoporotic fracture (hip, forearm, humerus, and clinical 
vertebral) through Month 12 
 
Subject incidence of clinical vertebral fracture through Month 12 
 
Percent change from baseline in BMD at the lumbar spine, total hip, and femoral 
neck at Month 12 
For the overall study period:  
 
Subject incidence of nonvertebral fractures at final analysis 
 
Subject incidence of major nonvertebral fracture (pelvis, distal femur, proximal tibia, 
ribs, proximal humerus, forearm, and hip) at final analysis 
 
Subject incidence of hip fracture at final analysis 
4.3 
Safety Endpoints 
The safety endpoints include the following: 
During the 12-month double-blind ALN-controlled study period: 
 
Subject incidence of adverse events by system organ class and preferred term 
 
Changes from baseline in laboratory assessments (serum chemistry and 
hematology) and the shifts from baseline to the worst value between baseline and 
Month 12 
 
Changes from baseline in vital signs 
 
Subject incidence of anti-romosozumab antibodies 


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During the primary analysis period:  
 
Subject incidence of adverse events by system organ class and preferred term 
 
Changes from baseline in laboratory assessments (serum chemistry and 
hematology) and the shift from baseline to the worst value between baseline and 
primary analysis 
 
Changes from baseline in vital signs 
 
Subject incidence of anti-romosozumab antibodies  
During the overall study period: 
 
Subject incidence of adverse events by system organ class and preferred term 
 
Changes from baseline in vital signs  
4.4 
Exploratory Endpoints 
The exploratory endpoints include the following: 
During the 12-month double-blind ALN-controlled study period: 
 
Subject incidence of new or worsening vertebral fracture through Month 12 
 
Subject incidence of major nonvertebral fracture (pelvis, distal femur, proximal tibia, 
ribs, proximal humerus, forearm, and hip) through Month 12 
 
Subject incidence of multiple new or worsening vertebral fractures through Month 12 
 
Actual value in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, and BPI 
worst pain) at Months 6 and 12 
 
Change from baseline in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, 
and BPI worst pain) at Months 6 and 12 
 
Actual value in PRO and ClinRO measures after experiencing a nonvertebral or 
clinical vertebral fracture (OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain) at 
reporting of the nonvertebral or clinical vertebral fracture and at 1, 2 and 3 months 
afterwards 
 
Change from pre-fracture baseline in PRO and ClinRO measures after experiencing 
a nonvertebral or clinical vertebral fracture (OPAQ SV, EQ-5D-5L, LAD, and 
BPI worst pain) at reporting of the nonvertebral or clinical vertebral fracture and at 
1, 2 and 3 months afterwards 
 
Proportion of subjects with a clinically meaningful improvement in worst pain (defined 
as a 2-point improvement in the BPI worst pain scale compared with the fracture 
reporting visit) at 1, 2, and 3 months after reporting of a nonvertebral or clinical 
vertebral fracture 
 
Change from baseline in height at Month 12 


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During the primary analysis period: 
 
Subject incidence of major osteoporotic fracture (hip, forearm, humerus, and clinical 
vertebral) at primary analysis 
 
Actual value in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, and BPI 
worst pain) at Months 18, 24, 30, and 36 
 
Change from baseline in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, 
and BPI worst pain) at Months 18, 24, 30, and 36 
 
Change from baseline in height at Month 24 
During the month 12 to 24 ALN study period 
 
Subject incidence of new vertebral fractures between Month 12 and Month 24 
 
Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral 
fracture) between Month 12 and Month 24 
 
Subject incidence of nonvertebral fracture between Month 12 and Month 24 
 
Subject incidence of hip fracture between Month 12 and Month 24 
 
Subject incidence of clinical vertebral fracture between Month 12 and Month 24 
4.5 
Imaging and PK/BTM/Biomarker Sub-study Endpoints 
During the 12-month double-blind ALN-controlled study period: 
 
Romosozumab serum concentrations at Day 1, Months 1, 3, 6, 9, and 12 
 
Percent change from baseline in P1NP, BSAP, OC, and sCTX at Months 
1, 3, 6, 9, and 12 
 
Percent change from baseline in iPTH and sclerostin at Months 1, 3, 6, 9, and 12 
 
For subjects participating in the imaging components:  
 
Percent change from baseline in integral (total) and trabecular vBMD at the 
lumbar spine by QCT at Months 6, and 12 
 
Percent change from baseline in lumbar spine strength as assessed by FEA at 
Months 6, and 12 
 
Percent change from baseline in DXA BMD at the lumbar spine, total hip, and 
femoral neck at Month 6 
During the primary analysis period: 
 
Percent change from baseline in P1NP and sCTX at Months 15, 18, 24, and 36 
 
Percent change from baseline in iPTH and sclerostin at Months 15, 18, 24, and 36 
 
For subjects participating in the imaging components: 
 
Percent change from baseline in integral (total) and trabecular vBMD at the 
lumbar spine by QCT at Months 24  


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 
Percent change from baseline in lumbar spine strength as assessed by FEA at 
Months 24 
 
Percent change from baseline in DXA BMD at the lumbar spine, total hip, and 
femoral neck at Month 18  
4.6 
Planned Covariates 
All analyses assessing treatment effect of new vertebral fracture, clinical fracture or 
nonvertebral fracture will include the stratification factor (age  75 or  75 years), 
presence or absence of severe vertebral fracture at baseline, and baseline total hip BMD 
T-score as main covariates in the model.  Additional covariates will be analyzed 
separately and simultaneously, if appropriate, as exploratory analyses. The additional 
covariates of interest include the following: 
 
baseline body mass index (BMI) 
 
years since menopause at baseline  
 
prior (history) nonvertebral osteoporotic fracture (yes, no)  
 
geographic region:  
 
Western Europe and New Zealand/Australia 
 
Central and Eastern Europe and Middle East 
 
Asia Pacific and South Africa 
 
North America (including Canada, and United States) 
 
Central/Latin America  
 
race/ethnicity (white and non-white) 
 
prior use of bone-specific therapeutic agents (yes, no) 
 
10-year probability of major osteoporotic fracture with BMD (FRAX, as calculated by 
third-party vendor) 
 
baseline lumbar spine BMD T-score 
5. 
Hypotheses and/or Estimation 
The primary clinical hypotheses are that romosozumab treatment for 12 months followed 
by ALN treatment compared with ALN treatment alone is effective in reducing the 
incidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture) and 
new vertebral fracture in postmenopausal women with osteoporosis.  It is expected that 
romosozumab treatment for 12 months followed by ALN treatment will reduce the 
incidence of clinical fractures by 30 and the incidence of new vertebral fractures by 
50 compared with the control group (ALN alone). 


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The primary safety hypothesis is that romosozumab treatment for 12 months is well 
tolerated in postmenopausal women with osteoporosis.  
6. 
Definitions 
6.1 
Basic Definitions 
Investigational Product (IP) 
Romosozumab, ALN and the respective matched placebo 
Interactive Voice Response System (IVRS) 
The system used to assign screened subjects to randomized treatment as well 
as to manage the supply of double-blind romosozumab and ALN, as well as 
the open-label ALN to the site and track subject study termination data 
6.1.1 
Study Points of Reference 
Baseline 
Baseline is the closest recorded measurement before the administration of the 
first dose of investigational product.  If the measurement is done on the same 
day as the first dose and the exact measurement time relative to the first dose is 
unknown, it will be assumed the measurement is done before the administration 
of the first dose of investigational product.  If a subject does not receive 
investigational product, baseline is the closest recorded measurement on or 
before the enrollment (randomization) date.   
Note:  If baseline result from lateral spine x-ray, DXA, or QCT assessment is not 
available, the result assessed on or before Study Day 14 will be considered 
baseline.   
Pre-fracture Baseline for PRO/ClinRO Endpoints 
Pre-fracture baseline for PRO/ClinRO endpoints is the closest recorded 
PRO/ClinRO measurements before the visit of reporting a nonvertebral fracture 
or clinical vertebral fracture.   
PRO/ClinRO Endpoints at Report of Fracture  
PRO/ClinRO Endpoints at Report of Fracture is the first recorded PRO/ClinRO 
measurements within 45 days after the date of the reported non-vertebral 
fracture or clinical vertebral fracture. 
Study Day 1 
The first day of investigational product administration or the day of randomization 
for subjects who were not administered any dose of investigational product  


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Study Day 
The number of days from Study Day 1, inclusive: 
Study Day  (Date of Interest – Date of Study Day 1)  1 
Visit Windows 
Based on protocol, all monthly study visits through Month 12, during the 
12-month double-blind ALN-controlled study period, have a  7-day window.  The 
study visits during the open-label ALN study period , have a  14-day window. 
Study procedures for a specific visit may be completed on multiple days as long 
as all the procedures are completed within the visit window. To allow for 
variations in scheduling, the analysis visit windows defined in section 13.1.1 will 
be used to assign evaluations to a most appropriate nominal visit for analysis and 
summarization.   
6.1.2 
Study Dates 
Informed Consent Date 
The date on which a subject signed the informed consent 
Enrollment (Randomization) Date 
The date on which a subject is assigned to one of the treatments through the 
IVRS 
End of Primary Analysis Period Date 
The date on which clinical fracture events have been confirmed for at least 
330 subjects and after all randomized subjects have had the opportunity to 
complete the Month 24 visit. For subjects who withdraw before this date, then 
their End of Study Date is used.  
End of Final Analysis Period Date  
If the study will continue to the final analysis, the date on which nonvertebral 
fracture events have been confirmed for at least 440 subjects if statistical 
significance of non-vertebral fractures is not demonstrated at primary analysis. 
For subjects who withdraw before this date, then their End of Study Date is used. 
End of Study Date 
The date recorded on the End of Study eCRF 
First Dose Date 
The date of administration of first dose of investigational product (ie, the first date 
recorded on the Investigational Product Administration eCRF for romosozumab 
or placebo with volume  0 or the first dose date of ALN or placebo in 


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Alendronate/Placebo Dispensation eCRF with the number of tablets taken  0, 
whichever is earlier), which may or may not be the same as the randomization 
date 
Last Double-blind SC Dose Date  
The date of administration of the last SC investigational product (ie, the last date 
recorded on the Investigational Product Administration eCRF for romosozumab 
or placebo with volume  0) 
Last Double-blind Oral Dose Date  
The date collected on the End of Blinded Alendronate Administration eCRF  
Last Dose Date in Double-blind Period 
The date of last double-blind SC dose date or the last double-blind oral dose 
date, whichever is later 
First Open-label ALN Dose Date 
The date collected on the First Dose of open-label Alendronate Dispensation 
eCRF 
First Open-label ALN Dispensation Date 
The date of dispensation of ALN collected on the Month 12 Alendronate 
Dispensation eCRF  
Last Open-label ALN Dose Date 
The date of last alendronate administration recorded in End of Alendronate 
Administration eCRF 
End of Double-blind Period Date 
End of the double-blind period date is defined as the following:  
1. First open-label ALN dose date if this date is prior to or on Study Day 366  30 
days  
2. Month 12 visit date if subject did not receive the open-label ALN prior to or on 
Study Day 396 and this date is prior to or on Study Day 396 days  
3. End of study day or Study Day 396, whichever occurs first, for subjects who 
did not complete the Month 12 visit prior to study day 396 days  
The Month 12 visit date is defined as the latest assessment collected at Month 
12.  
Start of Open-label Period Date 
For subjects entering in the ALN open-label period, the end of double-blind 
period date is the beginning of the open-label period date. All scheduled 


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assessments occurring on this date are attributed to the double-blind period.  The 
open-label ALN dose on the day is considered as occurring in the open-label 
follow-up period.  Any adverse event or concomitant medication with a start date 
on this date is considered having started in the open-label follow-up period. 
End of 24-Month ALN Study Period Date 
End of the 24-Month period date is defined as the following: 
1. Month 24 visit date if this date is prior to or on Study Day 731  30 days 
2. End of study date or Study Day 761, whichever occurs first,  for subjects who 
did not complete the Month 24 visit prior to Study Day 761 days 
The Month 24 visit date is defined as the latest assessment collected at Month 
24. 
Last Dose Date 
The last dose date in double-blind or open-label period, whichever is later 
Wrong Dose Date in Double-blind Period 
For subjects who are randomized to ALN and accidentally receive romosozumab, 
the wrong dose date is when they receive the 1st SC administration of 
romosozumab in the double-blinded period. For subjects who are randomized to 
romosozumab and receive oral ALN in the double-blinded period, if the wrong 
oral IP box is dispensed on Day 1, the wrong dose date is the 1st oral dose date;  
otherwise, the wrong dose date is when the 1st wrong oral IP box is dispensed 
because the oral ALN dosing dates are not collected in eCRF.  
6.1.3 
Study Time Intervals 
On-Study Period 
The time period from the enrollment date to the end of study date, inclusive 
Double-blind Period 
The time period from the enrollment date to the end of double-blind period date, 
inclusive 
Open-label ALN Period 
The time period from the end of double-blind period date to the end of study date, 
inclusive  


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Month 12 to Month 24 ALN Study Period  
For subjects entering in the ALN open-label period, the time period from the end 
of double-blind period date to the Month 24 visit date, study day 761, or end of 
study date, whichever is the earliest, inclusive.  
The Month 24 visit date is defined as the latest assessment collected at Month 
24.  
24-month ALN Study Period  
The time period from the enrollment date to the Month 24 visit date, study day 
761, or end of study date, whichever is the earliest, inclusive  
Primary Analysis Period 
The time period from the enrollment date to the end of primary analysis period 
date, inclusive  
Overall Study Period 
If the study will continue to the final analysis, the overall study period is defined 
as the time period from the enrollment date to the end of final analysis period 
date, inclusive.  
6.1.4 
Fracture Risk Assessment Tool: 10-year Probability of Major 
Osteoporotic Fracture (FRAX) 
FRAX is a computer-based algorithm (http://www.shef.ac.uk/FRAX) that provides 
country/ethnicity-specific models for the assessment of fracture probability in 
men and women [Kanis et al, 2001,2008].  The approach uses clinical risk factors 
to estimate 10-year probability of a major osteoporotic fracture (hip, clinical spine, 
forearm or humerus) or of a hip fracture alone. The estimate of probability can be 
calculated with clinical risk factors alone, or additionally with baseline femoral 
neck BMD.  The clinical risk factors used for the calculation include sex, age, 
body mass index (BMI), a prior fragility fracture, parental history of hip fracture, 
current tobacco smoking, ever long-term use of oral glucocorticoids, rheumatoid 
arthritis, other causes of secondary osteoporosis, and daily alcohol consumption 
of 3 or more units daily. 
6.2 
Subject Disposition 
Enrolled (Randomized) 
Individuals are considered enrolled if they have been assigned a randomization 
number.  Enrolled individuals are referred to as “subjects”. 


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Exposed to Investigational Product 
Subjects are defined as exposed if they have a value for the sum of 
investigational product dose that exceeds zero. 
Enrolled Into Sub-study 
Randomized subjects who sign the informed consent for the sub-study are 
considered enrolled into the sub-study. 
6.3 
Arithmetic Calculations 
Age at Randomization Date 
Number of whole years from a subject’s birth date to the randomization date as 
recorded on the eCRF.    
Estimated Glomerular Filtration Rate (eGFR) (mL/min) Using Modification of Diet 
in Renal Disease (MDRD) for Females 
Conventional units (creatinine as mg/dL; age in years): 
eGFR (mL/min/1.73 m2)  175 × (Serum creatinine)-1.154 x [Age]-0.203 × (0.742 
if female) × (1.212 if African American)   
 
SI units (creatinine as mol/L; age in years): 
eGFR (mL/min/1.73 m2)  175 × (Serum creatinine/88.4)-1.154 x [Age]-0.203 
× (0.742 if female) × (1.212 if African American)  
Percent Change From Baseline 
The change from baseline divided by baseline value and multiplied by 100: 
(Change From Baseline / Baseline) * 100 
Subject Incidence Rate for Adverse Events 
The subject incidence rate for a given event in a given time period (double-blind 
period, primary analysis period, or overall study period) is defined as the number 
of subjects with  1 reported occurrence of the event divided by the number of 
subjects who are at risk for having the event in the beginning of the given time 
period.  For subjects with multiple occurrences of the same event in a given 
period, the event will only be counted once per subject.   
Subject Years On-Study in Double-blind Period  
Defined for a given subject as the number of days between the first dose date to 
end of double-blind period date, inclusive, divided by 365.25 (ie, [End of 
Double-blind Period Date – First Dose Date  1] / 365.25).  The subject years on 
study will be summed over all subjects within a treatment group. For subjects 
who never received a dose of investigational product, the randomization date will 
be used. 


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Subject Years On-Study in Primary Analysis Period 
Defined for a given subject as the number of days between the first dose date to 
end of primary analysis period date, inclusive, divided by 365.25  
(ie, [End of Primary Analysis Period Date – First Dose Date 1] / 365.25).  The 
subject years on study will be summed over all subjects within a treatment group. 
For subjects who never received a dose of investigational product, the 
randomization date will be used. 
Subject Years On-Study in Overall Study Period 
Defined for a given subject as the number of days between the first dose date to 
end-of-study date, inclusive, divided by 365.25 (ie, [End of Study 
Date - First Dose Date 1] / 365.25).  The subject years on study will be summed 
over all subjects within a treatment group. For subjects who never received a 
dose of investigational product, the randomization date will be used. 
Time to First Event in Double-blind Period 
Time to event is calculated as the elapsed time interval in days between the 
occurrence date of the event of interest or censorship and the reference date:   
  
Time Interval  Date of the Event or Censorship - Reference Date 1 
Note for fracture endpoints, the date of event is the date that confirms the 
fracture provided by the central imaging reader (eg, date of x-ray used by the 
central imaging vendor to verify the fracture, or surgical report or discharge 
summary if x-ray date is not available).  For adverse events, nonvertebral 
fractures, and other events, which can be assessed at any time, subjects who did 
not have any event will be censored on the date of last evaluation for the event, 
which is the End of Double-blind Study Period; for vertebral fractures, which have 
to be identified on scheduled assessments, subjects who did not have any event 
will be considered censored at the last post-baseline assessment or day 1 if 
there were no post-baseline assessment. 
The reference date will be the randomization date for efficacy events or first dose 
date for safety endpoints.  
Time to First Event in 24-month Study Period 
The time to event in the 24-month study period is defined similarly as for time to 
first event in double-blind period. Subjects who did not have any event will be 
censored on the date of last evaluation for the event, which is the end of 
24-month ALN study period date.  
Time to First Event in Month 12 to Month 24 Study Period 
Time to first event in Month 12 to Month 24 study period is defined similarly as for 
time to first event in 24-month study period. The reference date will be the start of 
open-label period. 


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Time to First Event in Primary Analysis Period 
The time to event in the primary analysis study period is defined similarly as for 
time to first event in double-blind period. Subjects who did not have any event will 
be censored on the date of last evaluation for the event, which is the end of 
primary analysis period date.  
Time to First Event in Overall Study Period 
The time to event in the overall study period is defined similarly as for time to first 
event in double-blind period. Subjects who did not have any event will be 
censored on the date of last evaluation for the event, which is the End of Study 
Date recorded on the End of Study eCRF.   
6.4 
Fracture-related Study Endpoints 
All the fracture related efficacy endpoints are based on the results from the central 
imaging vendor analysis transferred to the Amgen database. 
6.4.1 
Trauma Severity Definitions 
Low Trauma Severity 
Assessed by the investigator and collected on the Clinical Non-vertebral Fracture 
Summary eCRF for each clinical fracture event and includes 
- 
Fall from standing height or less than 20 inches 
- 
Minimal or moderate trauma other than a fall 
- 
Unknown/don’t know 
High Trauma Severity 
Assessed by the investigator and collected on the Clinical Non-vertebral Fracture 
Summary eCRF for each clinical fracture event indicating severe trauma other 
than a fall 
Pathologic Fracture 
Assessed by the investigator and collected on the Clinical Non-vertebral Fracture 
Summary eCRF for each clinical fracture event occurring from a pathology other 
than osteoporosis is deemed a pathologic fracture 
6.4.2 
Vertebral Fracture 
The types of vertebral fractures below are defined based on an assessment of spinal 
radiographs using Genant Semiquantitative Scoring Method (Genant et al, 1993), which 
is described in detail in Section 13.2.   


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Imputation of Genant Grade for a Vertebra  
Because in an adult, a subject’s vertebral fracture can only get worse or at best 
remain at the same severity over time, for the evaluation of prevalent vertebral 
fracture, any vertebra(e) with a missing grade at baseline will be assumed to 
have had a grade of 0 if the subsequent x-ray shows a grade of 0 for the same 
vertebra(e). 
Prevalent Vertebral Fracture Status at Baseline 
Most subjects enrolled to this study will have at least one vertebral fracture. The 
most severe Genant semiquantitative grade from T4 to L4 at baseline is used to 
define the vertebral fracture status at baseline. A subject has a prevalent 
vertebral fracture if any vertebra from T4 to L4 has a grade of  1 at baseline. A 
subject does not have a prevalent vertebral fracture when all 13 grades from 
T4 to L4 are 0 on the first evaluable spinal radiograph collected during the study. 
Otherwise, the subject will have an unknown status for prevalent vertebral 
fracture.   
Presence of Severe Vertebral Fracture at Baseline 
A subject has a prevalent vertebral fracture if any vertebra from T4 to L4 has a 
grade of 3 at baseline. Otherwise, a subject is considered absence of severe 
vertebral fracture at baseline. 
New Vertebral Fracture 
A new vertebral fracture is identified when there is  1 grade increase from the 
previous grade of 0 in any vertebra from T4 to L4. 
Worsening Vertebral Fracture 
A worsening vertebral fracture is identified when there is  1 grade increase from 
the previous grade of  1 in any vertebra from T4 to L4.     
New or Worsening Vertebral Fracture   
A new or worsening vertebral fracture is identified when there is  1 grade 
increase from the previous grade in any vertebra from T4 to L4. 
Clinical Vertebral Fracture 
A clinical vertebral fracture is a new or worsening vertebral fracture assessed at 
either a scheduled or unscheduled visit and associated with any signs and/or 
symptoms of back pain indicative of a fracture, regardless of trauma severity or 
whether it is pathologic.  
Signs and symptoms indicative of a vertebral fracture will be assessed using the 
Clinical Vertebral Fracture Back Pain eCRF. Data from this eCRF will be 
combined with the post-baseline lateral spine x-ray data from the central imaging 


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vendor by taking all back pain assessments prior to or on the date of the x-ray 
and the first eCRF record on or after the date of the x-ray and prior or on to the 
next x-ray date. If the x-ray date corresponds exactly with an eCRF record that 
indicates no back pain was present at the time of the x-ray, the subsequent back 
pain assessment will also be considered, so long as it is on or before the next 
x-ray. If any selected records indicate the subject experienced back pain 
consistent with a vertebral fracture, then the vertebral fracture will be considered 
as associated with signs and/or symptoms indicative of a vertebral fracture, and 
therefore a clinical vertebral fracture. If all selected records indicate that the 
subject did not experience back pain deemed consistent with a vertebral fracture 
by the investigator around the time of the fracture, then the fracture will not be 
considered a clinical vertebral fracture. 
Multiple New or Worsening Vertebral Fractures   
A subject has multiple new or worsening vertebral fractures when there are  2 
vertebrae from T4 to L4 with  1 grade increase from the previous grade.  The 
multiple new or worsening vertebral fractures need not occur at the same visit.   
6.4.3 
Nonvertebral Fracture (Osteoporotic) 
Nonvertebral Fracture (Osteoporotic)  
Defined as a fracture present on a copy of radiographs or other diagnostic 
images such as computerized tomography (CT) or magnetic resonance imaging 
(MRI) confirming the fracture within 14 days of reported fracture image date on 
the eCRF (if day of the month is unknown, but month and year is known, then 
fracture images within the same month can be used to confirm), and/or 
documented in a copy of the radiology report, surgical report, or discharge 
summary, excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, 
lumbar vertebrae, metacarpus, finger phalanges, and toe phalanges.  In addition, 
fractures associated with high trauma severity or pathologic fractures will be 
excluded. 
Hip Fracture 
A subset of nonvertebral fractures including femoral neck, femur intertrochanter, 
femur subtrochanter, and “Other” location that are further specified as hip, 
pertrochanteric, or pertrochanteric femur. 
Distal Femur Fracture (ie, Femur Excluding Hip) 
A subset of nonvertebral fractures including femur distal and femur midshaft 
Wrist Fracture 
A subset of nonvertebral fractures including radius distal and ulna distal 


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Forearm Fracture 
A subset of nonvertebral fractures including radius, radius proximal, radius shaft, 
radius distal, ulna, ulna proximal, ulna shaft, and ulna distal 
Rib Fracture 
A subset of nonvertebral fractures including ribs 
Humerus Fracture 
A subset of nonvertebral fractures including humerus proximal, humerus shaft, 
and humerus distal 
Proximal Humerus Fracture (ie, Humerus Excluding Elbow) 
A subset of nonvertebral fractures including humerus proximal and humerus 
shaft 
Pelvic Fracture 
A subset of nonvertebral fractures including sacrum, acetabulum, ilium, ischium, 
and pubis 
Leg Fracture 
A subset of nonvertebral fractures including femur midshaft, femur distal, patella, 
fibula, fibula proximal, fibula shaft, fibula distal, tibia, tibia proximal, tibia shaft, 
and tibia distal 
Lower Leg With Ankle 
A subset of nonvertebral fractures including fibula, fibula proximal, fibula shaft, 
fibula distal, tibia, tibia proximal, tibia shaft, and tibia distal 
Ankle Fracture 
A subset of nonvertebral fractures including fibula distal and tibia distal 
Proximal Tibia Fracture (ie, Tibia Excluding Ankle) 
A subset of nonvertebral fractures including tibia proximal and tibia shaft 
Foot Fracture 
A subset of nonvertebral fractures including metatarsus and tarsus 


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Major Nonvertebral Fracture  
A subset of nonvertebral fractures including pelvis, distal femur (ie, femur 
excluding hip), proximal tibia (ie, tibia excluding ankle), ribs, proximal humerus 
(ie, humerus excluding elbow), forearm, and hip 
Any Nonvertebral Fracture  
Defined as any fractures recorded on the Clinical Non-vertebral Fracture 
Summary eCRF.  
6.4.4 
Clinical Fracture 
Clinical fractures include clinical vertebral as defined in Section 6.4.2 and nonvertebral 
fractures (excluding skull, facial, mandible, cervical vertebrae, thoracic vertebrae, lumbar 
vertebrae, metacarpus, finger phalanges, and toe phalanges) as defined in Section 6.4.3 
that are associated with signs and/or symptoms indicative of a fracture.  Nonvertebral 
fractures associated with high trauma severity or pathologic fractures will be excluded.    
6.4.5 
All Fracture (Osteoporotic) 
All osteoporotic fractures include any osteoporotic nonvertebral fractures that are not 
associated with high trauma severity or pathologic fractures and new or worsening 
vertebral fractures regardless of trauma severity or pathologic fractures.   
6.4.6 
Major Osteoporotic Fracture 
Major osteoporotic fractures include hip, forearm, or humerus fractures that are not 
associated with a pathologic fracture regardless of trauma severity, and clinical vertebral 
fractures.   
6.4.7 
Historical Fracture 
Any Historical Fracture 
Any nonvertebral fractures recorded on the Subject Fracture History eCRF 
regardless of trauma severity or vertebral fracture based on baseline spinal 
radiograph. 
Historical Osteoporotic Fracture 
Any nonvertebral fracture  recorded on the Subject Fracture History eCRF not 
including skull, facial bones, fingers, toes, spine and tailbone  and not associated 
with known high trauma severity or pathologic fractures, or vertebral fracture 
based on baseline spinal radiograph   


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Historical Nonvertebral Fracture 
Fractures recorded on the Subject Fracture History eCRF not including skull, 
facial bones, fingers, toes, spine, and tailbone and not associated with known 
high trauma severity or pathologic fractures  
Historical Nonvertebral Fracture At or After Age 55 
Historical nonvertebral fractures occurring at or after age 55 
Historical Major Nonvertebral Fracture 
A subset of historical nonvertebral fractures including the following locations:  
pelvis (not hip), hip, lower leg (not knee or ankle), ribs, shoulder, forearm, and 
wrist and not associated with known high trauma severity or pathologic fractures 
Historical Fragility Fracture 
Historical fragility fractures include moderate or severe vertebral prevalent 
fractures and nonvertebral fractures occurring at or after age 55.  
6.5 
PRO Measurements 
OPAQ-SV Physical Function Score 
The physical function score is calculated by averaging nonmissing rating for 
19 standardized items (question item numbers of 1 to 19;  10 items as 
nonmissing; otherwise set score to missing).  The OPAQ-SV physical function 
score ranges from 0 to 100.  A higher score represents better physical function.  
See Section 13.3.1 for detailed scoring algorithm. 
OPAQ-SV Emotional Status Score 
The emotional status score is calculated by averaging nonmissing rating of 
11 standardized items (question item numbers of 20 to 24, and 29 to 34;  6 
items as nonmissing; otherwise set score to missing).  The OPAQ-SV emotional 
status score ranges from 0 to 100.  A higher score represents better emotional 
status.  See Section 13.3.1 for detailed scoring algorithm. 
OPAQ-SV Back Pain Score 
The score is calculated by averaging nonmissing rating of 4 standardized items 
(question item numbers of 25 to 28;  2 items as nonmissing; otherwise set score 
to missing).  The maximum OPAQ-SV back pain score is 100.  A higher score 
indicates less back pain.  See Section 13.3.1 for detailed scoring algorithm. 
EQ-5D-5L Health State Index Score 
The EQ-5D-5L health state index score is calculated using the dimension scores 
from Question 35 a-e.  The score ranges between –0.594 and 1.0, where 


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1 indicates full health; 0 indicates death.  A score  0 indicates a state worse 
than death.  See Section 13.3.2 for detailed scoring algorithm. 
EQ-5D-5L VAS Score 
The EQ-5D-5L VAS score ranges between 0 and 100 based on Question 36 
(See Section 13.3.2 for detailed question description).  The score of 0 indicates 
“worst imaginable health state” and 100 for “best imaginable health state.” 
7. 
Analysis Subsets 
7.1 
Primary Efficacy Analysis Set For Vertebral Fractures 
This analysis set includes all randomized subjects who have a baseline and 
 1 post-baseline evaluation of vertebral fracture at or before the time point under 
consideration.  This analysis set will additionally include subjects who have vertebrae 
with missing Genant semiquantitative scores at baseline and whose first post-baseline 
spinal radiograph shows no fracture on the same vertebrae because it can be inferred 
that the baseline scores would have also shown no fracture had they been available.  
Subjects in this subset will be analyzed according to their randomized treatment 
assignment, regardless of treatment received. This analysis set will be used as the 
primary analysis set for the following endpoints: new, new or worsening, and multiple 
new or worsening vertebral fractures. 
7.2 
Full Analysis Set 
This set includes all randomized subjects.  Subjects in the full analysis set will be 
analyzed according to their randomized treatment assignment, regardless of treatment 
received.  The full analysis set will be used as the primary analysis set for the following 
endpoints:  nonvertebral fracture, clinical fracture, clinical vertebral fracture, all fracture, 
major nonvertebral fracture, major osteoporotic fracture, and hip fracture.   
7.3 
Per Protocol Analysis Set for 12-month of Double-blind Period 
The per protocol analysis set will only be used to analyze the following endpoints: 
subject incidence of clinical fracture, new vertebral fracture, and nonvertebral fracture 
through Month 12 as sensitivity analyses.  This subset includes subjects defined in 
Section 7.1 (for new vertebral fractures) or Section 7.2 (for clinical fracture and 
nonvertebral fracture) who receive active investigational product and did not violate any 
of the important inclusion/exclusion criteria for subject eligibility at enrollment per study 
important protocol deviation documents.  


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During the double-blind study period, for subjects who (a) received the investigational 
product not matching the subject’s randomized treatment group, (b) had an 
investigational product related important protocol violation for romosozumab /placebo or 
ALN/placebo during the double-blind period, or (c) received proscribed therapy on study, 
all vertebral fracture data collected after the first occurrence of either of the above 
violations will be excluded from analysis; and nonvertebral and clinical fracture endpoints 
analyzed as time-to-event will be censored at the time of the first violation for subjects 
who have not had the fracture prior to the violation date. If subjects had an 
investigational product related important protocol deviation during the double-blind 
period, the violation date is determined as follows: 
 
if the subject is randomized to romosozumab, the time of violation for subjects 
missing  3 doses of romosozumab is defined as the planned dosing date for the 
4th (missed) dose or the subject’s end of study date, whichever occurs first; 
 
if the subject is randomized to ALN, the first deviation date for “Less than 75 or 
more than 125 of planned ALN/placebo doses” IPD recorded in eClinical or the 
subject’s end of study date, whichever occurs first.  
The use of proscribed treatments will result in excluding or censoring the data from the 
per protocol analysis set. The list of proscribed treatments is provided in protocol 
Section 6.5. 
7.4 
Per Protocol Analysis Set for 24-Month Study Period, Primary 
Analysis Period, and Overall Study Period  
The per protocol analysis set will be used to analyze the clinical fracture, new vertebral 
fracture, and nonvertebral fracture through Month 24, clinical fracture and nonvertebral 
fracture at primary analysis, and nonvertebral fracture at final analysis (if the study 
continue to final analysis) as a sensitivity analysis.  This subset includes subjects 
defined in Section 7.1 (for vertebral fracture related endpoints) or Section 7.2 (for 
nonvertebral related endpoints) who did not violate any of the important 
inclusion/exclusion criteria for subject eligibility at enrollment per study important 
protocol deviation documents.   
For subjects who received (a) the investigational product not matching the subject’s 
randomized treatment group during the double-blind period, (b) investigational product 
related important protocol violation for romosozumab/placebo or ALN/placebo during the 


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double-blind period, (c) investigational product related important protocol violation for 
open-label ALN during the open-label period of primary analysis period, or (d) proscribed 
therapy on study during the overall study period, all vertebral fracture data collected after 
the first occurrence of either of the above violations will be excluded from analysis; and 
nonvertebral and clinical fracture endpoints analyzed as time-to-event will be censored 
at the time of the first violation for subjects who have not had the fracture prior to the 
violation time.  The use of proscribed therapies and investigational product related 
important protocol deviations during the double-blind period that will result in excluding 
or censoring the data from the per protocol analysis set is specified in Section 7.3.  In 
addition, if subjects had an investigational product related important protocol deviation 
during the open-label period, the violation date is determined as the first deviation date 
for “Less than 75 or more than 125 of planned ALN doses” IPD recorded in eClinical 
or the subject’s end of study date, whichever occurs first during the open-label period.   
7.5 
Safety Analysis Set  
This safety analysis set includes all randomized subjects who receive  1 active dose of 
investigational product in the 12-month double-blind ALN-controlled study period.  This 
analysis set will be used to analyze safety data for the double-blind study period, primary 
analysis period, and overall study period.  AEs that begin  on the end of double-blind 
period date will not be included in the 12-month double-blind study period. AEs that 
begin on the date of the end of primary analysis study period will be included in the 
primary analysis study period. These subjects will be analyzed according to their actual 
treatment received, where subjects who received  1 dose of romosozumab will be 
analyzed in the romosozumab treatment group regardless of the randomized treatment.  
The subject incidence rates for the primary analysis study period include all events that 
occurred in the double-blind study period and all events occurred on and before the end 
of primary analysis date for those subjects who received at least one dose of open-label 
ALN. 
If the study continues to the finaly analysis, the subject incidence rates for the overall 
study period include all events that occurred in the double-blind study period and all 
events occurred in the open-label ALN period for those subjects who received at least 
one dose of open-label ALN. 


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7.6 
Primary Efficacy Analysis Set for BMD, Height, and PRO/ClinRO 
Endpoints for the Double-blind ALN-controlled Study Period and 
Primary Analysis Period 
This analysis set includes all randomized subjects who have a baseline and 
 1 post-baseline evaluation at or before the time point under consideration. Note that 
this subset could potentially be different from endpoint to endpoint due to missing data.  
Subjects in this subset will be analyzed according to their randomized treatment 
assignment, regardless of treatment received. 
7.7 
Analysis Set for Post Fracture PRO/ClinRO Endpoints 
This analysis set includes all randomized subjects who experienced a nonvertebral or 
clinical vertebral fracture in the double-blind period and have a pre-fracture baseline and 
 1 post fracture evaluation at or before the time point under consideration.  Note that 
this subset could potentially be different from endpoint to endpoint due to missing data. 
Subjects in this subset will be analyzed according to the randomized treatment 
assignment. 
7.8 
Analysis Subsets for Imaging and Pharmacokinetics (PK) / Bone 
Turnover Marker (BTM) / Biomarker Sub-study 
7.8.1 
Sub-study Imaging Efficacy Analysis Set  
The respective subset includes all randomized subjects who enrolled in the sub-study 
and have a baseline and  1 post-baseline evaluation at or before the time point under 
consideration and will be used to evaluate vBMD, bone strength measure by FEA and 
DXA BMD.  Subjects will be analyzed according to their randomized treatment 
assignment. 
7.8.2 
Sub-study BTM  Efficacy Analysis Set 
The subset includes all randomized subjects who enrolled in the sub-study who have a 
baseline and  1 post-baseline reported BTM result  at or before the time point under 
consideration and will be used to evaluate P1NP, BSAP, OC and sCTX.  Subjects will be 
analyzed according to their randomized treatment assignment, regardless of treatment 
received. 


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7.8.3 
Sub-study BTM  Safety Analysis Set 
The subset includes all randomized subjects who enrolled in the sub-study who 
receive  1 dose of investigational product, have a baseline and  1 post-baseline 
reported BTM result  at or before the time point under consideration and will be used to 
evaluate iPTH and serum sclerostin level.  Subjects will be analyzed according to the 
actual reatment received, where subjects who received  1 dose of romosozumab will be 
analyzed in the romosozumab treatment group regardless of the randomized treatment. 
7.8.4 
 Sub-study PK Analysis Set  
The subset includes all randomized subjects who enrolled in the PK sub-study, 
receive  1 dose of romosozumab, and have  1 reported result.  Subjects will be 
analyzed according to their actual treatment received.   
7.9 
Subgroup Analyses 
The new vertebral fracture through Month 12 or Month 24, clinical fracture and 
nonvertebral fracture through Month 12 or at primary analysis, will be analyzed within 
each of the following subgroups: 
 
Age ( 75 years,  75 years) 
 
Presence or absence of severe vertebral fracture at baseline (based on most 
severe Genant semiquantitative grade at baseline on screening spinal 
radiograph) 
 
Number of prevalent vertebral fractures at baseline (0-1, 2,  3; based on 
screening spinal radiograph) 
 
Race (White and non-White) 
 
Geographic region 
Western Europe and New Zealand/Australia 
Central and Eastern Europe and Middle East 
Asia Pacific and South Africa 
North America  
Central/Latin America  
 
Central/Latin America and all regions excluding Central/Latin America 
 
Baseline lumbar spine BMD T-score ( -3,  -3 and  -2.5,   -2.5) 
 
Baseline total hip or femoral neck BMD T-score  -3 vs both total hip and femoral 
BMD T-score  -3  


Product:  Romosozumab 
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 
Baseline BMI (tertiles) 
 
FRAX score for major osteoporotic fracture (tertiles) 
 
History of nonvertebral fracture at age  55 years (yes, no) 
The percent changes from baseline in lumbar spine BMD and total hip BMD at month 12 
and month 24 will be analyzed by the following subgroups:   
 
Age ( 75 years, 75 years) 
 
Geographic region 
 
Baseline lumbar spine BMD T-score ( -3,  -3 and  -2.5,   -2.5; for lumbar 
spine BMD analysis only) 
 
Baseline total hip BMD T-score ( -3,  -3 and  -2.5,  -2.5; for total hip BMD 
analysis only) 
These subgroups, except for age strata, will be re-examined for appropriateness and 
may be re-categorized or omitted (due to small sample size, for example, if there are 
 10 of subjects within a subgroup) before unblinding.  The analyses of these 
subgroups will be exploratory in nature.   
7.10 
Efficacy Analysis Set in Month 12 to 24 Study Period 
This set includes all randomized subjects who received at least one open-label ALN 
dose.  Subjects in the analysis set will be analyzed according to their randomized 
treatment assignment, regardless of treatment received.  The analysis set will be used 
as the primary analysis set for the following endpoints between Month 12 and Month 24:  
nonvertebral fracture, clinical fracture, clinical vertebral fracture, and hip fracture.  
7.11 
Efficacy Analysis Set for Vertebral Fracture in Month 12 to 24 Study 
Period 
This analysis set includes all randomized subjects who received at least one open-label 
ALN dose and have evaluation of vertebral fracture at Month 12 and at or before Month 
24.  This analysis set will additionally include subjects who have vertebrae with missing 
Genant semiquantitative scores prior to Month 12 and whose first spinal radiograph after 
Month 12 shows no fracture on the same vertebrae because it can be inferred that the 
baseline and Month 12 scores would have also shown no fracture had they been 
available.  This analysis set will be used as the primary analysis set for new vertebral 
fracture between Month 12 and Month 24.   


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8. 
Interim Analysis and Early Stopping Guidelines 
No formal interim analysis is planned for this study prior to the evaluation of the primary 
endpoints. 
An external, independent DMC will monitor unblinded safety data on an ongoing basis 
throughout the entire study period and, if a potential safety signal is identified, may 
consider efficacy data in order to assess the risk/benefit profile of romosozumab.  DMC 
members will have access to treatment assignments if knowledge of treatment 
assignment at the individual level is essential to evaluate safety.  To minimize the 
potential introduction of bias, these individuals will not have direct contact with the study 
site personnel or subjects.  An independent statistical service provider will generate 
unblinded reports for review by the DMC.  If at any time there are safety concerns, the 
DMC will communicate the concerns to a representative from Amgen senior 
management.  The DMC will convene approximately every 3 to 6 months.  The start date 
will depend on the subject accrual rates. Roles and groups requiring access to restricted 
and interim data at the time of the primary analyses and any time before initial database 
lock will be pre-specified to ensure the integrity of the trial.  
Records of all meetings will be maintained by the DMC for the duration of the study.  
Records of all meetings will be stored in the Amgen official document management 
system Trial Master File at the conclusion of the study.  Further details are provided in 
the DMC Charter. 
Staff from the Pharmacokinetics and Drug Metabolism group will be unblinded to 
treatment assignments before study final unblinding to perform exposure-response 
analyses. These individuals will ensure potentially unblinding data are not distributed to 
blinded individuals until the study is unblinded.  
Early access to data for exposure-response analysis is solely for the purpose of 
preparing datasets and statistical programs (ie, administrative processing). Any 
in-process results from this early access will not be distributed and do not constitute an 
interim analysis. 


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9. 
Data Screening and Acceptance 
9.1 
Data Handling and Electronic Transfer of Data  
All data for this study will be received from Amgen’s data management department and 
will be housed within the Electronic Data Capture (EDC) database, RAVE. All screening 
and on-study blood samples will be processed by the central laboratory (with the 
exception of the serum electrophoresis samples that are processed/analyzed by a local 
laboratory) and will be electronically transferred to the Amgen database.  All imaging 
data (eg, X-ray, QCT, FEA, and DXA), will be submitted to the central imaging vendor for 
final analysis. The results from the central imaging vendor analysis will be electronically 
transferred to the Amgen database. All other data will be captured on the eCRF. 
An Analysis Dataset for Pharmacokinetics Concentrations (ADPC) will be provided to the 
Clinical Pharmacology, and Modeling and Simulation group from Biostatistics.   
9.2 
Handling of Missing and Incomplete Data 
Subjects may have missing specific data points for a variety of causes.  In general, data 
may be missing due to a subject’s early withdrawal from study, a missed visit, or 
non-evaluability of a specific clinical measurement at its planned clinical visit. Unless 
specified, no imputation will be used.  The general procedures outlined below describe 
what will be done when a data point is missing. 
9.2.1 
Genant Semiquantitative Grades  
Missing semiquantitative grades will not be imputed to determine vertebral fracture 
status.   
9.2.2 
Vertebral Fracture Assessment  
Because in an adult, a vertebral fracture can only get worse or at best remain at the 
same severity over time, the Genant semiquantitative grade for a vertebra can only 
increase or remain the same.  In other words, once a vertebral fracture is identified, the 
subsequent spinal radiographs will always show fracture. Therefore, any missing 
post-baseline vertebral fracture status due to missing spinal x-ray assessment will be 
imputed using the status from the last nonmissing post-baseline visit (ie, last observation 
carried forward [LOCF]).   


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9.2.3 
DXA or QCT Endpoints 
Missing baseline values for endpoints by DXA or QCT at any anatomical site will not be 
imputed.  Missing post-baseline values will be imputed using LOCF approach (by 
carrying forward the last nonmissing post-baseline value prior to the missing value from 
the same anatomical site). For the open-label period endpoints, only the open-label 
period value will be used for imputation, the values in the double-blind period will not be 
carried forward into open-label period.  The LOCF imputation will be done up to 
Month 36.  Missing post-baseline data will not be imputed when repeated measures 
model is employed as a sensitivity analysis.   
If a subject has values from different DXA machine types (ie, Hologic and Lunar) or QCT 
machine types only those values that are collected from the same machine type as the 
baseline will be used for analyses and imputation.  For anatomical sites that can be 
measured on different body sides (ie, left and right), only those values that are collected 
from the same body side as the baseline will be used for analyses and imputation.       
9.2.4 
Bone Turnover Markers/Biomarkers and PK 
Missing bone turnover maker or biomarkers (either baseline or post-baseline values) or 
PK will not be imputed.  Any values below the lower limit of quantification will be imputed 
using the lower limit of quantification for analysis.    
9.2.5 
PRO Measurements 
9.2.5.1 
OPAQ-SV 
Missing baseline or post-baseline OPAQ scores will not be imputed.   
9.2.5.2 
EQ-5D-5L 
Missing baseline or post-baseline EQ-5D-5L scores will not be imputed.   
9.2.5.3 
BPI Worst Pain 
Missing baseline or post-baseline BPI worst pain score will not be imputed.   
9.2.5.4 
LAD 
Subjects answering “no” to cutting down on things (Question 1) will be assigned 0 day of 
cutting down on things for Questions 2a (due to health reasons) and 2b (due to a 
fracture if a fracture is reported before the PRO assessment).  For subjects answering 
 


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“subject does not know” to cut down on things (Question 1), the missing days of cutting 
down on things will not be imputed.  For subjects answering “yes” to cut down on things 
(Question 1) but not knowing the number of days cutting down on things in Question 2a 
or Question 2b, the missing days of cutting down on things will not be imputed.  Days of 
cutting down on things will not be imputed if the question is not answered at all.     
Similarly, subjects answering “no” to hospitalization overnight (Question 3) will be 
assigned 0 day of hospitalization overnight for Question 3a (due to health reasons) and 
3b (due to a fracture if a fracture is reported before the PRO assessment).  For subjects 
answering “yes” to hospitalization overnight (Question 3) but not knowing the number of 
days of hospitalization overnight, the missing days will not be imputed.  For subjects 
answering “subject does not know” to hospitalization overnight (Question 3), the missing 
days will not be imputed.  Days of hospitalization overnight will not be imputed if the 
question is not answered at all. Similar approach will be applied to days of stay in bed 
(Question 4).  
If the reported days of cutting down on things, hospitalization overnight, or stay in bed 
are greater than the recall period (30 days), minimum (30, reported days) will be applied 
to baseline and post-baseline visit.  
9.2.6 
Dates  
No imputation will be done on incomplete stop date of an adverse event or a 
concomitant medication unless specified otherwise.  For the purposes of deriving 
time-to-event variable from adverse event data or identifying from which point forward 
the data collected should be excluded or censored for the per-protocol analysis because 
of subjects receiving incorrect investigational product or proscribed therapies, 
incomplete start dates of adverse events or concomitant medications will be imputed as 
follows.  Partial dates will be listed as is on the listings.   


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Table 3.  Imputation Rules on Incomplete Start Date of Adverse Event or 
Concomitant Medication 
 
Missing 
Impute 
Exception 
Start Date 
Day 
01 
Default to Study Day 1 Date if the event started in 
the same year and month as Study Day 1 
Day / 
Month 
01JAN 
Default to Study Day 1 Date if the event started in 
the same year as Study Day 1 
Month 
JAN 
Default to Study Day 1 if the event started in the 
same year as Study Day 1 
Day / 
Month / 
Year 
First Dose 
Date 
Use randomization date for subjects who did not 
receive investigational product 
If a death date (ie, End of Study date) is incomplete and missing only the day field, it will 
be imputed as the first day of the month if the latest date from other data is before the 
month of the death.  However, if the latest assessment date is during the same month as 
the death, the partial death date will be imputed using the latest assessment date.   
For dates of last period for menopause, the imputation rules for partial date are as 
follows: if the day is missing, default to day 15; if both month and day are missing, 
default to July 1.  If the imputed date is on or after the randomization date, default to 
randomization date minus 1.  Missing years will not be imputed. 
If the date on the PRO administration page is partially or completely missing, the date of 
SC IP administration (or vital sign collection if SC IP is missing during the the 
double-blind period or during the open-label period) at the corresponding visit with the 
same CPEVENT will be used.  Because it is expected that all PRO questionnaires be 
completed on the same day, EQ-5D-5L, BPI worst pain and LAD will use the same 
assessment date and the same imputation algorithm as that for OPAQ-SV. 
9.2.7 
Lab Parameters 
Lab parameters with value below the lower limit of quantification (LLOQ) or above the 
upper limit of quantification (ULOQ) will be imputed as the LLOQ or ULOQ value, 
respectively. 
9.2.8 
Height 
Missing post-baseline heights will be imputed using LOCF approach (by carrying forward 
the last nonmissing post-baseline value prior to the missing value). For the open-label 
period endpoints, only the open-label period value will be used for imputation, the values 


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in the double-blind period will not be carried forward into open-label period.  The LOCF 
imputation will be done up to Month 24.   
9.2.9 
Oral IP Alendronate  
Boxes containing oral IP alendronate/placebo are dispensed to subjects every 2 months 
during the double-blinded period and oral IP alendronate are dispensed every 6 months 
during the open-label period.  The number of tablets returned are collected in eCRF.  
Before the datasnapshot, these data will be cleaned.  If the number of returned 
alendronate were missing, it will be imputed that subjects did not take any IP.   
9.3 
Outliers 
Scatter plots will be examined to identify potential outliers in any of the continuous 
variables identified in Section 4.  Frequencies of the categorical data listed in Section 4 
will be examined to identify questionable values.  Before data snapshot the validity of 
any questionable values will be verified and observations found to be due to data entry 
errors will be corrected by the study team.  Potential outliers that are not due to data 
entry error will be included in the analysis.  No valid measurement will be purposely 
excluded from descriptive or inferential analyses.  However, sensitivity analyses may be 
conducted to evaluate the influence of extreme values in the data.  These analyses will 
be documented in the clinical study report. 
9.4 
Distributional Characteristics 
The assumptions underlying the parametric models analyzed for continuous data will be 
checked.  In cases where residuals indicate marked departures from the assumptions, 
additional sensitivity analyses will be performed using transformations or alternate 
methods such as nonparametric or robust procedures.   
9.5 
Validation and Configuration Management 
Programs will be developed and maintained, and output will be verified according to 
processes described in procedures or technical manuals about the “Configuration 
Management of Statistical Analysis and Reporting Systems”, “Statistical Analysis and 
Reporting System Development and Validation”, and “Development of Statistical 
Analysis and Reporting Systems”.   
Tables, figures and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   


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The production environment consists of Amgen-supported versions of The SAS System 
running on the Sun Solaris operating system.  Because it is common for multiple 
versions of SAS to be available during the study period, the SAS version used to 
produce analyses will be documented in the validation documentation and the clinical 
study report. 
10. 
Statistical Methods of Analysis 
10.1 
General Principles 
The analytical approach for this study will be to use inferential testing to evaluate the 
following: 
 
the effect of romosozumab treatment for 12 months followed by ALN treatment on 
fracture outcome as compared with ALN alone 
 
the effect of romosozumab treatment for 12 months on fracture outcomes as 
compared with ALN alone 
All efficacy analyses will be performed by randomized treatment, regardless of actual 
treatment received. 
At primary analysis, to maintain the overall significance level of 0.05, Hochberg’s method 
will be used to evaluate the primary endpoints: 
 
Subject incidence of clinical fracture at primary analysis 
 
Subject incidence of new vertebral fracture through Month 24 
If both the primary endpoints are significant at the 0.05 level (2-sided), each of the 
following secondary DXA BMD endpoints will be tested hierarchically at 0.05 (2-sided) 
according to the following sequence: percent change from baseline in BMD at lumbar 
spine at Month 24, percent change from baseline in BMD at total hip at Month 24, 
percent change from baseline in BMD at femoral neck at Month 24, percent change from 
baseline in BMD at lumbar spine at Month 12, percent change from baseline in BMD at 
total hip at Month 12, and percent change from baseline in BMD at femoral neck at 
Month 12.   
If all preceding endpoints are significant, the nonvertebral fracture at the primary 
analysis will be evaluated based on a 1-sided test at the significance level determined by 
the alpha spending function specified in Section 3.2.3.  The adjusted 2-sided p-value will 
be provided to demonstrate the overall significance level of 0.05.  All remaining 
secondary and exploratory efficacy endpoints will be explored at significance level of 


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0.05 (2-sided). If superiority of the nonvertebral fracture endpoint is achieved at the 
primary analysis and the study is stopped after the primary analysis has been 
performed, all data, including the additional safety and nonvertebral fracture data, 
collected after the primary analysis will be summarized descriptively. Study completion 
constitutes either completion of primary analysis if superiority is proven for nonvertebral 
fractures or until 440 subjects experience a nonvertebral fracture. 
For analyses where the age stratification factor needs to be incorporated, the following 
general principles will be followed: 
 
For stratified analyses that are intended to evaluate the treatment effect, the 
analyses will be done using the randomized stratum, regardless of the subject’s 
actual stratum.  If the stratification error rate is  5, a sensitivity analysis using 
the stratification factor of the actual value will be done for the primary efficacy 
endpoint.   
 
When the stratification factor is used as a covariate in the covariate analysis 
where the analysis interest is on the association between the covariate and the 
outcome, the stratification factor based on the actual value will be used. 
Continuous parameters will be summarized using descriptive statistics, which include the 
mean, standard deviation, minimum, 25th percentile, median (50th percentile), 
75th percentile, maximum, and number of non-missing observations (n).  Nominal and 
ordinal categorical variables will be summarized using frequencies and percentages.  
Unless otherwise specified, the percentages will be based on the number of subjects in 
the specific analysis set for the endpoint.  Time-to-event parameters will be summarized 
using the Kaplan-Meier event rates. 
10.2 
Subject Accountability 
The disposition of all randomized subjects will be tabulated by randomized treatment 
group.  Subject enrollment and disposition for the number of subjects randomized, 
number of randomized subjects participating in the sub-study, successfully completing 
investigational product administration in the double-blind and overall study periods, and 
completing the study will be included.  The disposition of subjects will also include the 
number of subjects who withdrew from the investigational product and their reasons for 
withdrawal for SC and oral investigation product. The disposition of the number of 
subjects who withdrew from study and their reasons for withdrawal will be provided.       


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10.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject visit and updated during the IPD reviews throughout the study prior to 
database lock. These definitions of IPD categories, sub-category codes and descriptions 
will be used during the course of the study. The final IPD list is used to produce the 
Summary of IPDs table and the List of Subjects with IPDs. Important protocol violations 
including eligibility violations will be summarized and listed.  
10.4 
Demographic and Baseline Characteristics 
The following demographic and baseline disease characteristics will be summarized by 
randomized treatment group based on all randomized subjects:   
 
Race  
 
Age (years) 
 
Age groups (65, 75  and  75) 
 
Years since menopause 
 
Body composition (height [cm], weight [kg], and BMI [kg/m2]) 
 
10-year probability of major osteoporotic and hip fractures based on WHO risk 
factor criteria (FRAX) calculated with femoral neck BMD T-score 
 
10-year probability of major osteoporotic and hip fractures based on WHO risk 
factor criteria (FRAX) calculated without femoral neck BMD T-score 
 
Fracture history including any fracture, osteoporotic fractures, vertebral fractures, 
nonvertebral fractures, major nonvertebral fracture, any historical fracture after 
age 55,  and any historical fracture after age 45 
 
Presence or absence of severe vertebral fracture at baseline; based on most 
severe Genant semiquantitative grade at baseline on screening spinal 
radiograph) 
 
Number of prevalent vertebral fractures at baseline (0, 1, 2,  3; based on 
screening spinal radiograph) 
 
Most severe Genant semiquantitative grade at baseline (based on screening 
spinal radiograph) 
 
 BMD T-score of lumbar spine, total hip, and femoral neck 


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 
Selected laboratory analytes (calcium corrected by albumin, phosphorus, 
creatinine, estimated GFR, and estimated GFR level [ 15, 15 to  30, 30 to 
 60, 60 to  90, and  90 mL/min]) 
 
Baseline serum 25 (OH) vitamin D level 
 
Prior use of any osteoporosis medication (yes, no) 
 
Prior use of oral bisphosphonate (yes, no) 
 
Prior use of intravenous bisphosphonate (yes, no) 
 
Prior use of SERM (yes, no) 
 
Prior use of PTH or PTH derivatives (yes, no) 
 
Prior use of hormone replacement therapy (yes, no) 
 
Prior use of calcitonin (yes, no) 
 
Prior use of strontium (yes, no) 
 
Prior use of fluoride (yes, no) 
 
Prior use of calcitriol (yes, no) 
 
Prior use of denosumab (yes, no) 
 
Baseline use of calcium and vitamin D (yes, no)  
 
Substance use during the past 5 years including tobacco use (never, former, and 
currently); alcoholic beverages (none,   2 per day,  3 per day);  
10.4.1 
Vitamin D Loading Dose Administration 
Subjects with a serum 25 (OH) vitamin D level  20 ng/mL and  40 ng/mL at screening 
were to receive an initial loading dose of 50,000 to 60,000 IU vitamin D after 
randomization.  Receipt of this loading dose will be summarized by baseline vitamin D 
level ( 20 ng/mL,  20 ng/mL and  40 ng/mL, and  40 ng/mL) and randomized 
treatment group.  Baseline vitamin D level is based on the last screening level prior to 
randomization.  The loading dose will be identified based on the concomitant medication 
eCRF as follows: 
1. Select vitamin D medication records with start date within 1 week of Study Day 1 
2. Derive dose per day and total dose as: 
a. If dose  50,000 IU then dose per day and total dose are set to recorded 
dose 


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b. If dose  50,000 IU then do the following to derive the total dose received: 
i. If duration is missing or greater than 7 days, set duration to 7 days  
ii. Dose per day and total dose are derived as follows based on 
recorded dose, frequency, and duration: 
Frequency 
Frequency code 
Dose Per Day (DPD) 
Total Dose 
PER YEAR 
PA 
CMDOSE 
CMDOSE 
EVERY 2 MONTHS 
Q2M 
CMDOSE 
CMDOSE 
EVERY 2 WEEKS 
Q2S 
CMDOSE 
CMDOSE 
EVERY 3 MONTHS 
Q3M 
CMDOSE 
CMDOSE 
EVERY 3 WEEKS 
Q3S 
CMDOSE 
CMDOSE 
EVERY 4 WEEKS 
Q4S 
CMDOSE 
CMDOSE 
EVERY 6 MONTHS 
Q6M 
CMDOSE 
CMDOSE 
EVERY 6 WEEKS 
Q6S 
CMDOSE 
CMDOSE 
EVERY 8 MONTHS 
Q8S 
CMDOSE 
CMDOSE 
EVERY 8 WEEKS 
Q8W 
CMDOSE 
CMDOSE 
EVERY MONTH 
QM 
CMDOSE 
CMDOSE 
EVERY WEEK 
QS 
CMDOSE 
CMDOSE 
ONCE 
ONCE 
CMDOSE 
CMDOSE 
IMMEDIATELY 
STAT 
CMDOSE 
CMDOSE 
AT BEDTIME 
HS 
CMDOSE 
DPD*duration 
AS NEEDED 
PRN 
CMDOSE 
DPD*duration 
DAILY 
QD 
CMDOSE 
DPD*duration 
TWICE PER DAY 
BID 
CMDOSE * 2 
DPD*duration 
EVERY 12 HOURS 
Q12H 
CMDOSE * 2 
DPD*duration 
TWICE PER WEEK 
BIS 
CMDOSE * 2/7 
DPD*duration 
EVERY HOUR 
QH 
CMDOSE * 24 
DPD*duration 
EVERY 8 HOURS 
Q8H 
CMDOSE * 3 
DPD*duration 
3 TIMES PER DAY 
TID 
CMDOSE * 3 
DPD*duration 
THREE TIMES A 
WEEK 
TIS 
CMDOSE * 3/7 
DPD*duration 
EVERY 6 HOURS 
Q6H 
CMDOSE * 4 
DPD*duration 
4 TIMES PER DAY 
QID 
CMDOSE * 4 
DPD*duration 
4 TIMES PER WEEK 
QIS 
CMDOSE * 4/7 
DPD*duration 
Page 1 of 2 


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Frequency 
Frequency code 
Dose Per Day (DPD) 
Total Dose 
EVERY 4 HOURS 
Q4H 
CMDOSE * 6 
DPD*duration 
EVERY OTHER DAY 
QOD 
CMDOSE / 2 
DPD*duration 
EVERY 3 DAYS 
Q3D 
CMDOSE / 3 
DPD*duration 
EVERY 4 DAYS 
Q4D 
CMDOSE / 4 
DPD*duration 
Page 2 of 2 
3. Sum all total dose records for each subject to get total daily dose 
4. Subjects with a total daily dose  50,000 IU will be considered as having received 
the loading dose of vitamin D 
For subjects who enrolled in the sub-study, demographics, body composition, baseline 
BMD, and the following baseline laboratory data will also be summarized: 
 
Bone turnover markers (CTX, OC, BSAP, and P1NP) 
 
Selected laboratory analytes (calcium corrected by albumin, phosphorus, and 
iPTH) 
10.5 
Efficacy Analyses  
The age stratification factor will be included in the statistical models when analyzing data 
from the entire study but will not be included in analyses of sub-study. 
10.5.1 
Descriptions of Standard Summaries and Statistical Models  
10.5.1.1 
Standard Analyses for Binary Endpoints  
All binary endpoints will be summarized using the number and percentage of subjects 
having the response of interest by treatment group.  Unless otherwise specified, the 
percentages will be based on the number of subjects in the specific analysis set for the 
endpoint. 
Treatment comparisons on binary endpoints will be done using a logistic regression 
model (Agresti, 1990) with treatment as the main effect (using control arm as the 
reference category) and age stratification, baseline total hip BMD T-score, and presence 
or absence of severe vertebral fracture at baseline as covariate to assess the 
significance of the treatment difference between treatment arm and control arm.  The 
odds ratio and the corresponding 95 2-sided confidence interval and p-values using a 


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score test will be provided.  In the case that the logistic regression model does not 
converge due to sparse data or separation, a conditional logistic regression stratified by 
age strata, and baseline total hip BMD T-score and presence or absence of severe 
vertebral fracture at baseline will be used. This will also apply to other analyses using 
logistic regression in this analysis plan (SAS code in Section 13.4.1) 
In addition to the estimate of the odds ratio from the logistic regression model, point 
estimates of absolute risk reduction (difference in proportions, control – treatment) and 
risk ratio (ratio of proportions, treatment over control) as well as the corresponding 
95 confidence intervals will also be calculated via the Mantel-Haenszel method 
(Agresti and Hartzel, 2000) adjusting for age strata, total hip BMD T-score ( -2.5 and  
 -2.5), and presence or absence of severe vertebral fracture at baseline (SAS code in 
Section 13.4.1, Section 13.4.2 and Section 13.4.3).   
10.5.1.2 
Standard Analyses for Ordinal Endpoints 
All ordinal endpoints will be summarized using the number and percent of subjects in 
each category by treatment group. Unless otherwise specified, the percentages will be 
based on the subjects with non-missing observations. Treatment comparisons on ordinal 
endpoints will be done using a repeated measures proportional odds model adjusting for 
age strata and presence or absence of severe vertebral fracture at baseline, visit and 
treatment by visit interaction. The odds ratios and their corresponding 95 2-sided Wald 
confidence interval will be provided (SAS code in Section 13.4.5). 
10.5.1.3 
Standard Analyses for Time-to-event Endpoints 
All time-to-event endpoints will be summarized descriptively using the Kaplan-Meier 
estimates at time point(s) of interest (SAS code in Section 13.4.7).  Further analysis 
using a stratified Cox proportional hazards model controlling for age strata with presence 
or absence of severe vertebral fracture at baseline, baseline total hip BMD T-score, and 
treatment as the independent variable will also be provided (SAS code in 
Section 13.4.8).  The significance of the treatment effect between treatment arm and 
control arm will be assessed based on the Cox proportional hazards model. The 
estimated hazard ratio, corresponding 95 confidence interval, and the p-value of the 
score test from the model will be provided.  In addition, the point estimate of the adjusted 
risk difference (difference in Kaplan-Meier estimates at the time point of interest, control 
arm - treatment arm) and the corresponding 95 confidence interval will be provided 


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using the inverse variance-weighted method (SAS code in Section 13.4.14).  For 
12 months analysis, subjects without having the event of interest in the double-blind 
period will be censored at the end of double-blind period date. For 24 months analysis, 
subjects without having the event of interest in the study will be censored at the end of 
24-month study period. 
The proportional hazards assumption will be examined visually using log-log survival 
plots versus time and plots of Schoenfeld residuals versus time (Schoenfeld, 1982).  If 
the proportional hazards assumption is violated, a piecewise Cox proportional hazards 
model assuming proportional hazards in the 1st year, the 2nd year, and all remaining 
years thereafter, will be used. 
10.5.1.4 
Standard Analyses for Continuous Endpoints 
All continuous endpoints will be summarized using descriptive statistics including mean, 
standard deviation, minimum, 25th percentile, median (50th percentile), 75th percentile, 
maximum, and number of nonmissing observations (n).   
10.5.1.5 
ANCOVA Model  
The ANCOVA model (SAS code in Section 13.4.9) will include treatment, age 
(stratification factor), presence or absence of severe vertebral fracture at baseline, and 
baseline value of the endpoint.  The model will allow different variances for the treatment 
groups for DXA or QCT endpoints.  Additional covariates of machine type and 
machine type-by-baseline value interaction will also be included in the model to adjust 
for the effect of machine type on baseline value for parameters derived by DXA.  The 
age strata will not be included in analyses for the sub-study. 
The least-squares mean of the treatment difference (treatment – control) and the 
corresponding 95 confidence interval will be summarized by time points of interest, 
where each time point is estimated using a separate ANCOVA model.  Graphical display 
of the least-squares means by randomized treatment group across time points may also 
be provided to visually summarize the results from the model.   
10.5.1.6 
Repeated Measures Model 
The likelihood-based repeated measures model (Longford, 1993) will include treatment, 
age strata (stratification factor), presence or absence of severe vertebral fracture at 
baseline, visit, baseline value of the endpoint, and treatment-by-visit interaction as fixed 


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effects using an unstructured variance-covariance structure.  The model will allow 
different variances for the treatment groups for endpoints. Additional covariates of 
machine type (Hologic or Lunar) and machine type-by-baseline value interaction will also 
be included in the model to adjust for the effect of machine type on baseline value for 
parameters derived by DXA.  The visit will be treated as a categorical variable.  The age 
strata will not be included in analyses for the sub-study.  The approach of 
Kenward and Roger (1997) for estimating the denominator degrees of freedom for the 
hypothesis test will be followed (SAS code in Section 13.4.10). Other 
variance-covariance structure may be substituted if converg ence problem arises. The 
least-squares mean of the treatment difference (treatment – control) and the 
corresponding 95 confidence interval will be summarized by time points of interest. 
Graphical displays of least-squares means by randomized treatment group across time 
points may also be provided to visually summarize the results from the model.   
10.5.1.7 
Wilcoxon Rank-sum Test  
Wilcoxon rank-sum test (SAS code in Section 13.4.11) will be used to assess the 
significance of the treatment difference at each time point for bone turnover markers and 
biomarkers and any other endpoints where parametric methods may not be appropriate. 
10.5.1.8 
Van Elteren Stratified Rank Test  
Van Elteren stratified rank test (van Elteren, 1960; SAS code in Section 13.4.13) 
adjusting for age strata (stratification factor) and presence of severe vertebral fracture at 
baseline will be used to assess the significance of the treatment difference at each time 
point for continuous data from the main study where parametric methods may not be 
appropriate.   
10.5.2 
Analyses of Primary Efficacy Endpoints 
10.5.2.1 
Primary Analytical Approach 
The primary analytical model for comparing subject incidence of new vertebral fractures 
through Month 24 between the randomized treatment groups will use a logistic 
regression model as described in Section 10.5.1.1 based on the primary efficacy 
analysis set for vertebral fractures as described in Section 7.1. The number and 
percentage of subjects with  1 new vertebral fracture through Month 24 will be 
summarized by randomized treatment group.  The adjusted odds ratio of romosozumab 


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as compared with ALN and the corresponding 95 confidence interval will also be 
provided.   
The primary analytical model for comparing subject incidence of clinical fractures at 
primary analysis between the randomized treatment groups will use a stratified Cox 
proportional hazards model as described in Section 10.5.1.3 based on the full analysis 
set as described in Section 7.2.  The cumulative incidence of fractures will be 
summarized using the Kaplan-Meier estimates, and the hazard ratios of romosozumab 
as compared with ALN and the confidence intervals for the risk reduction relative to ALN 
control arm will be based on the model.   
10.5.2.2 
Supportive Analyses 
To demonstrate the robustness of the results from the primary analytical models, 
additional supportive analyses will be performed: 
Per protocol analyses 
Primary analytical models will be repeated using the per protocol subset as described in 
Section  7.4 for new vertebral fracture through Month 24 and clinical fracture at primary 
analysis.  For subjects who received the investigational product not matching their 
randomized treatment group or proscribed therapy on study and had investigational 
product IPD, their vertebral fracture evaluations will be ignored at or after the first 
occurrence of violation.  The imputation described in Section 9.2.2 will be used to impute 
their new vertebral fracture status at Month 24.     
Time-to-event analysis based on full analysis set 
A supportive analysis for new vertebral fracture through Month 24 will be performed 
based on time-to-first new vertebral fracture using the stratified Cox proportional hazards 
model as described in Section 10.5.1.3.   
10.5.2.3 
Covariate Analysis 
For new vertebral fracture the odds ratio of romosozumab as compared with ALN and 
corresponding 95 confidence interval and p-value, adjusting for each of the covariates 
listed in Section 4.6 using the logistic regression model as described in Section 10.5.1.1, 
as well as adjusting for all covariates simultaneously in a multivariate analysis, will be 
presented.  The analysis subset and the imputation method will be the same as those 
used in the primary analytical model.  


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Similarly, for clinical fracture, the adjusted hazard ratio of romosozumab as compared 
with ALN and corresponding 95 confidence interval and p-value adjusting for each of 
the covariates listed in Section 4.6 using the stratified Cox proportional hazards model 
as described in Section 10.5.1.3, as well as adjusting for all covariates simultaneously in 
a multiple regression analysis, will be presented.   
10.5.2.4 
Subgroup Analysis  
To assess the consistency of the treatment effect in different subgroups, the incidence of 
new vertebral fractures and incidence of clinical fracture will be analyzed within each 
subgroup stratum listed in Section 7.9.  For incidence of new vertebral fracture, the odds 
ratio of romosozumab as compared with ALN, and their respective 95 confidence 
intervals, will also be summarized for each category of a subgroup.  The 
treatment-by-subgroup interaction will be tested using a logistic regression as described 
in Section 10.5.1.1 and including individual subgroup and treatment-by-subgroup 
interaction.  If the p-value of the interaction is  0.05, the treatment-by-subgroup 
interaction is considered not significant.  Otherwise, a 2-sided Gail and Simon test 
(Gail and Simon, 1985) will be used to test whether there is qualitative interaction (SAS 
code in Section 13.4.6).  
For clinical fracture, the hazard ratio of romosozumab as compared with ALN, and their 
respective 95 confidence intervals, will also be summarized for each category of a 
subgroup.  The treatment-by-subgroup interaction will be tested using stratified Cox 
proportional hazards model as described in Section 10.5.1.3 and individual subgroup 
and treatment-by-subgroup interaction. Similarly, the interaction will be further evaluated 
for qualitative interaction using Gail and Simon test if the p-value of the score test for the 
interaction is  0.05.  
The verified age will be used to stratify subgroups for the analysis of age subgroup. 
10.5.3 
Analyses of Secondary and Exploratory Efficacy Endpoints 
10.5.3.1 
Nonvertebral Fracture, Clinical Fracture, Clinical Vertebral Fracture, 
All Fracture, Major Nonvertebral Fracture, Major Osteoporotic 
Fracture and Hip Fracture 
The full analysis set as described in Section 7.2 will be used for the analyses of following 
efficacy endpoints:  
 
subject incidence of nonvertebral fracture through Month 12, through Month 24, 
at primary analysis and final analysis 
 
subject incidence of clinical fracture through Month 12 and through Month 24  


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 
subject incidence of clinical vertebral fracture through Month 12 and through 
Month 24  
 
subject incidence of all fracture through Month 12 and at primary analysis  
 
subject incidence of major nonvertebral fracture through Month 12, at primary 
analysis and at final analysis  
 
subject incidence of major osteoporotic fracture through Month 12 and at primary 
analysis  
 
subject incidence of hip fracture through Month 12, through Month 24, at primary 
analysis and at final analysis.   
As described in Section 10.5.1.3, the cumulative incidence of fractures will be 
summarized using the Kaplan-Meier estimates, and the hazard ratios of romosozumab 
as compared with ALN and the confidence intervals will be based on the stratified Cox 
proportional hazards model.   
The primary analytical model for clinical fracture through Month 12, nonvertebral fracture 
through Month 12 ,at primary and final analyses, will be repeated using the per protocol 
subset as described in Section 7.3 and 7.4 as a supportive analysis.  Further, the hazard 
ratio and corresponding 95 confidence interval and p-value adjusting for each of the 
covariates listed in Section 4.6 using the stratified Cox proportional hazards model as 
described in Section 10.5.1.3, as well as adjusting for all covariates simultaneously in a 
multiple regression  analysis, will be presented.   
For nonvertebral fracture through Month 12 and at primary analysis, the hazard ratio of 
romosozumab as compared with ALN, and their respective 95 confidence intervals, will 
also be summarized for each category of a subgroup.  The treatment-by-subgroup 
interaction will be tested using stratified Cox proportional hazards model as described in 
Section 10.5.1.3 and individual subgroup and treatment-by-subgroup interaction. 
Similarly, the interaction will be further evaluated for qualitative interaction using Gail and 
Simon test if the p-value of the score test for the interaction is  0.05.  
The efficacy analysis set in Month 12 to 24 study period as described in Section 7.10 will 
be used for the analyses of following efficacy endpoints between Month 12 and Month 
24: subject incidence of clinical fracture, subject incidence of nonvertebral fracture, 
subject incidence of hip fracture, and subject incidence of clinical vertebral fracture.  The 
incidence of fractures will be summarized using the Kaplan-Meier estimates, and the 
hazard ratios of romosozumab as compared with ALN and the confidence intervals will 
be based on the stratified Cox proportional hazards model as described in 


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Section 10.5.1.3.  Due to the lack of randomization at Month 12, the comparability 
between the two arms is not ensured and therefore the analysis is more susceptible to 
bias. 
10.5.3.2 
New Vertebral Fracture, New or Worsening Vertebral Fracture, and 
Multiple New or Worsening Vertebral Fracture  
The primary efficacy analysis set for vertebral fracture as described in Section 7.1 will be 
used for the analyses of following efficacy endpoints: subject incidence of new vertebral 
fracture through Month 12, subject incidence of new or worsening vertebral fracture 
through Month 12 and Month 24, subject incidence of multiple new or worsening 
vertebral fracture through Month 12 and Month 24. The above subject incidences 
between subjects in the treatment group and subjects in the control group will be 
compared using a logistic regression model adjusting for age strata as described in 
Section 10.5.1.1.  The number and percentage of subjects with  1 above specified 
vertebral fracture will be summarized by treatment group for first 12-month of 
double-blind period and for 24-month study period.  The adjusted odds ratio and the 
corresponding 95 confidence interval will also be provided.   
The efficacy analysis set for vertebral fracture during 24-month study period as 
described in Section 7.11 will be used for the analysis of subject incidence of new 
vertebral fractures between Month 12 and Month 24.  The number and percent of 
subjects with new vertebral fracture between Month 12 and Month 24 in this efficacy 
analysis set will be summarized by treatment group.  The treatment comparison will be 
done using a logistic regression model as described in Section 10.5.1.1.  Due to the lack 
of randomization at Month 12, the comparability between the two arms is not ensured 
and therefore the analysis is more susceptible to bias.   
10.5.3.3 
Percent Changes in Lumbar Spine, Total Hip and Femoral Neck BMD 
by DXA  
The primary efficacy subset for BMD described in Section 7.6 will be used for the 
analyses of percent changes from baseline in lumbar spine, total hip and femoral neck 
by DXA at month 12, 24, and 36.   
The treatment comparisons of the BMD in lumbar spine, total hip and femoral neck at 
months 12 and 24 will be analyzed using the ANCOVA model described in 
Section 10.5.1.5 with LOCF imputation as the primary analysis.  Descriptive summary of 


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observed DXA values at Month 36 will be provided without LOCF.  Graphical displays to 
assess the model will include response versus fitted values, response versus 
standardized residuals and a normal probability plot of the standardized residuals. The 
sensitivity analyses include the repeated measures model as described in 
Section 10.5.1.6, where each body site is estimated using a separate repeated 
measures model. 
Absolute values and change from baseline for BMD will also be summarized 
descriptively by time point and machine type. 
10.5.3.4 
Change from Baseline in Height 
The subset as described in Section 7.6  will be used for the analyses of change from 
baseline in height at months 12 and 24.  A nonparametric method, Van Elteren rank test, 
as described in Section 10.5.1.8, will be used for treatment comparisons for change from 
baseline in height.  ANCOVA models as described in Section 10.5.1.5 will also be used 
for treatment comparisons. 
10.5.4 
PRO/ClinRO Exploratory Endpoints 
The subset described in Section 7.6 will be used for the analysis of PRO/ClinRO  
endpoints and the subset described in Section 7.7 will be used for the analysis of post 
fracture PRO endpoints. 
Descriptive summary statistics will be provided for actual values and changes from study 
baseline by visit as described in Section 10.5.1.4. Descriptive summary statistics will 
also be provided for the changes from the pre-fracture baseline by visit since fracture. 
The comparison of treatments on the post-fracture PRO data includes subjects who 
have a clinical fracture on study, however, the fracture type, fracture location and patient 
characteristics might be different in these fractured subjects between two treatment 
arms. Although various factors will be adjusted in the analysis, due to the lack of 
randomization, the comparability is not ensured and therefore the analysis is more 
susceptible to bias. 
OPAQ-SV 
The analyses of changes from study baseline at months 6, 12, 18, 24, 30, and 36 in 
OPAQ-SV dimension scores of physical function, emotional status, and back pain will be 
performed using the repeated measures model separately as described in 


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Section 10.5.1.6.  The analyses of changes from pre-fracture baseline at month 1, 2 and 
3 after reporting a clinical fracture in OPAQ-SV dimension scores will be performed 
using the repeated measures model adjusting for age strata, presence or absence of 
severe vertebral fracture at baseline, treatment, visit, fracture type, pre-fracture baseline 
score, change from pre-fracture baseline at report of fracture and treatment by visit 
interaction. The missing OPAQ SV dimension scores at reporting of the fracture will be 
handled by multiple imputation.  
EQ-5D-5L 
The analyses of changes from study baseline at months 6, 12, 18, 24, 30, and 36 in 
EQ-5D-5L VAS score will be performed using the repeated measures model as 
described in Section 10.5.1.6.  
Each of the 5 EQ-5D-5L dimension scores (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) at month 6, 12, 18, 24, 30, and 36 will be analyzed 
using repeated measure proportional odds model adjusting for age strata, presence or 
absence of severe vertebral fracture at baseline, treatment, visit, baseline score and 
treatment-by-visit interaction as described in Section 10.5.1.2.  
The change from study baseline at month 6, 12, 18 24, 30, 36 and the change from 
pre-fracture baseline at month 1, 2 and 3 after fracture in 5 EQ-5D-5L dimension scores 
will be summarized by shift tables. 
The analyses of changes from pre-fracture baseline at month 1, 2 and 3 after reporting a 
clinical fracture in EQ-5D-5L VAS score will be performed using the repeated measures 
model adjusting for age strata, presence or absence of severe vertebral fracture at 
baseline, treatment, visit, fracture type, pre-fracture baseline score, change from pre-
fracture baseline at report of fracture and treatment by visit interaction.  The missing 
EQ-5D-5L VAS score at reporting of the fracture will be handled by multiple imputation. 
BPI Worst Pain Score 
The analyses of changes from study baseline at months 6, 12, 18, 24, 30, and 36 in BPI 
worst pain score will be performed using the repeated measures model as described in 
Section 10.5.1.6.  The analyses of changes from pre-fracture baseline at month 1, 2 and 
3 after reporting a clinical fracture in BPI worst pain score will be performed using the 
repeated measures model adjusting for age strata, presence or absence of severe 


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vertebral fracture at baseline, treatment, visit, fracture type, pre-fracture baseline score, 
change from pre-fracture baseline at report of fracture and treatment by visit interaction. 
The missing BPI worst pain score at reporting of the fracture will be handled by multiple 
imputation. 
The proportion of subjects with a clinically meaningful improvement in worst pain in 
3 months after experiencing a nonvertebral or clinical vertebral fracture (defined as a 
2-point improvement in the BPI worst pain scale compared with the fracture reporting 
visit) will be analyzed using a logistic regression model adjusting for age strata, 
presence or absence of severe vertebral fracture at baseline, treatment, fracture type, 
worst pain score at report of fracture and change from pre-fracture baseline at report of 
fracture. The proportion of subjects with a clinically meaningful improvement in worst 
pain at each post fracture reporting visit and within 3 months from pre-fracture baseline 
will be analyzed using same approach. 
LAD Questionnaire 
The number and percent of subjects reporting in the past month cutting down on things 
due to health reasons (Question 1), in hospital overnight due to health reasons 
(Question 3), and stay in bed due to health reasons (Question 4) at months 6, 12, 18, 
24, 30, and 36, and at month 1, 2 and 3 after fracture will be summarized descriptively.  
Subjects reporting cutting down things but with missing value for number of days will not 
be included in the respective analysis of number of days. 
Number of days in the past month of cutting down things due to health reasons 
(Question 2a), in hospital overnight due to health reasons (Question 3a), and stay in bed 
due to health reasons (Question 4a) at months 6, 12, 18, 24, 30, and 36 will be 
summarized descriptively.  The treatment comparison at months 6, 12, 18, and 24, will 
be done using the repeated measures model adjusted for age strata, presence or 
absence of severe vertebral fracture at baseline, treatment, visit, treatment by visit 
interaction, and baseline.  
Number of days in the past month of cutting down on things due to a fracture 
(Question 2b), in hospital overnight due to a fracture (Question 3b), and stay in bed due 
to a fracture (Question 4b) at month 1, month 2 and month 3 after fracture will be 
summarized descriptively in subjects who have a fracture during the 12-month 
double-blind period. The treatment comparison will be done using the repeated 
 


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measures model adjusted for age strata, presence or absence of severe vertebral 
fracture at baseline, treatment, visit, treatment by visit interaction, fracture type, 
pre-fracture baseline and change from pre-fracture baseline at report of fracture.  
Change from pre-fracture baseline in number of days in the past month of cutting down 
things due to health reasons, in hospital overnight due to health reasons, and stay in bed 
due to health reasons at month 1, month 2 and month 3 after fracture and each first post 
fracture visit will be summarized descriptively in subjects who have a fracture during the 
12-month double-blind period. The treatment comparison will be done using the 
repeated measures model adjusted for age strata, presence or absence of severe 
vertebral fracture at baseline, treatment, visit, fracture type, pre-fracture baseline, 
change from pre-fracture baseline at report of fracture and treatment by visit interaction. 
Change from pre-fracture baseline in number of days in the past month of cutting down 
things due to a fracture, in hospital overnight due to a fracture, and stay in bed due to a 
fracture at fracture reporting visit and each first post fracture visit will be summarized 
descriptively in subjects who have a fracture during the 12-month double-blind period. 
The treatment comparison will be done using the repeated measures model adjusted for 
age strata, presence or absence of severe vertebral fracture at baseline, treatment, visit, 
fracture type, pre-fracture baseline, change from pre-fracture baseline at report of 
fracture and treatment by visit interaction.  
10.6 
Safety Analyses 
Safety data will be summarized for subjects who received  1 dose of active 
investigational product by the actual treatment received in the double-blind period (any 
subject randomized to ALN arm who incorrectly receives  1 dose of romosozumab will 
be analyzed as receiving romosozumab).  
Safety data for the double-blind period and for primary analysis period will be 
summarized separately using analysis set defined in Section 7.5. Safety data will also be 
summarized for the overall study period (at final analysis) using analysis set defined in 
Section 7.5.  
A listing of adverse events will be prepared for subjects who did not received any 
active dose of investigational product in the 12-month of double-blind period. A 
listing of adverse events occurring after double-blind period will be prepared for subjects 


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who received at least one active dose of investigational product in the 12-month of 
double-blind period, remained on study in the open-label period without open-label 
alendronate exposure.  
10.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 19.1 or later will be 
used to code all adverse events to a system organ class and a preferred term for the 
12-month double-blind period, the primary analysis period (at the primary analysis) , and 
the overall study period (at the final analysis). Adverse events will be summarized in the 
double-blind period, in the primary analysis study period (at the primary analysis), and 
overall study period (at the final analysis) for all subjects who receive at least one dose 
of investigational product in the double-blind period.  The subject incidence rates for the 
primary study and overall study period will include all events that occurred in the 
double-blind period, and in addition, all events that occurred in the open-label period for 
those subjects who received at least one dose of open-label ALN. 
 All adverse event tables will be summarized by actual treatment group. The subject 
incidence of adverse events will be summarized for all treatment-emergent, serious, 
treatment-related, serious treatment-related, those leading to withdrawal of study, 
leading to withdrawal of investigational product, fatal, and of special interest.  Subject 
incidence of special interest adverse events will also be summarized according to their 
categories. 
Subject incidence of all treatment-emergent, serious, treatment-related, serious 
treatment-related, those leading to withdrawal of study, leading to withdrawal of 
investigational product, and fatal adverse events will be tabulated by system organ class 
and preferred term in descending order of frequency.  Subject incidence of all 
treatment-emergent adverse events will be tabulated by system organ class, high-level 
group term, and preferred term in descending order of frequency as well as by preferred 
term. 
Summaries of treatment-emergent adverse events occurring in at least 5 of the 
subjects and serious treatment-related adverse events occurring in at least 0.1 of the 
subjects will be provided by preferred term in descending order of frequency.  
Treatment-emergent adverse events occurring in at least 2 of the subjects and also 


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have a 1 difference than ALN will also be summarized by preferred term in 
descending order of frequency. 
Subgroups group analyses for age strata ( 75,  75 years) will be presented by system 
organ class and preferred term in descending order of frequency. 
In addition, subject incidence rates of adverse events corresponding to preferred terms 
of events of interest of hypocalcemia, injection site reactions, potentially related to 
hypersensitivity (Standardized MedDRA Query [SMQ], narrow scope), malignant or 
unspecified tumor (SMQ, narrow scope), hyperostosis, osteoarthritis, adjudicated 
adverse events of osteonecrosis of the jaw, and atypical femoral fracture will be 
provided.   
Unless otherwise specified, there is no planned statistical testing in the safety analyses.    
10.6.2 
Osteonecrosis of the Jaw Adjudication 
The events of osteonecrosis of the jaw (ONJ) which occurred in the study will be 
adjudicated and summarized. All potential events of ONJ identified through a pre-defined 
search of the MedDRA terms will be submitted to the Osteonecrosis of the Jaw 
Adjudication Committee for blinded review and adjudication. The committee will 
determine whether the event meets the case definition criteria for ONJ.  
Number of adjudicated positive ONJ events will be summarized. 
10.6.3 
Adjudicated Positive Cardiovascular Events 
All deaths and potential cardiovascular-related serious adverse events will be submitted 
to an external independent committee comprised of experienced cardiologists for blinded 
adjudication.  The committee will adjudicate the events and determine whether the event 
is cardiovascular in nature.  
Baseline cardiovascular risk factors will be summarized descriptively. These risk factors 
are defined as age ( 75,  75), smoking history, and other clinical history including 
hypertension, diabetes, cardiovascular disease, and hypercholesterolemia. The 
cardiovascular risk factors of history of hypertension, diabetes, cardiovascular disease, 
and hypercholesterolemia will be identified based on the Medical & Surgical History 
eCRF based on MedDRA version 19.1. The SMQ for Hypertension, the SMQ for 
Hyperglycaemia, and the System Organ Classes of Cardiac Disorders and Vascular 


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Disorders will be used to identify preferred terms associated with hypertension, diabetes 
and cardiovascular disease, respectively. The Dyslipidaemia SMQ will be used to 
identify history of hypercholesterolemia, excluding terms associated with conditions of 
low cholesterol or increased high-density lipoprotein.  
Only events confirmed positive by the adjudication committee to meet cardiovascular 
event definition criteria will be included for analyses. Adjudicated cardiovascular events 
of death, cardiac ischemic event, cerebrovascular event, non-coronary revascularization, 
heart failure and peripheral vascular events not requiring revascularization will be 
summarized using subject incidence rates, odds ratios and 95 confidence intervals.  
No statistical tests will be performed. 
10.6.4 
Atypical Femoral Fracture Adjudication 
The events of atypical femoral fracture (AFF) which occurred in the study will be 
adjudicated and summarized. All potential events of AFF identified through a pre-defined 
search of the MedDRA terms will be submitted to the Atypical Femoral Fracture 
Adjudication Committee for blinded review and adjudication. The committee will 
determine whether the event meets the case definition criteria for AFF. 
Number of adjudicated positive AFF events will be summarized. 
10.6.5 
On Study Cancer 
Number and percentage of subjects who reported new malignancy on study will be 
summarized by cancer category and cancer status.  
10.6.6 
Injection Site Reaction 
The number of episodes of injection site reaction, duration, nature (concomitant versus 
recurrent) and severity will be summarized during the double-blind study period. The 
time (in days) to first injection site reaction during the double-blind study period will also 
be summarized descriptively.  
10.6.7 
Hypersensitivity 
Subject incidence of hypersensitivity as an EOI with on-set day within 2 days since 
receiving any dosing of investigational product by preferred term will be provided for the 
double-blind study period. Similarly, the analyses will be repeated for hypersensitivity 
with on-set day  2 and  7 days since receiving any dosing of investigational product.  


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In addition, subject incidence of concomitant/recurrent hypersensitivity EOIs, 
hypersensitivity leading to investigational product discontinuation, and hypersensitivity 
leading to study discontinuation will be provided by preferred term for the double-blind 
study period.   
10.6.8 
Tumor Necrosis Factor Mediated Inflammatory Diseases 
Subject incidence rates of adverse events corresponding to a Amgen search strategy of 
preferred terms for tumor necrosis factor (TNF) mediated inflammatory diseases will be 
provided using the safety analysis set for all subjects, subjects with prior history of TNF 
disease, and subjects without prior history of TNF disease.   
10.6.9 
Laboratory Test Results 
Subjects with missing data for a scheduled visit will not contribute to the safety 
tabulations for that time point (no imputation).  Descriptive statistics for the actual value 
at each visit and the change from baseline at each post-baseline visit during the study 
period will be summarized. Figures showing central tendency and dispersion of the 
actual values and/or changes from baseline of select laboratory parameters (calcium 
corrected by albumin, phosphorus, magnesium and alkaline phosphatase) during the 
double-blind period will be provided.  Above summary statistics and figures will also be 
done for percent change from baseline in calcium corrected by albumin, phosphorus, 
magnesium, and alkaline phosphatase. Visit windows will be used for these summaries 
as described in Section 13.1.1 
Laboratory parameters will be summarized showing the shift from baseline to the most 
extreme post-baseline value between baseline and the end of double-blind period based 
on Common Terminology Criteria for Adverse Events v3.0 (CTCAE).  Subject incidence 
of most extreme post-baseline calcium corrected by albumin decrease grade will also be 
summarized. The percentages of subjects with laboratory toxicities  grade 2 CTCAE will 
be summarized.  In addition, subject listings of grades 3 and 4 laboratory values will be 
provided. 
Drug-induced liver injury will be assessed by evaluating subjects for Hy’s Law criteria in 
the double-blind period and in the primary analysis study period. Hy’s law lab value 
criteria is defined as aspartate amino transferase or alanine amino transferase  3 times 
upper limit of normal (ULN), total bilirubin  2 times ULN, and alkaline phosphatase 
 2 times ULN assessed within 7 days. Subjects who meet these lab criteria on study will 


Product:  Romosozumab 
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be further evaluated to assess whether there exist underlying conditions or concomitant 
medications which can explain the elevation in laboratory analytes.  
Summaries of abnormal laboratory values, including summaries of shifts, worst 
post-baseline calcium, and evaluation of potential Hy’s law cases will be summarized in 
the double-blind period and in the primary analysis period for all subjects who receive at 
least one dose of investigational product in the double-blind period. The subject 
incidence rates for the 24-month study period will include all laboratory measurements 
collected in the double-blind period, and in addition, all laboratory measurements 
collected in the open-label period for those subjects who received at least one dose of 
open-label alendronate. 
10.6.10 
Vital Signs, Height, Body Weight, and BMI 
Descriptive statistics of actual values and changes from baseline in vital signs (systolic 
and diastolic blood pressure, heart rate, and temperature), body weight, and BMI will be 
presented by scheduled visit.  Height, which is analyzed as an efficacy endpoint, will be 
summarized as well using the safety analysis set.  
10.6.11 
Anti-Romosozumab Antibody 
Immunogenic response during the study will be described by tabulating the numbers and 
percentages of subjects who tested positive (binding and neutralizing) for 
anti-romosozumab antibodies in subjects receiving  1 dose of romosozumab at each 
visit and at any visit during study.  Analysis will be performed using safety analysis set 
defined in Section 7.5.  Subjects who test positive for either binding or neutralizing 
antibodies against romosozumab will be interpreted as persistently positive if the 
antibody status remains positive throughout the last time point tested.  Subjects who test 
positive for binding antibodies against romosozumab will be interpreted as transient 
positive if the binding antibody status was negative at the subject’s last time point tested 
within the study period. Subjects who test positive for neutralizing antibodies against 
romosozumab will be interpreted as transient positive if the neutralizing antibody status 
was negative at the subject’s last time point tested within study period.  
If a subject tests positive for antibodies against romosozumab, the relationship between 
the presence of antibodies, adverse events, concomitant medications, and bone mineral 
density will be evaluated; the immunogenic response will be listed by subject and study 
day along with the serum romosozumab levels if available.  Note that the serum 


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romosozumab levels are only collected on subjects who participate in the sub-study. The 
subject incidence of injection site reaction EOIs, hypersensitivity EOIs, and adverse 
events corresponding to the MedDRA high level group term of autoimmune disorders will 
be provided by binding and neutralizing anti-romosozumab antibody status.   
10.6.12 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure of SC and oral 
investigational product by randomized treatment group for subjects exposed to 
investigational product for the double-blind period and open-label period, respectively.  
The total ALN exposure for the subject randomized to ALN arm will also be provided.  
10.6.13 
Exposure to Concomitant Medication  
Types of concomitant medications will not be summarized.  
10.7 
Endpoints From Sub-study 
10.7.1 
Bone Turnover Marker and Biomarker   
The subset described in Section 7.8.2 and 7.8.3 will be used for the analyses of percent 
change in bone turnover markers and biomarkers. These include values, changes from 
baseline, and percent changes from baseline at month 1, 3, 6, ,9, 12, 15, 18, 24, and 
36 in P1NP, sCTX, BSAP, OC and sclerostin. The Wilcoxon rank-sum test as described 
in Section 10.5.1.7 will be used for treatment comparisons for percent change in bone 
turnover markers or biomarkers.  In addition, percent changes from baseline at 
post-baseline visits in iPTH and serum sclerostin level will be provided.  
10.7.2 
BMD by DXA  
The subset described in Section 7.8.1 will be used for the analyses of percent changes 
in lumbar spine, total hip and femoral neck BMD by DXA.  Percent changes from 
baseline at months 6, 12, 18, and 24 in DXA BMD will be compared between treatment 
groups using a repeated measures model as described in Section 10.5.1.2 and an 
ANCOVA model described in Section 10.5.1.5 with treatment group, baseline BMD, 
machine type and interaction of baseline BMD and machine type as independent 
variables.  Any missing value during the 12-month double-blind ALN-controlled study 
period will be imputed by carrying forward the last non-missing post-baseline value prior 
to the missing value.  Descriptive summary of observed DXA values at Month 36 will be 
provided.      


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10.7.3 
vBMD by QCT and Lumber Spine Strength by FEA 
The primary efficacy subset described in Section 7.8.1 will be used for the analyses of 
percent changes from baseline in for integral (total) and trabecular volumetric BMD by 
QCT and lumbar spine strength by FEA.  Percent changes from baseline at months 
6, 12, and 24 in QCT vBMD and lumbar spine strength will be compared between 
treatment groups using a repeated measures model as described in Section 10.5.1.2 
and an ANCOVA model described in Section 10.5.1.5 with treatment group and baseline 
vBMD as independent variables.  Any missing value during the 12-month double-blind 
ALN-controlled study period will be imputed by carrying forward the last non-missing 
post-baseline value prior to the missing value.   
10.7.4 
PK 
Serum concentration data described in Section 7.8.4 will be provided to PKDM group for 
analyses.  Details regarding objectives, data handling, and methodology of the analysis 
will be provided in a separate analysis plan. 
11. 
Changes From Protocol-Specified Analyses  
Protocol Section 10.5.2.1 specified a logistic regression model adjusting for fracture 
location and potentially other factors impacting the pain score to analyze the incidence of 
subjects with a clinical meaningful improvement in worset pain.  Fracture type is used as 
a covariate instead of the fracture location.  


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Date:  06 April 2017 
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12. 
Literature Citations  References 
Agresti A.  Categorical Data Analysis, New York:  John Wiley & Sons, Inc, 1990. 
Agresti A and Hartzel J.  Strategies for comparing treatments on a binary response with 
multi-centre data. Statistics in Medicine. 2000; 19:1115-1139. 
Black DM, Cummings SR, Karpf DB, et al.  Randomised trial of effect of alendronate on 
risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial 
Research Group.  Lancet.  1996;348:1535-1541. 
Black DM, Thompson DE, Bauer DC et al.  Fracture Risk Reduction with Alendronate in 
Women with Osteoporosis: The Fracture Intervention Trial.  J Clin Endocrinol Metab.  
2000;85: 4118–4124. 
Cummings SR, San Martin J, McClung MR, et al.  Denosumab for prevention of 
fractures in postmenopausal women with osteoporosis.  N Engl J Med.  
2009;361(8):756-765. 
Gail MH and Simon R. Testing for qualitative interactions between treatment effects and 
patients subsets. Biometrics. 1985; 41: 361-372.  
Genant HK, Wu CY, Van Kuijk C, and Nevitt MC.  Vertebral fracture assessment using a 
semiquantitative technique.  Journal of Bone and Mineral Research. 1993; 8(9): 
1137-1148  
Greenspan SL, Shneider DL, McClung MR, et al.  Alendronate improves bone mineral 
density in elderly women with osteoporosis residing in long-term care facilities.  A 
randomized, double-blind, placebo-controlled trail. Ann Intern Med 2002; 136:742-746 
Hochberg Y.  A Sharper Bonferroni Procedure for Multiple Tests of Significance.  
Biometrika.  1988; (74):800-802. 
Kanis JA, Johnell O, Oden A, De Laet C, Johnsson B. Ten year probabilities of 
osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporosis 
International. 2001; 12: 989-995. 
Kanis JA, Johnell O, Oden A, Johansson H, and McCloskey E.  FRAX and the 
assessment of fracture probability in men and women from the UK.  Osteoporosis 
International. 2008; 19: 385-397.   
Kenward MG and Roger JH.  Small sample inference for fixed effects from restricted 
maximum likelihood.  Biometrics. 1997; 53: 983-997  
Longford NT. Random Coefficient Models, New York: Oxford University Press, Inc, 1993   
Schnitzer T, Bone HG, Crepaldi G, et al. Therapeutic equivalence of alendronate 70 mg 
once weekly and alendronate 10 mg daily in the treatment of osteoporosis Aging Clin 
Exp Res. 2000; 25(5): 976-982.  
Schoenfeld D. Partial Residuals for the Proportional Hazards Regression Model. 
Biometrika. 1982; 69: 239 -241.  


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Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
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Silverman SL. The osteoporosis assessment questionnaire (OPAQ): a reliable and valid 
disease-targeted measure of health-related quality of life (HRQOL) in osteoporosis. 
Quality of Life Research. 2000; 9: 767-774. 
Van Elteren PH.  On the combination of independent two-sample test of Wilcoxon, 
Bulletin of the International Statistical Institute. 1960; 37: 351-361. 


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Statistical Analysis Plan:  20110142 
Date:  06 April 2017 
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13. 
Appendices  
13.1 
Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs 
13.1.1 
Visit Windows 
Per protocol, all monthly study visits up to Month 13 have a  7-day window.  Following 
the 12-month double-blind ALN-controlled study period, study visits have a  14-day 
window. To allow for variations in scheduling, the following sets of visit windows will be 
used to assign evaluations to a most appropriate nominal visit for analysis.  Furthermore, 
there will be no gaps between visit windows in order to include as many data points as 
possible for summarization.  
Regardless of the width of the visit window, if more than 1 visit falls within the defined 
window, the result from the visit closest to the target day will be used.  If 2 evaluations 
are of the same distance from the target day, the result from the later visit will be used.  
If more than one evaluation on the same date and time, the average of the results will be 
used. Only laboratory results collected from the central laboratory will be averaged in the 
case of duplicate results. Results not included for analysis will be included in listings 
only.   
For LOCF imputation, the last evaluation on or prior to the upper bound of the specified 
window (ie, no lower bound) would be used for each nominal visit.    
The window for the monthly phone contact in between clinic visits throughout the study 
is  7 days. The window for the end of primary analysis period phone call is −14 days to 
end of primary analysis.  Unscheduled follow-up clinic visits after the monthly phone 
contact have a  21-day window.  The window for the end of study phone contact is 
−14 days to  7 days. 
13.1.1.1 
Spine X-ray  
Nominal 
Visit 
Target 
Day 
Window Definition (Study Day) 
Baseline a 
1 
Last evaluation prior to or on Study Day 1 
Month 12 
366 
Study Day 2 to End of Double-blind Period Date  
Month 24 
731 
End of Double-blind Period Date 1 to End of Open-label M24 
Study Period Date  
Month 36 
1096 
End of Open-label M24 Study Period Date 1 to Study Day 1278 
Month 48 
1461 
Study Day 1279 to 1643 
Month 60 
1826 
Study Day 1644 to 2008 
a If results from baseline x-ray are not available, the results from scan taken on or before Study Day 14 will 
be considered baseline values.  


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Lateral spine X-rays are collected every 12 months after M36 until the end of the primary 
analysis period. 
13.1.1.2 
DXA (lumbar spine and proximal femur) for All Subjects 
Nominal 
Visit 
Target 
Day 
Window Definition (Study Day) 
Baseline a 
1 
Last evaluation prior to or on Study Day 1 
Month 12 
366 
Study Day 2 to End of Double-blind Period Date  30 
Month 24 
731 
End of Double-blind Period Date  31 to End of Open-label 
M24 Study Period Date  30 
Month 36 
1096 
End of Open-label M24 Study Period Date  31 to Study Day 
1278 
Month 48 
1461 
Study Day 1279 to 1643 
Month 60 
1826 
Study Day 1644 to 2008 
a If results from baseline DXA are not available, the results from scan taken on or before Study Day 
14 will be considered baseline values and not the Month 12 values. 
DXA of lumbar spine and proximal femur are collected every 12 months after M36 
until the end of the primary analysis period. 
13.1.1.3 
DXA (lumbar spine and proximal femur) for imaging component of 
Sub-study  
Nominal Visit 
Target 
Day 
Window Definition (Study Day) 
Baseline a 
1 
Last evaluation prior to or on Study Day 1 
Month 6 
183 
Study Day 2 to 274  
Month 12 
366 
Study Day 275 to End of Double-blind Period Date  30 
Month 18 
548 
End of Double-blind Period Date 31 to Study Day 639 
Month 24 
731 
Study Day 640 to End of Open-label M24 Study Period Date 
30 
Month 36 
1096 
 Study Day End of Open-label M24 Study Period Date 31 
a  If results from baseline DXA are not available, the results from scan taken on or before Study Day 14 
will be considered baseline values and not the Month 6 values.   
13.1.1.4 
QCT for imaging component of Sub-study 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline a 
1 
Last evaluation prior to or on Study Day 1 
Month 6 
183 
Study Day 2 to 274  
Month 12 
366 
Study Day 275 to End of Double-blind Period Date  30 
Month 24 
731 
 End of Double-blind Period Date 31  
a If results from baseline QCT is not available, the results from scan taken on or before Study Day 14 will 
be considered baseline values and not the Month 6 or Month 12 values. 


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13.1.1.5 
OC and BSAP for Sub-study 
Nominal 
Visit 
Target Day 
Window Definition (Study Day) 
Baseline  
1 
Last evaluation prior to or on Study Day 1 before dosing 
Month 1 
31 
Study Day 2 to 61 
Month 3 
92 
Study Day 62 to 137 
Month 6  
183 
Study Day 138 to 229 
Month 9  
275 
Study Day 230 to 320 
Month 12 
366 
Study Day 321 to End of Double-blind Period Date 
13.1.1.6 
BTM (Excluding OC and BSAP) or Biomarker for Sub-study 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline  
1 
Last evaluation prior to or on Study Day 1 before dosing 
Month 1 
31 
Study Day 2 to 61 
Month 3 
92 
Study Day 62 to 137  
Month 6  
183 
Study Day 138 to 229 
Month 9  
275 
Study Day 230 to 320 
Month 12  
366 
Study Day 321 to End of Double-blind Period Date 
 
 
 
Month 18 
548 
End of Double-blind Period Date 1 to Study Day 639 
Month 24 
731 
Study Day 640 to End of Open-label M24 Study Period 
Date 
Month 36 
1096 
End of Open-label M24 Study Period Date1 to Study 
Day 1278 
Month 48 
1461 
Study Day 1279 to 1643 
Month 60 
1826 
Study Day 1644 to 2008 
Data are collected every 12 months after Month 36 until the end of the primary analysis period. 


Product:  Romosozumab 
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13.1.1.7 
Laboratory 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline  
1 
Last evaluation prior to or on Study Day 1 before dosing 
Month 1 
31 
Study Day 2 to 61 
Month 3 
92 
Study Day 62 to 137  
Month 6  
183 
Study Day 138 to 229 
Month 9  
275 
Study Day 230 to 320 
Month 12  
366 
Study Day 321 to End of Double-blind Period Date 
Month 18 
548 
End of Double-blind Period Date 1  to 685 
Month 24 
731 
Study Day  686 to End of Open-label M24 Study Period 
Date 
Month 30 
913 
End of Open-label M24 Study Period Date 1 to Study 
Day  1004 
Month 36 
1096 
Study Day 1005 to 1187 
Month 42 
1278 
Study Day 1188 to 1369 
Month 48 
1461 
Study Day 1370 to 1552 
Month 54 
1643 
Study Day 1553 to 1734 
Month 60 
1826 
Study Day 1735 to 1917 
Data are collected every 6 months after Month 36 until the end of the study. To be 
processed and sent to the central laboratory during the primary analysis period; to be 
analyzed at local laboratories following the primary analysis period.  
13.1.1.8 
Antibody (AB)  
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline  
1 
Last evaluation prior to or on Study Day 1 
Month 1a 
31 
Study Day 2 to 61 
Month 3 
92 
Study Day 62 to 137  
Month 6 
183 
Study Day 138 to 274  
Month 12 
366 
Study Day 275 to End of Double-blind Period Study Day 
Month 18 
548 
End of Double-blind Period Date 1  to 685 
Month 24 
731 
 Study Day 686  
a Any antibody assessment done on Study Day 1 but after the administration of the investigational product 
will be classified into Month 1.   


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13.1.1.9 
Weight and Height 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline  
1 
Last evaluation prior to or on Study Day 1 
Month 6 
183 
Study Day 2 to 274  
Month 12 
366 
Study Day 275 to End of Double-blind Period Date 
Month 18 
548 
End of Double-blind Period Date 1 to Study Day 639 
Month 24 
731 
Study Day 640 to End of Open-label M24 Study Period Date 
Month 30 
913 
End of Open-label M24 Study Period Date 1 to Study Day 1004 
Month 36 
1096 
Study Day 1005 to 1187 
Month 42 
1278 
Study Day 1188 to 1369 
Month 48 
1461 
Study Day 1370 to 1552 
Month 54 
1643 
Study Day 1553 to 1734 
Month 60 
1826 
Study Day 1735 to 1917 
Data are collected every 6 months after Month 36 until the end of the study.  
13.1.1.10 
OPAQ-SV, LAD, BPI and EQ-5D 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline  
1 
Last evaluation prior to or on Study Day 1 
Month 6 
183 
Study Day 2 to 274  
Month 12 
366 
Study Day 275 to End of Double-blind Period Date 
Month 18 
548 
End of Double-blind Period Date 1 to Study Day 639 
Month 24 
731 
Study Day 640 to End of Open-label M24 Study Period Date 
Month 30 
913 
End of Open-label M24 Study Period Date 1 to Study Day 1004 
Month 36 
1096 
Study Day 1005 to 1187 
Month 42 
1278 
Study Day 1188 to 1369 
Month 48 
1461 
Study Day 1370 to 1552 
Month 54 
1643 
Study Day 1553 to 1734 
Month 60 
1826 
Study Day 1735 to 1917 
Data are collected every 6 months after Month 36 until the end of the primary analysis 
period. 


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13.1.1.11 
Post-fracture OPAQ-SV and EQ-5D-5L, LAD and BPI 
Visit Relative to 
Fracture 
Target Day Post-fracture Visit Window Definition  
Pre-fracture 
Baseline  
NA 
Last evaluation prior to the reported nonvertebral or clinical 
fracture date 
Month 1 * 
31 
The scheduled monthly post-fracture visit within day 16 to day 
45 post-fracture window 
Month 2 * 
61 
The scheduled monthly post-fracture visit within day 46 to day 
75 post-fracture window 
Month 3 * 
91 
The scheduled monthly post-fracture visit within day 76 to day 
105 post-fracture window 
*If more than one actual visit falls within the same defined window, the closest visit to the target day will be 
considered for analysis. If two assessment actual dates are at the same distance from the target day, the 
later visit will be considered for analysis. 
13.1.1.12 
Vital Signs 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline  
1 
Last evaluation prior to or on Study Day 1 
Month 1a 
31 
Study Day 2 to 106 
Month 6 
183 
Study Day 107 to 274  
Month 12 
366 
Study Day 275 to End of Double-blind Period Date  
Month 18 
548 
End of Double-blind Period Date 1 to Study Day 639 
Month 24 
731 
Study Day 640 to End of Open-label M24 Study Period Date 
Month 30 
913 
End of Open-label M24 Study Period Date 1 to Study Day 1004 
Month 36 
1096 
Study Day 1005 to 1187 
Month 42 
1278 
Study Day 1188 to 1369 
Month 48 
1461 
Study Day 1370 to 1552 
Month 54 
1643 
Study Day 1553 to 1734 
Month 60 
1826 
Study Day 1735 to 1917 
a Any laboratory or antibody assessment done on Study Day 1 but after the 
  administration of the investigational product will be classified into Month 1.   
Data are collected every 6 months after Month 36 until the end of the primary analysis 
period. 


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Date:  06 April 2017 
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13.2 
Genant Semiquantitative Scoring Method 
Both incident and prevalent vertebral fractures present on a radiograph are defined by 
using the Genant Semiquantitative Scoring Method (Genant et al, 1993) for each 
vertebra (T4 through L4) as described in the table below. 
Grade 
Fracture Severity 
Definition 
0 
Normal 
Normal; (Approximately less than 20 reduction in 
anterior, middle, and/or posterior height) 
1 
Mild 
Approximately 20 to 25 reduction in anterior, middle, 
and/or posterior height 
2 
Moderate 
Approximately 25 to 40 reduction in anterior, middle, 
and/or posterior height 
3 
Severe 
Approximately 40 or greater reduction in anterior, 
middle, and/or posterior height 
13.3 
Reliability, Validity, and Scoring Algorithm for PRO Measurements   
13.3.1 
OPAQ-SV 
Reliability and Validity  
The OPAQ-SV is a comprehensive instrument designed to evaluate the impact of 
vertebral and nonvertebral fractures on different aspects of health-related quality of life.  
The OPAQ-SV contains 34 questions that can be summarized into 7 scales 
(walking/bending, daily activities, transfer, fear of falls, back pain, body image, and 
independence) and 3 dimensions (physical function, emotional status, and back pain). 
The OPAQ-SV has been validated in osteoporotic subjects and used extensively.  
Internal consistency for the OPAQ-SV is high (Cronbach’s alpha  0.86; 
Silverman SL, 2000). 
Question Mapping 
Dimension 
Scale 
Questions 
Physical function 
Walking/bending 
Daily activities 
Transfer 
1 – 7 
8 – 15 
16 – 19 
Emotional status 
Fear of falls 
Body image 
Independence 
20 – 24 
29 – 31 
32 – 34 
Back pain 
Back pain 
25 – 28 


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Date:  06 April 2017 
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Scoring Algorithm 
1. Standardize the response for each question to a 0 – 100 scale according to the table 
below. 
2. Average the standardized values within each of the 7 scales and 3 dimensions to 
create the summary or scale scores based on the question mapping.  The score will 
only be calculated if  50 of the items within the scale or dimension are 
nonmissing.  Otherwise, set the score to missing.   
Question Number 
Question Response 
Question 
Score 
Standardized Value 
2, 5, 6, 7, 16 - 19, 25, 27, 28 
All days 
Most days 
Some days 
Few days 
No days 
1 
2 
3 
4 
5 
0 
25 
50 
75 
100 
1, 3, 4, 8, 9, 10  
All days 
Most days 
Some days 
Few days 
No days 
1 
2 
3 
4 
5 
100 
75 
50 
25 
0 
11,12, 20,21, 22, 23, 24, 29, 30, 
31, 33, 34 
Always 
Very often 
Sometimes 
Almost never 
Never 
1 
2 
3 
4 
5 
0 
25 
50 
75 
100 
13, 14, 15, 32 
Always 
Very often 
Sometimes 
Almost never 
Never 
1 
2 
3 
4 
5 
100 
75 
50 
25 
0 
26 
Severe 
Moderate 
Mild 
Very mild 
None 
1 
2 
3 
4 
5 
0 
25 
50 
75 
100 
13.3.2 
EQ-5D-5L 
Visual Analog Scale 
Questionnaire asks respondents to rate their present health status on a vertical 0 to 
100 visual analog scale of 20 cm, with 0 labeled as “Worst imaginable health state” and 
100 labeled as “Best imaginable health state.” The scale is marked in increments of 
“1,” with values labeled at each decile. The person scoring this question must observe 


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Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 2 of 118 
CONFIDENTIAL 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the study staff and members 
of the independent ethics committee/institutional review board/institutional scientific 
review board or equivalent.   
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  1- 800-77-AMGEN (in the USA), 1-866-50-AMGEN 
(in Canada), 1-805-447-1000 (all other countries).  For all other study-related questions, 
continue to contact the Key Sponsor Contact. 
NCT Number: 1631214
purposes of posting on clinicaltrials.gov
NCT Number: 1631214
This NCT number has been applied to the document 
for purposes of posting on clinicaltrials.gov


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 3 of 118 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Multicenter, International, Randomized, 
Double-blind, Alendronate-controlled Study to Determine the Efficacy and Safety of 
Romosozumab in the Treatment of Postmenopausal Women With Osteoporosis, dated 
14 September 2016, and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice and applicable FDA regulations/guidelines set forth 
in 21 CFR Parts 11, 50, 54, 56, and 312. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
 
 
Signature 
 
 
Name of Principal Investigator 
 
Date (DD Month YYYY) 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 4 of 118 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Multicenter, International, Randomized, Double-blind, Alendronate-controlled Study to 
Determine the Efficacy and Safety of Romosozumab in the Treatment of Postmenopausal 
Women With Osteoporosis  
Study Phase:  Phase 3 
Indication:  Treatment of postmenopausal women with osteoporosis 
Primary Objectives:   
For the primary analysis period (randomization to primary analysis)  
• 
To assess the effect of romosozumab treatment for 12 months followed by alendronate (ALN) 
treatment compared with ALN treatment alone on the subject incidence of clinical fracture 
(nonvertebral fracture and clinical vertebral fracture) in postmenopausal women with 
osteoporosis 
• 
To assess the effect of romosozumab treatment for 12 months followed by ALN treatment 
compared with ALN treatment alone on the subject incidence of new vertebral fracture in 
postmenopausal women with osteoporosis 
Secondary Objectives:   
For the primary analysis period 
To assess the effect of romosozumab treatment for 12 months followed by ALN treatment 
compared with ALN treatment alone on: 
• 
Subject incidence of fractures (all fractures [nonvertebral fractures and new or worsening 
vertebral fractures], new or worsening vertebral fracture, nonvertebral fracture, major 
nonvertebral fracture [pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, 
and hip], hip fracture, multiple new or worsening vertebral fracture, and clinical vertebral 
fracture) 
• 
Percent changes in Dual energy X-ray Absorptiometry (DXA) bone mineral density (BMD) at 
the lumbar spine, total hip, and femoral neck 
For the 12-month double-blind ALN-controlled study period 
To assess the effect of romosozumab treatment for 12 months compared with ALN treatment on: 
• 
Subject incidence of fractures (clinical fracture [nonvertebral fracture and clinical vertebral 
fracture], new vertebral fracture, all fractures [nonvertebral fractures and new or worsening 
vertebral fractures] nonvertebral fracture, hip fracture, clinical vertebral fracture, and 
major osteoporotic fracture [hip, forearm, humerus, and clinical vertebral])  
• 
Percent changes in DXA BMD at the lumbar spine, total hip, and femoral neck 
For the overall study period (randomization to end of study) 
• 
To assess the effect of romosozumab treatment for 12 months followed by ALN treatment 
compared with ALN treatment alone on subject incidence of hip fracture, major 
nonvertebral fracture [pelvis, distal femur, proximal tibia, ribs, proximal humerus, 
forearm, and hip], nonvertebral fractures 
Exploratory Objectives:   
For the 12-month double-blind ALN-controlled study period 
• 
To assess the effect of romosozumab treatment for 12 months compared with ALN treatment 
on subject incidence of fractures (new or worsening vertebral fracture, major nonvertebral 
fracture [pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and hip], and 
multiple new or worsening vertebral fracture)  
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 5 of 118 
CONFIDENTIAL 
 
 
• 
To describe subjects’ experience of pain and its impact on subjects’ activities and 
health-related quality of life at 6-month intervals for postmenopausal women with 
osteoporosis using Patient Reported Outcome (PRO) and Clinician Reported Outcome 
(ClinRO) questionnaires (Osteoporosis Assessment Questionnaire Short Version [OPAQ SV], 
EuroQoL-5 Dimensions-5 Levels Health Survey [EQ-5D-5L], Limited Activity Days [LAD] 
survey, and one item extracted from the Brief Pain Inventory [BPI] assessing the worst pain 
experienced in the past 24 hours [BPI worst pain]) 
• 
To describe subjects’ experience of pain and its impact on subjects’ activities and 
health-related quality of life for 3 months at 1-month intervals after experiencing a 
nonvertebral or clinical vertebral fracture (OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain) 
• 
To describe the effect of romosozumab treatment for 12 months compared with ALN 
treatment on the percent of subjects with a clinically meaningful improvement in worst pain 
for 3 months at 1-month intervals after experiencing a nonvertebral or clinical vertebral 
fracture (defined as a 2-point improvement in the BPI worst pain scale compared with the 
fracture reporting visit)  
• 
To assess the effect of romosozumab treatment for 12 months compared with ALN treatment 
on changes in height 
For the primary analysis period 
• 
To assess the effect of romosozumab treatment for 12 months followed by ALN treatment 
compared with ALN treatment alone on subject incidence of major osteoporotic fracture (hip, 
forearm, humerus, and clinical vertebral) 
• 
To describe subjects’ experience of pain and its impact on subjects’ activities and 
health-related quality of life at 6-month intervals for postmenopausal women with 
osteoporosis using PRO and ClinRO questionnaires (OPAQ SV, EQ-5D-5L, LAD, and BPI 
worst pain) 
• 
To assess the effect of romosozumab treatment for 12 months followed by ALN treatment 
compared with ALN treatment alone on changes in height 
During the Month 12 to 24 ALN study period 
• 
To assess the effect of one year of romosozumab treatment compared with ALN 
treatment alone on subject incidence of new vertebral fractures, clinical fracture 
(nonvertebral fracture and clinical vertebral fracture), nonvertebral fracture, hip 
fracture, and clinical vertebral fracture during the subsequent year during which all 
subjects receive ALN treatment. 
Safety Objectives:   
For the 12-month double-blind ALN-controlled study period 
• 
To characterize the safety and tolerability of romosozumab treatment for 12 months as 
determined by a review of reported adverse events, laboratory data, vital signs, and formation 
of anti-romosozumab antibodies 
For the primary analysis period 
• 
To characterize the safety and tolerability of romosozumab treatment for 12 months followed 
by ALN treatment as determined by a review of reported adverse events, laboratory data, 
vital signs, and formation of anti-romosozumab antibodies 
For the overall study period 
• 
To characterize the safety and tolerability of romosozumab treatment for 12 months followed 
by ALN treatment as determined by a review of reported adverse events and vital signs 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 6 of 118 
CONFIDENTIAL 
 
 
Imaging and Pharmacokinetics (PK) / Bone Turnover Marker (BTM) / Biomarker Sub-study 
Objectives:  
For the 12-month double-blind ALN-controlled study period 
• 
To characterize the serum romosozumab concentration 
• 
To assess the effect of romosozumab treatment for 12 months compared with ALN treatment 
on: 
- 
Percent changes in bone formation markers Procollagen Type 1 N-telopeptide (P1NP), 
Bone Specific Alkaline Phosphatase (BSAP), and Osteocalcin (OC) and in bone 
resorption marker serum Type I collagen C-telopeptide (sCTX) 
- 
Percent changes in sclerostin and intact Parathyroid Hormone (iPTH) 
- 
For subjects participating in the imaging components:  
- 
Percent changes in integral (total) and trabecular volumetric BMD (vBMD) at the 
lumbar spine by Quantitative Computed Tomography (QCT) 
- 
Percent changes in lumbar spine strength as assessed by Finite Element Analysis 
(FEA) 
• 
For subjects participating in the imaging components: To assess the effect of romosozumab 
treatment for 6 months compared with ALN treatment for 6 months on percent changes in 
DXA BMD at the lumbar spine, total hip, and femoral neck 
• 
To enable exploratory assessments of novel biomarkers through prospective collection of 
blood samples 
For the primary analysis period 
• 
To assess the effect of romosozumab treatment for 12 months followed by ALN treatment 
compared with ALN treatment alone on: 
- 
Percent changes in bone formation marker P1NP and bone resorption marker sCTX 
- 
Percent changes in sclerostin and iPTH 
- 
For subjects participating in the imaging components:  
- 
Percent changes in integral (total) and trabecular vBMD at the lumbar spine by 
QCT 
- 
Percent changes in lumbar spine strength as assessed by FEA 
• 
For subjects participating in the imaging components: To assess the effect of romosozumab 
treatment for 12 months followed by ALN treatment for 6 months compared with ALN 
treatment alone on percent changes in DXA BMD at the lumbar spine, total hip, and femoral 
neck 
• 
To enable exploratory assessments of novel biomarkers through prospective collection of 
blood samples 
Hypotheses:  The primary clinical hypotheses are that romosozumab treatment for 12 months 
followed by ALN treatment compared with ALN treatment alone is effective in reducing the 
incidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture) and new 
vertebral fracture in postmenopausal women with osteoporosis.  It is expected that romosozumab 
treatment for 12 months followed by ALN treatment will reduce the incidence of clinical fractures 
by 30% and the incidence of new vertebral fractures by 50% compared with the control group 
(ALN alone).   
The primary safety hypothesis is that romosozumab treatment for 12 months is well tolerated in 
postmenopausal women with osteoporosis.  
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 7 of 118 
CONFIDENTIAL 
 
 
Primary Endpoints:   
During the primary analysis period 
• 
Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture) at 
primary analysis 
• 
Subject incidence of new vertebral fracture through Month 24 
Secondary Endpoints:   
During the primary analysis period  
• 
Subject incidence of nonvertebral fracture at primary analysis 
• 
Subject incidence of all fractures (nonvertebral fracture and new or worsening vertebral 
fracture) at primary analysis 
• 
Subject incidence of new or worsening vertebral fracture through Month 24 
• 
Subject incidence of major nonvertebral fracture (pelvis, distal femur, proximal tibia, ribs, 
proximal humerus, forearm, and hip) at primary analysis 
• 
Subject incidence of hip fracture at primary analysis 
• 
Subject incidence of multiple new or worsening vertebral fractures through Month 24 
• 
Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral 
fracture) through Month 24 
• 
Subject incidence of nonvertebral fracture through Month 24 
• 
Subject incidence of hip fracture through Month 24 
• 
Subject incidence of clinical vertebral fracture through Month 24 
• 
Percent change from baseline in BMD at the lumbar spine, total hip, and femoral neck at 
Months 24 and 36 
During the 12-month double-blind ALN-controlled study period 
• 
Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture) 
through Month 12 
• 
Subject incidence of new vertebral fracture through Month 12 
• 
Subject incidence of all fractures (nonvertebral fracture and new or worsening vertebral 
fracture) through Month 12 
• 
Subject incidence of nonvertebral fracture through Month 12 
• 
Subject incidence of hip fracture through Month 12 
• 
Subject incidence of major osteoporotic fracture (hip, forearm, humerus, and clinical 
vertebral) through Month 12 
• 
Subject incidence of clinical vertebral fracture through Month 12 
• 
Percent change from baseline in BMD at the lumbar spine, total hip and femoral neck at 
Month 12 
During the overall study period 
• 
Subject incidence of nonvertebral fracture at final analysis 
• 
Subject incidence of major nonvertebral fracture (pelvis, distal femur, proximal tibia, 
ribs, proximal humerus, forearm, and hip) at final analysis 
• 
Subject incidence of hip fracture at final analysis 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 8 of 118 
CONFIDENTIAL 
 
 
Exploratory Endpoints:   
During the 12-month double-blind ALN-controlled study period 
• 
Subject incidence of new or worsening vertebral fracture through Month 12 
• 
Subject incidence of major nonvertebral fracture (pelvis, distal femur, proximal tibia, ribs, 
proximal humerus, forearm, and hip) through Month 12 
• 
Subject incidence of multiple new or worsening vertebral fractures through Month 12 
• 
Actual value in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain) 
at Months 6 and 12 
• 
Change from baseline in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, and BPI 
worst pain) at Months 6 and 12 
• 
Actual value in PRO and ClinRO measures after experiencing a nonvertebral or clinical 
vertebral fracture (OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain) at reporting of the 
nonvertebral or clinical vertebral fracture and at 1, 2, and 3 months after the fracture 
• 
Change from pre-fracture baseline in PRO and ClinRO measures after experiencing a 
nonvertebral or clinical vertebral fracture (OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain) at 
reporting of the nonvertebral or clinical vertebral fracture and at 1, 2, and 3 months after the 
fracture 
• 
Proportion of subjects with a clinically meaningful improvement in worst pain (defined as a 
2-point improvement in the BPI worst pain scale compared with the fracture reporting visit) at 
1, 2, and 3 months after reporting of a nonvertebral or clinical vertebral fracture 
• 
Change from baseline in height at Month 12 
During the primary analysis period 
• 
Subject incidence of major osteoporotic fracture (hip, forearm, humerus, and clinical 
vertebral) at primary analysis 
• 
Actual value in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain) 
at Months 18, 24, 30, and 36 
• 
Change from baseline in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, and BPI 
worst pain) at Months 18, 24, 30, and 36 
• 
Change from baseline in height at Month 24 
During the Month 12 to 24 ALN study period 
• 
Subject incidence of new vertebral fractures between Month 12 and Month 24 
• 
Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral 
fracture) between Month 12 and Month 24 
• 
Subject incidence of nonvertebral fracture between Month 12 and Month 24 
• 
Subject incidence of hip fracture between Month 12 and Month 24 
• 
Subject incidence of clinical vertebral fracture between Month 12 and Month 24 
Safety Endpoints:  
During the 12-month double-blind ALN-controlled study period 
• 
Subject incidence of adverse events by system organ class and preferred term 
• 
Changes from baseline in laboratory assessments (serum chemistry and hematology) and 
the shifts from baseline to the worst value between baseline and Month 12 
• 
Changes from baseline in vital signs 
• 
Subject incidence of anti-romosozumab antibodies 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 9 of 118 
CONFIDENTIAL 
 
 
During the primary analysis period 
• 
Subject incidence of adverse events by system organ class and preferred term 
• 
Changes from baseline in laboratory assessments (serum chemistry and hematology) and 
the shifts from baseline to the worst value between baseline and primary analysis 
• 
Changes from baseline in vital signs 
• 
Subject incidence of anti-romosozumab antibodies 
During the overall study period 
• 
Subject incidence of adverse events by system organ class and preferred term 
• 
Changes from baseline in vital signs 
Imaging and PK/BTM/Biomarker Sub-study Endpoints: 
During the 12-month double-blind ALN-controlled study period 
• 
Romosozumab serum concentrations at Day 1, Months 1, 3, 6, 9, and 12 
• 
Percent change from baseline in P1NP, BSAP, OC, and sCTX at Months 1, 3, 6, 9, and 12 
• 
Percent change from baseline in iPTH and sclerostin at Months 1, 3, 6, 9, and 12 
• 
For subjects participating in the imaging components:  
• 
Percent change from baseline in integral (total) and trabecular vBMD at the lumbar spine 
by QCT at Months 6, and 12 
• 
Percent change from baseline in lumbar spine strength as assessed by FEA at Months 6, 
and 12 
• 
Percent change from baseline in DXA BMD at the lumbar spine, total hip, and femoral 
neck at Month 6 
During the primary analysis period 
• 
Percent change from baseline in P1NP and sCTX at Months 15, 18, 24, and 36 
• 
Percent change from baseline in iPTH and sclerostin at Months 15, 18, 24, and 36 
• 
For subjects participating in the imaging components:  
• 
Percent change from baseline in integral (total) and trabecular vBMD at the lumbar spine 
by QCT at Month 24 
• 
Percent change from baseline in lumbar spine strength as assessed by FEA at Month 24 
• 
Percent change from baseline in DXA BMD at the lumbar spine, total hip, and femoral 
neck at Month 18 
Study Design:   
This is a phase 3 multicenter, international, randomized, double-blind, ALN-controlled study of 
romosozumab in postmenopausal women with osteoporosis.  The study is designed to evaluate if 
romosozumab treatment for 12 months followed by ALN treatment, compared with ALN treatment 
alone, is effective in reducing the incidence of clinical fracture (nonvertebral fracture and clinical 
vertebral fracture) and new vertebral fracture.   
 
 
 


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Approximately 4,000 subjects will be randomized 1:1 to receive either 210 mg romosozumab 
subcutaneous (SC) every month (QM) or 70 mg ALN orally (PO) every week (QW) in a blinded 
fashion for the duration of the 12-month double-blind ALN-controlled study period.  
Randomization will be stratified by age (< 75 years, ≥ 75 years).  Subjects will also receive 
matched placebo for either ALN or romosozumab.  After the initial 12-month study period, 
subjects will receive ALN while remaining blinded to their initial treatment assignment 
(romosozumab or ALN).  The primary analysis period will end and the primary analysis will be 
performed when:  
• 
clinical fracture events (nonvertebral fracture or clinical vertebral fracture) have been 
confirmed for at least 330 subjects 
AND 
• 
all subjects have had the opportunity to complete the Month 24 study visit   
If more than 330 subjects have confirmed clinical fractures at the time each subject has 
completed her Month 24 visit, the primary analysis will be based on all available data, which may 
include more than 330 events. 
Upon completion of the primary analysis period, subjects will continue to be followed for the 
secondary endpoint of nonvertebral fractures.  Subjects and site personnel will remain blinded to 
initial treatment assignments.  The study will proceed in an event-driven manner.  The final 
analysis (end of study) will be performed when nonvertebral fracture events have been confirmed 
for at least 440 subjects across the lifetime of the study.  The study may be terminated earlier if 
the primary analysis demonstrates superiority of romosozumab treatment for nonvertebral 
fracture risk reduction (see Section 10.2 for details on testing strategy).  Study completion 
constitutes either completion of primary analysis if superiority is proven for nonvertebral fractures 
or when at least 440 subjects have experienced a nonvertebral fracture. 
The estimated study duration for an individual subject, including the screening period, is 25 to 
59 months (if study completion is achieved at primary analysis) or 37 to 71 months (if study 
completion is achieved when ≥440 subjects have experienced a nonvertebral fracture), based on 
projected enrollment, and estimated fracture rates.  However, actual study duration for individual 
subjects may be longer, depending on actual enrollment and observed fracture rates. 
From screening to end of study, subjects will receive daily calcium and vitamin D supplementation 
that at a minimum should be in the range of 500 to 1,000 mg elemental calcium and 600 to 
800 IU vitamin D.  In addition, subjects with a serum 25 (OH) vitamin D level of ≥ 20 ng/mL and 
≤ 40 ng/mL at screening will receive an initial loading dose of 50,000 to 60,000 IU of vitamin D 
after randomization, preferably by the oral route.  Subjects with a serum 25 (OH) vitamin D level 
of > 40 ng/mL at screening may also receive the vitamin D loading dose at the principal 
investigator’s discretion.   
Approximately 200 subjects at participating centers will be enrolled in an Imaging and 
PK/BTM/Biomarker sub-study.  Within this sub-study, a subset of approximately 100 subjects will 
participate in the imaging (DXA, QCT) component of the sub-study. 
If there is insufficient enrollment into the blood only portion of the sub-study, additional sub-study 
sites will be initiated.  Subjects already on trial will be invited to participate and consent will be 
obtained for the use of blood samples from earlier time points for sub-study analyses. 
From study start until primary analysis, an external, independent Data Monitoring Committee 
(DMC) will monitor unblinded safety data on an ongoing basis and consider efficacy data in order 
to assess the risk/benefit profile of romosozumab. 
Sample Size:  Approximately 4,000 subjects (approximately 2,000 subjects per arm) 
Summary of Subject Eligibility Criteria:   
Subjects must be postmenopausal women age 55 to 90 years who meet at least one of the 
following BMD and fracture criteria: 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
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• 
BMD T-score ≤ -2.50 at the total hip or femoral neck 
AND 
EITHER at least one moderate (SQ2) or severe (SQ3) vertebral fracture OR at least 2 mild 
(SQ1) vertebral fractures 
or 
• 
BMD T-score ≤ -2.00 at the total hip or femoral neck 
AND 
EITHER at least 2 moderate (SQ2) or severe (SQ3) vertebral fractures OR a fracture of the 
proximal femur that occurred within 3 to 24 months prior to randomization 
Subjects with severe metabolic or bone diseases or significant lab abnormalities are not eligible 
for participation.  The use of agents affecting bone metabolism is also exclusionary, however, for 
selected therapies permissible off-treatment periods prior to randomization are defined in 
Section 4.2.   
For a full list of eligibility criteria, please refer to Section 4.1 and Section 4.2. 
Amgen Investigational Product Dosage and Administration:   
During the 12-month double-blind ALN controlled study period, the romosozumab treatment 
group will receive 210 mg romosozumab SC QM and matched placebo for ALN PO QW in a 
blinded fashion. 
Following the 12-month double-blind ALN controlled study period, the romosozumab treatment 
group will receive open-label 70 mg ALN PO QW while remaining blinded to their initial treatment 
assignment (romosozumab). 
Non Amgen Investigational Product Dosage and Administration:   
During the 12-month double-blind ALN controlled study period, the ALN treatment group will 
receive 70 mg ALN PO QW and matched placebo for 210 mg romosozumab SC QM in a blinded 
fashion.  
Following the 12-month double-blind ALN controlled study period, the ALN treatment group will 
receive open-label 70 mg ALN PO QW while remaining blinded to their initial treatment 
assignment (ALN). 
Non Amgen Non-investigational Product Dosage and Administration:   
From screening to end of study, subjects will receive daily calcium and vitamin D supplementation 
that at a minimum should be in the range of 500 to 1,000 mg elemental calcium and 600 to 
800 IU vitamin D.  In addition, subjects with a serum 25 (OH) vitamin D level of ≥ 20 ng/mL and 
≤ 40 ng/mL at screening will receive an initial loading dose of 50,000 to 60,000 IU of vitamin D 
after randomization, preferably by the oral route.  Subjects with a serum 25 (OH) vitamin D level 
of > 40 ng/mL at screening may also receive the vitamin D loading dose at the principal 
investigator’s discretion.   
Control Group:  Subjects randomized to receive ALN treatment will serve as the control group. 
Procedures:  Key procedures will include informed consent, medical, fracture, and medication 
history, instructions for daily calcium and vitamin D supplementation, physical examination, vital 
signs, height and weight, laboratory assessments (serum chemistry/ hematology, 25 (OH) 
vitamin D, and anti-romosozumab antibody), lateral spine x-ray, DXA scans of the lumbar spine 
and proximal femur, reporting of nonvertebral and suspected clinical vertebral fractures, 
PROs/ClinROs (OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain), adverse event/concomitant 
medication data collection, investigational product (IP) administration and IP dispensation. 
The following assessments will be performed for subjects participating in the Imaging and 
PK/BTM/Biomarker sub-study: additional blood draws (romosozumab levels, BTMs, sclerostin, 
iPTH, and for potential biomarker development) and for subjects also participating in the imaging 
components, QCT scans of the spine and additional DXA scans of the lumbar spine and proximal 
femur. 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 12 of 118 
CONFIDENTIAL 
 
 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and Appendix A. 
Statistical Considerations:  The study is designed to evaluate the effect of romosozumab 
treatment for 12 months followed by ALN treatment compared with ALN alone in reducing the 
subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture), 
vertebral fracture and nonvertebral fracture.  The primary analysis will be performed when clinical 
fractures have been confirmed for at least 330 subjects and after all subjects have had the 
opportunity to complete the Month 24 visit.  If 330 subjects have confirmed clinical fractures prior 
to all subjects having completed the Month 24 visit, the analysis will be based on all available 
data, which may include more than 330 events.  The final analysis will be performed when 
nonvertebral fractures have been confirmed for at least 440 subjects.  If superiority of the 
nonvertebral fracture endpoint is achieved at the primary analysis and the study is stopped after 
the primary analysis has been performed, all data, including the additional safety and 
nonvertebral fracture data, collected after the primary analysis will be summarized descriptively 
and not be included in confirmatory testing. Study completion constitutes either completion of 
primary analysis if superiority is proven for nonvertebral fractures or when at least 440 subjects 
have experienced a nonvertebral fracture. 
In order to maintain the overall significance level at 0.05, the primary endpoints will be assessed 
using Hochberg’s procedure.  If both primary endpoints are significant at the 0.05 level, each of 
the following secondary DXA BMD endpoints will be tested hierarchically at 0.05 according 
to the following sequence: percent change from baseline in BMD at lumbar spine at 
Month 24, percent change from baseline in BMD at total hip at Month 24, percent change 
from baseline in BMD at femoral neck at Month 24, percent change from baseline in BMD 
at lumbar spine at Month 12, percent change from baseline in BMD at total hip at Month 12, 
and percent change from baseline in BMD at femoral neck at Month 12.  If all preceding 
endpoints are significant, the nonvertebral fracture endpoint will be tested using a group 
sequential approach at the primary analysis and the final analysis based on a 1-sided test  
(α = 0.025).  The Lan-Demets alpha spending function that approximates a Pocock boundary will 
be used to determine the significance level at the time of the primary analysis. 
Subject incidence of clinical fractures will be compared between treatment groups using a Cox 
proportional hazards model controlling for age (< 75 years, ≥ 75 years), presence or absence of 
severe vertebral fracture at baseline, and baseline total hip BMD T-score.  Nonvertebral fractures, 
major nonvertebral fractures, hip fractures, clinical vertebral fracture, and all fractures will be 
analyzed using the same approach as for clinical fractures.  The Kaplan-Meier method will be 
used to summarize the cumulative fracture incidence at pre-specified time points.   
Subject incidence of new vertebral fracture at  pre-specified time points will be compared 
between treatment groups using a logistic regression model adjusting for age (< 75 years, 
≥ 75 years), presence or absence of severe vertebral fracture at baseline, and baseline total hip 
BMD T-score.  Subject incidence of new or worsening vertebral fractures and multiple new or 
worsening vertebral fractures will be analyzed using the same approach as for new vertebral 
fractures.  Subject incidence of new vertebral fractures between Month 12 and Month 24 
will be estimated. 
Subject incidence rates of adverse events in the 12-month double-blind ALN-controlled study 
period will be tabulated by system organ class and preferred term.  Summaries of deaths, events 
of interest, serious adverse events and IP related adverse events, adverse events leading to early 
discontinuation from IP or study in the 12-month double-blind ALN-controlled study period will 
also be provided.  
The adverse events following the 12-month double-blind study period and in the overall study 
period will be summarized using the same approach as for the 12-month double-blind 
ALN-controlled study period. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc. 
 
 
 


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Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 14 of 118 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ALN 
Alendronate 
ALP 
Alkaline Phosphatase 
ALT (SGPT) 
Alanine Aminotransferase (Serum Glutamic Pyruvic Transaminase) 
AMG 785 (romosozumab) Anti-human sclerostin antibody, also referred to as hu13C7, h13C7, 
or Mab-B 
ARCH 
Active-contRolled FraCture Study in Postmenopausal Women with 
Osteoporosis at High Risk of Fracture 
AST (SGOT) 
Aspartate Aminotransferase (Serum Glutamic Oxaloacetic 
Transaminase) 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
BPI 
Brief Pain Inventory  
BSAP 
Bone Specific Alkaline Phosphatase 
BTM 
Bone Turnover Marker 
BUN 
Blood Urea Nitrogen 
ClinRO 
Clinician Reported Outcome; questionnaires completed by physician 
or site staff using information provided by the subject 
CTCAE 
Common Terminology Criteria for Adverse Events 
Date of Randomization 
Date on which the randomization number is assigned; synonymous 
with enrollment date 
DILI 
Drug-Induced Liver Injury 
DMC 
Data Monitoring Committee; term synonymous with Data Safety 
Monitoring Board 
DXA 
Dual energy X-ray Absorptiometry 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
Electronic Trial 
Operations System 
An electronic system that is used to facilitate the operations of a 
clinical trial through the collection of study related data.  Most 
common applications of an Electronic Trial Operations system within 
a clinical trial are: subject randomization and investigational product 
management.  Term synonymous with the industry term IVRS. 
End of study for individual 
subject 
Defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of study (primary 
completion) 
Defined as the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
outcomes  
End of study (end of trial) Defined as when the last subject is assessed or receives an 
intervention for evaluation in the study 
EQ-5D-5L 
EuroQoL-5 Dimensions-5 Levels Health Survey 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 15 of 118 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
eSAE 
Electronic Serious Adverse Event 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FEA 
Finite Element Analysis 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IP 
Investigational Product 
IPIM 
Investigational Product Instruction Manual 
iPTH 
intact Parathyroid Hormone 
IV 
Intravenous 
Interactive Voice 
Response System (IVRS) 
Telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information.  
LAD 
Limited Activity Days 
NHANES 
National Health and Nutritional Examination Survey 
OC 
Osteocalcin 
ONJ 
Osteonecrosis of the Jaw 
OPAQ SV 
Osteoporosis Assessment Questionnaire Short Version 
Overall study period 
Randomization to end of study 
P1NP 
Procollagen Type 1 N-telopeptide 
PD 
Pharmacodynamics 
PFS 
Prefilled Syringe 
PK 
Pharmacokinetics 
PMO 
Postmenopausal Osteoporosis 
PO 
Orally 
Primary analysis period 
Randomization to primary analysis 
PRO 
Patient Reported Outcome 
PTH 
Parathyroid Hormone 
QCT 
Quantitative Computed Tomography 
 
 
QM 
Every month 
QW 
Every week 
RBC 
Red Blood Cell 
Romosozumab 
International Nonproprietary Name for AMG 785 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 16 of 118 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
RRR 
Relative Risk Reduction 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
Screening Period 
Begins when the subject signs the informed consent form and ends 
on date of randomization 
sCTX 
Serum Type I collagen C-telopeptide 
SERM 
Selective Estrogen Receptor Modulator 
Source Data 
Information from an original record or certified a copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies). [ICH 
Guideline (E6)].  Examples of source data include Subject ID, 
Randomization ID, and Stratification Value. 
SQ0, SQ1, SQ2, SQ3 
Visual semiquantitative grading scale for vertebral fractures on 
lateral spine x-rays: SQ0=no fracture; SQ1=mild fracture; 
SQ2=moderate fracture; SQ3=severe fracture (Genant et al, 1993) 
Study Day 1 
Defined as the first day that protocol-specified investigational 
product is administered to the subject (ie, first injection of 
romosozumab/placebo) 
Study Start Date 
Defined as the date on which the first subject is enrolled into the 
study 
Study End Date 
Defined as the date on which the last subject completes their final 
study procedure 
TBL 
Total Bilirubin 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper Limit of Normal 
US 
United States 
vBMD 
Volume BMD 
WBC 
White Blood Cell 
 
 
 


Product:  Romosozumab 
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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 4 
Study Design and Treatment Schema ........................................................................... 13 
Study Glossary .............................................................................................................. 14 
1. 
OBJECTIVES ....................................................................................................... 22 
1.1 
Primary ..................................................................................................... 22 
1.2 
Secondary ................................................................................................. 22 
1.3 
Exploratory ................................................................................................ 23 
1.4 
Safety ........................................................................................................ 24 
1.5 
Imaging and Pharmacokinetics (PK) / Bone Turnover Marker 
(BTM) / Biomarker Sub-study .................................................................... 24 
2. 
BACKGROUND AND RATIONALE ...................................................................... 25 
2.1 
Disease ..................................................................................................... 25 
2.2 
Romosozumab Background ...................................................................... 26 
2.3 
Justification for Romosozumab Treatment Duration and Dosing 
Regimen ................................................................................................... 28 
2.4 
Alendronate Background ........................................................................... 29 
2.5 
Calcium and Vitamin D Background .......................................................... 30 
2.6 
Rationale ................................................................................................... 31 
2.7 
Clinical Hypotheses ................................................................................... 33 
3. 
EXPERIMENTAL PLAN ........................................................................................ 33 
3.1 
Study Design ............................................................................................. 33 
3.2 
Number of Centers .................................................................................... 35 
3.3 
Number of Subjects ................................................................................... 35 
3.4 
Estimated Study Duration .......................................................................... 35 
3.4.1 
Study Duration for Participants .................................................. 35 
3.4.2 
End of Study .............................................................................. 36 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 36 
4.1 
Inclusion Criteria ....................................................................................... 36 
4.2 
Exclusion Criteria ...................................................................................... 37 
4.3 
Inclusion Criteria for the Imaging and PK/BTM/Biomarker 
Sub-study .................................................................................................. 39 
4.4 
Exclusion Criteria for the Imaging and PK/BTM/Biomarker 
Sub-study .................................................................................................. 40 
5. 
SUBJECT ENROLLMENT .................................................................................... 40 
5.1 
Randomization .......................................................................................... 41 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 41 
6. 
TREATMENT PROCEDURES .............................................................................. 42 
 
 
 


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6.1 
Romosozumab and Matched Placebo ....................................................... 42 
6.1.1 
Romosozumab/Placebo Dosage, Administration, and 
Schedule ................................................................................... 42 
6.1.2 
Romosozumab/Placebo Dosage Adjustments ........................... 43 
6.1.3 
Guidance on Hepatotoxicity Stopping and 
Rechallenge Rules for Romosozumab/Placebo ......................... 43 
6.2 
ALN / Matched Placebo and Open-label ALN ............................................ 43 
6.2.1 
ALN/Placebo and ALN Dosage, Administration, and 
Schedule ................................................................................... 44 
6.2.2 
Dosage Adjustments ................................................................. 45 
6.3 
Other Protocol-required Therapies ............................................................ 45 
6.4 
Concomitant Therapy ................................................................................ 46 
6.5 
Excluded Treatments During Study Period ................................................ 46 
7. 
STUDY PROCEDURES ....................................................................................... 47 
7.1 
General Study Procedures ........................................................................ 47 
7.1.1 
Study Visit Definitions ................................................................ 47 
7.1.2 
Study Windows .......................................................................... 48 
7.2 
Screening and Rescreening ...................................................................... 48 
7.2.1 
Screening .................................................................................. 48 
7.2.2 
Partial Rescreening for low Vitamin D........................................ 49 
7.2.3 
Full Rescreening ....................................................................... 50 
7.3 
Study Visits ............................................................................................... 51 
7.3.1 
Study Day 1/Baseline ................................................................ 51 
7.3.2 
Month 1 (± 7 Days) .................................................................... 51 
7.3.3 
Month 2 (± 7 Days) .................................................................... 52 
7.3.4 
Month 3 (± 7 Days) .................................................................... 52 
7.3.5 
Month 4 (± 7 Days) .................................................................... 53 
7.3.6 
Month 5 (± 7 Days) .................................................................... 53 
7.3.7 
Month 6 (± 7 Days) .................................................................... 54 
7.3.8 
Month 7 (± 7 Days) .................................................................... 54 
7.3.9 
Month 8 (± 7 Days) .................................................................... 55 
7.3.10 
Month 9 (± 7 Days) .................................................................... 55 
7.3.11 
Month 10 (± 7 Days) .................................................................. 56 
7.3.12 
Month 11 (± 7 Days) .................................................................. 56 
7.3.13 
Month 12 (± 7 Days) / Early Termination for the 
12-month Double-blind ALN-controlled Study Period................. 57 
7.3.14 
Month 15 (± 14 Days) for Sub-study Subjects Only ................... 57 
7.3.15 
Month 18 (± 14 Days) ................................................................ 58 
7.3.16 
Month 24 (± 14 Days) / Early Termination for Month 
12 to Month 24 of the Primary Analysis Period .......................... 58 
7.3.17 
Month 30 (± 14 Days) ................................................................ 59 
 
 
 


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7.3.18 
Month 36 and Subsequent Clinic Visits  (± 14 Days) to 
End of Primary Analysis Period ................................................. 59 
7.3.19 
Clinical Visits After the Primary Analysis Period to End 
of Study ..................................................................................... 60 
7.3.20 
Monthly Telephone Contacts in Between Clinic Visits 
(± 7 Days) Until end of Study ..................................................... 61 
7.3.21 
Unscheduled Follow-up Clinic Visit (+ 21 Days After 
Monthly Phone Contact) (Primary Analysis Period 
Only) ......................................................................................... 61 
7.3.22 
Telephone Contact at “End of Primary Analysis 
Period” (−14 Days to end of Primary Analysis Period) ............... 62 
7.3.23 
End of Study Telephone Contact (−14 to + 7 Days) ................... 62 
7.4 
Medical History ......................................................................................... 63 
7.5 
Medication History ..................................................................................... 63 
7.6 
Physical Examination ................................................................................ 63 
7.7 
Vital Signs ................................................................................................. 63 
7.8 
Laboratory Assessments ........................................................................... 63 
7.8.1 
General ..................................................................................... 63 
7.8.2 
Bone Turnover Markers ............................................................. 66 
7.8.3 
Romosozumab Levels and Sclerostin ........................................ 66 
7.8.4 
Antibody Testing Procedures ..................................................... 66 
7.9 
Adverse Event Data Collection and Adjudication ....................................... 67 
7.10 
Concomitant Medication Data Collection ................................................... 68 
7.11 
Clinical Fracture Recording ....................................................................... 68 
7.11.1 
Suspected Clinical Vertebral Fractures (Primary 
Analysis Period) ........................................................................ 68 
7.11.2 
Nonvertebral Fractures .............................................................. 69 
7.12 
Patient Reported and Clinician Reported Outcomes ................................. 69 
7.12.1 
OPAQ SV .................................................................................. 70 
7.12.2 
EQ-5D-5L .................................................................................. 70 
7.12.3 
Limited Activity day Survey ........................................................ 70 
7.12.4 
BPI Worst Pain .......................................................................... 70 
7.13 
Dual-energy X-ray Absorptiometry ............................................................ 71 
7.13.1 
Screening BMD Assessment ..................................................... 71 
7.13.2 
On-study BMD Assessments ..................................................... 71 
7.13.3 
Monitoring of BMD Decreases ................................................... 72 
7.14 
Lateral Spine X-ray Assessments ............................................................. 72 
7.15 
Quantitative Computed Tomography (QCT) .............................................. 73 
7.16 
Biomarker Development ............................................................................ 73 
7.16.1 
Biomarker Development ............................................................ 73 
7.16.2 
Sample Storage and Destruction ............................................... 74 
8. 
REMOVAL AND REPLACEMENT OF SUBJECTS ............................................... 74 
8.1 
Removal of Subjects ................................................................................. 74 
 
 
 


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8.2 
Replacement of Subjects .......................................................................... 75 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 76 
9.1 
Adverse Events ......................................................................................... 76 
9.1.1 
Definition of Adverse Events ...................................................... 76 
9.1.2 
Reporting Procedures for Adverse Events ................................. 76 
9.2 
Serious Adverse Events ............................................................................ 77 
9.2.1 
Definition of Serious Adverse Events ......................................... 77 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 78 
9.3 
Pregnancy Reporting ................................................................................ 79 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 80 
10.1 
Study Endpoints, Subsets, and Covariates ................................................ 80 
10.1.1 
Primary Endpoints ..................................................................... 80 
10.1.2 
Secondary Endpoints ................................................................ 80 
10.1.3 
Exploratory Endpoints ............................................................... 81 
10.1.4 
Safety Endpoints ....................................................................... 82 
10.1.5 
Imaging and PK/BTM/Biomarker Sub-study Endpoints .............. 82 
10.1.6 
Analyses Subsets ...................................................................... 83 
10.1.6.1 
Primary Efficacy Analysis Set for Vertebral 
Fracture ................................................................... 83 
10.1.6.2 
Full Analysis Set ...................................................... 83 
10.1.6.3 
Per-protocol Analysis Set ........................................ 83 
10.1.6.4 
Primary Efficacy Analysis Set for BMD, 
Height, and PRO/ClinRO Endpoints for the 
Double-blind ALN-controlled Study Period 
and Primary Analysis Period ................................... 84 
10.1.6.5 
Safety Analysis Set for the Double-blind 
ALN-controlled Study Period, Primary 
Analysis Period, and Overall Study Period .............. 84 
10.1.6.6 
Analysis Set for Imaging and 
PK/BTM/Biomarker Sub-study ................................. 84 
10.1.7 
Covariates ................................................................................. 84 
10.2 
Sample Size Considerations ..................................................................... 85 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ............................................................................................. 89 
10.4 
Interim Analysis and Early Stopping Guidelines ........................................ 89 
10.5 
Planned Methods of Analysis .................................................................... 90 
10.5.1 
General Approach/Considerations ............................................. 90 
10.5.2 
Analysis of Key Study Endpoints ............................................... 91 
10.5.2.1 
Efficacy Endpoints ................................................... 91 
10.5.2.2 
Safety Endpoints ..................................................... 94 
11. 
REGULATORY OBLIGATIONS ............................................................................ 95 
11.1 
Informed Consent ...................................................................................... 95 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
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11.2 
Independent Ethics Committee/Institutional Review Board ........................ 96 
11.3 
Subject Confidentiality ............................................................................... 96 
11.4 
Investigator Signatory Obligations ............................................................. 97 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 97 
12.1 
Protocol Amendments and Study Termination .......................................... 97 
12.2 
Study Documentation and Archive ............................................................ 97 
12.3 
Study Monitoring and Data Collection ....................................................... 98 
12.4 
Language .................................................................................................. 99 
12.5 
Publication Policy .................................................................................... 100 
12.6 
Compensation ......................................................................................... 101 
13. 
REFERENCES ................................................................................................... 102 
14. 
APPENDICES .................................................................................................... 106 
List of Tables 
Table 1.  Blood Sample Analyte Listing
 
 ......................................................................... 65
Table 2.  Mean Percent Change From Baseline in BMD for Alendronate
 
 ....................... 87
Table 3.  Mean Percent Change From Baseline in BMD at Month 12 for 
Romosozumab
 
 ....................................................................................... 87
List of Appendices 
Appendix A.  Schedule of Assessments
 
 ...................................................................... 107
Appendix B.  Additional Safety Assessment Information
 
 .............................................. 111
Appendix C.  Pregnancy Notification Worksheet
 
 .......................................................... 115
Appendix D.  eSAE Contingency Report Form
 
 ............................................................ 116
 
 
 
 


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1. 
OBJECTIVES 
1.1 
Primary 
For the primary analysis period (randomization to primary analysis) 
• 
To assess the effect of romosozumab treatment for 12 months followed by 
alendronate (ALN) treatment compared with ALN treatment alone on the subject 
incidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture) in 
postmenopausal women with osteoporosis 
• 
To assess the effect of romosozumab treatment for 12 months followed by ALN 
treatment compared with ALN treatment alone on the subject incidence of new 
vertebral fracture in postmenopausal women with osteoporosis 
1.2 
Secondary 
For the primary analysis period 
To assess the effect of romosozumab treatment for 12 months followed by ALN 
treatment compared with ALN treatment alone on: 
• 
Subject incidence of fractures (all fractures [nonvertebral fractures and new or 
worsening vertebral fractures], new or worsening vertebral fracture, nonvertebral 
fracture, major nonvertebral fracture [pelvis, distal femur, proximal tibia, ribs, 
proximal humerus, forearm, and hip], hip fracture, multiple new or worsening 
vertebral fracture, and clinical vertebral fracture) 
• 
Percent changes in Dual energy X-ray Absorptiometry (DXA) bone mineral density 
(BMD) at the lumbar spine, total hip, and femoral neck 
For the 12-month double-blind ALN-controlled study period 
To assess the effect of romosozumab treatment for 12 months compared with ALN 
treatment on: 
• 
Subject incidence of fractures (clinical fracture [nonvertebral fracture and clinical 
vertebral fracture], new vertebral fracture, all fractures [nonvertebral fractures and 
new or worsening vertebral fractures], nonvertebral fracture, hip fracture, clinical 
vertebral fracture, and major osteoporotic fracture [hip, forearm, humerus, and 
clinical vertebral]) 
• 
Percent changes in DXA BMD at the lumbar spine, total hip and femoral neck 
For the overall study (randomization to end of study) 
• 
To assess the effect of romosozumab treatment for 12 months followed by ALN 
treatment compared with ALN treatment alone on subject incidence of hip fracture, 
major nonvertebral fracture [pelvis, distal femur, proximal tibia, ribs, proximal 
humerus, forearm, and hip], and nonvertebral fractures 
 
 
 


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1.3 
Exploratory 
For the 12-month double-blind ALN-controlled study period 
• 
To assess the effect of romosozumab treatment for 12 months compared with ALN 
treatment on subject incidence of fractures (new or worsening vertebral fracture, 
major nonvertebral fracture [pelvis, distal femur, proximal tibia, ribs, proximal 
humerus, forearm, and hip], and multiple new or worsening vertebral fracture) 
• 
To describe subjects’ experience of pain and its impact on subjects’ activities and 
health-related quality of life at 6-month intervals for postmenopausal women with 
osteoporosis using Patient Reported Outcome (PRO) and Clinician Reported 
Outcome (ClinRO) questionnaires (Osteoporosis Assessment Questionnaire Short 
Version [OPAQ SV], EuroQoL-5 Dimensions-5 Levels Health Survey [EQ-5D-5L], 
Limited Activity Days [LAD] survey, and one item extracted from the Brief Pain 
Inventory [BPI] assessing the worst pain experienced in the past 24 hours [BPI worst 
pain]) 
• 
To describe subjects’ experience of pain and its impact on subjects’ activities and 
health-related quality of life for 3 months at 1-month intervals after experiencing a 
nonvertebral or clinical vertebral fracture (OPAQ SV, EQ-5D-5L, LAD, and BPI 
worst pain) 
• 
To describe the effect of romosozumab treatment for 12 months compared with ALN 
treatment on the percent of subjects with a clinically meaningful improvement in 
worst pain for 3 months at 1-month intervals after experiencing a nonvertebral or 
clinical vertebral fracture (defined as a 2-point improvement in the BPI worst pain 
scale compared with the fracture reporting visit)  
• 
To assess the effect of romosozumab treatment for 12 months compared with ALN 
treatment on changes in height 
For the primary analysis period 
• 
To assess the effect of romosozumab treatment for 12 months followed by ALN 
treatment compared with ALN treatment alone on subject incidence of major 
osteoporotic fracture (hip, forearm, humerus, and clinical vertebral) 
• 
To describe subjects’ experience of pain and its impact on subjects’ activities and 
health-related quality of life at 6-month intervals for postmenopausal women with 
osteoporosis using PRO and ClinRO questionnaires (OPAQ SV), EQ-5D-5L, LAD, 
and BPI worst pain) 
• 
To assess the effect of romosozumab treatment for 12 months followed by ALN 
treatment compared with ALN treatment alone on changes in height 
During the Month 12 to 24 ALN study period 
• 
To assess the effect of one year of romosozumab treatment compared with 
ALN treatment alone on subject incidence of new vertebral fractures, clinical 
fracture (nonvertebral fracture and clinical vertebral fracture), nonvertebral 
fracture, hip fracture, and clinical vertebral fracture during the subsequent 
year during which all subjects receive ALN treatment. 
 
 
 


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1.4 
Safety 
For the 12-month double-blind ALN-controlled study period 
• 
To characterize the safety and tolerability of romosozumab treatment for 12 months 
as determined by a review of reported adverse events, laboratory data, vital signs, 
and formation of anti-romosozumab antibodies. 
For the primary analysis period 
• 
To characterize the safety and tolerability of romosozumab treatment for 12 months 
followed by ALN treatment as determined by a review of reported adverse events, 
laboratory data, vital signs, and formation of anti-romosozumab antibodies 
For the overall study 
• 
To characterize the safety and tolerability of romosozumab treatment for 12 months 
followed by ALN treatment as determined by a review of reported adverse events 
and vital signs 
1.5 
Imaging and Pharmacokinetics (PK) / Bone Turnover Marker (BTM) / 
Biomarker Sub-study   
For the 12-month double-blind ALN-controlled study period 
• 
To characterize the serum romosozumab concentration 
• 
To assess the effect of romosozumab treatment for 12 months compared with ALN 
treatment on: 
− 
Percent changes in bone formation markers Procollagen Type 1 N-telopeptide 
(P1NP), Bone Specific Alkaline Phosphatase (BSAP), and Osteocalcin (OC), and 
in bone resorption marker serum Type I collagen C-telopeptide (sCTX) 
− 
Percent changes in sclerostin and intact Parathyroid Hormone (iPTH) 
− 
For subjects also participating in the imaging components: Percent changes in 
integral (total) and trabecular volumetric BMD (vBMD) at the lumbar spine by 
Quantitative Computed Tomography (QCT) 
− 
For subjects also participating in the imaging components: Percent changes in 
lumbar spine strength as assessed by Finite Element Analysis (FEA) 
• 
For subjects participating in the imaging components: To assess the effect of 
romosozumab treatment for 6 months compared with ALN treatment for 6 months on 
percent changes in DXA BMD at the lumbar spine, total hip, and femoral neck 
• 
To enable exploratory assessments of novel biomarkers through prospective 
collection of blood samples 
 
 
 


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For the primary analysis period 
• 
To assess the effect of romosozumab treatment for 12 months followed by ALN 
treatment compared with ALN treatment alone on 
− 
Percent changes in bone formation marker P1NP and bone resorption marker 
sCTX 
− 
Percent changes in sclerostin and iPTH 
− 
For subjects participating in the imaging components: Percent changes in 
integral (total) and trabecular vBMD at the lumbar spine by QCT 
− 
For subjects participating in the imaging components: Percent changes in lumbar 
spine strength as assessed by FEA 
• 
For subjects participating in the imaging components: To assess the effect of 
romosozumab treatment for 12 months followed by ALN treatment for 6 months 
compared with ALN treatment alone on percent changes in DXA BMD at the lumbar 
spine, total hip, and femoral neck 
• 
To enable exploratory assessments of novel biomarkers through prospective 
collection of blood samples 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Osteoporosis is defined as a skeletal disorder characterized by compromised bone 
strength predisposing to an increased risk of fracture (NIH Consensus Development 
Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001).  Osteoporosis is a 
common disorder, based on the World Health Organization’s current definition of 
osteoporosis (BMD T-score ≥ 2.5 standard deviations below the mean for normal 
young adults) (World Health Organization, 1994); the worldwide prevalence of 
osteoporosis has been estimated as 200 million people (Reginster and Burlet, 2006), 
including more than 75 million people in the United States (US), Europe, and Japan 
(World Health Organization, 2007).  The morbidity and mortality associated with 
osteoporotic-related fractures is significant in terms of disability to an individual and cost 
to the global economy (Cree et al, 2003; Kanis et al, 2001a, Kanis et al, 2001b).  
Approved treatments for postmenopausal women with osteoporosis include inhibitors of 
bone resorption such as selective estrogen receptor modulators (SERMs, 
eg, raloxifene), bisphosphonates (eg, ALN, risedronate, ibandronate, and zoledronate), 
calcitonin, denosumab, or agents that stimulate bone formation like teriparatide (the 
1-34 fragment of iPTH) (Greenblatt, 2005).   
Antiresorptive therapies prevent osteoclasts from resorbing bone, slowing the 
progression of bone breakdown, increasing BMD, and lowering the risk of vertebral 
 
 
 


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fractures (relative risk reduction [RRR]:  40% to 70%) and, to a lesser extent, 
nonvertebral fractures (RRR:  20% to 25%) (Cummings et al, 2009; Black et al, 2007; 
Chestnut et al, 2004; McClung et al, 2001; Chestnut et al, 2000; Cummings et al, 1998; 
Ettinger et al, 1999; Harris et al, 1999; Black et al, 1996).  Osteoporosis is a chronic 
disease and despite long-term administration of bisphosphonates, the most commonly 
prescribed class of antiresorptives, postmenopausal women with severe osteoporosis 
remain at increased risk of fracture and are in need of therapies with strong efficacy and 
the potential to reverse their disease condition by increasing bone formation and 
improving bone structure.   
In contrast, bone forming agents can promote larger improvements in bone mass and 
bone strength compared with antiresorptives and restore bone architecture, thereby 
addressing the need for improved protection against fractures, in particular at 
nonvertebral sites (Canalis, 2010; Papapoulos and Makras, 2008).  Analogs of 
parathyroid hormone (PTH) (PTH 1-34 [teriparatide] and PTH 1-84) increase bone 
remodeling by stimulating both bone formation and bone resorption with a net gain in 
bone mass.  As a result, there is a marked improvement in BMD, as well as indices of 
bone microstructure, that are associated with improved mechanical strength 
(Borggrefe et al, 2010).  Teriparatide shows a RRR of nonvertebral fractures of 
approximately 35% to 50% and lowers the risk of one or more new vertebral fractures by 
65% (Neer et al, 2001).   
A novel bone forming agent for the treatment of osteoporosis in postmenopausal 
women, with a different mechanism of action and the potential to reverse the features of 
osteoporosis by increasing bone volume and BMD and by improving bone architecture, 
ultimately resulting in increased bone strength and reduced risk for fracture, would be a 
welcome new therapeutic option particularly for subjects with significantly compromised 
bone strength at high risk of fracture. 
2.2 
Romosozumab Background   
Sclerostin, the protein product of SOST, produced by the osteocyte, is an inhibitor of 
osteoblast-mediated bone formation (Balemans et al, 2001; Brunkow et al, 2001; 
Poole et al, 2005; van Bezooijen et al, 2004; Winkler et al, 2003).  Humans with inherited 
sclerostin deficiencies have high bone mass and BMD throughout the skeleton and are 
resistant to fractures (Hamersma et al, 2003; Vanhoenacker et al, 2003).  Administration 
of a sclerostin antibody, resulting in the blocking of the inhibitory effect of sclerostin on 
bone formation, has been shown to increase bone formation, BMD, and bone strength in 
 
 
 


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multiple animal models (normal and osteoporotic rats, monkeys) (Li et al, 2009; 
Li et al, 2007a; Li et al, 2007b; Ominsky et al, 2010a; Ominsky et al, 2010b).   
Romosozumab is a humanized monoclonal antibody that is designed to bind and inhibit 
sclerostin, thereby promoting osteoblast differentiation and activity, leading to an 
increase in bone formation, BMD, and bone strength.  Proof of biological activity for 
romosozumab has been established in a first-in-human, ascending-single-dose study in 
healthy men and postmenopausal women, an ascending-multiple-dose study in healthy 
men and postmenopausal women with low bone mass and a phase 2 dose-ranging 
study in postmenopausal women with low bone mass.  In all studies, treatment with 
romosozumab was generally well tolerated and resulted in a transient increase of the 
bone formation markers P1NP, OC, and BSAP, and a decrease in the bone resorption 
marker sCTX.  Increases in BMD at the lumbar spine, total hip and femoral neck have 
also been demonstrated, by DXA and QCT.   
Additional clinical studies have been completed or are currently ongoing:  
• 
A phase 1b ALN-to-romosozumab transition study in postmenopausal women with 
low bone mass who had been receiving ALN or were treatment naïve 
• 
A phase 1b multiple-dose study using peripheral QCT to evaluate the effect of 
romosozumab on parameters of bone quality of the forearm in postmenopausal 
women with low bone mass 
• 
A phase 1 single-dose study in healthy postmenopausal Japanese women 
• 
A phase 2a multiple-dose fracture-healing study in subjects with tibial diaphyseal 
fractures 
• 
A phase 2 multiple-dose fracture-healing study in subjects with proximal femur 
fractures 
As of 19 April 2011, 417 subjects treated with romosozumab have been tested for 
anti-romosozumab antibodies.  Of these, approximately 20% developed binding 
antibodies and approximately 5% developed neutralizing antibodies.  There were no 
clinically relevant adverse events associated with binding or neutralizing antibodies.  
For additional information about the romosozumab nonclinical experience and clinical 
experience, refer to the Investigator’s Brochure. 
 
 
 


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2.3 
Justification for Romosozumab Treatment Duration and Dosing 
Regimen   
A 12-month romosozumab treatment duration is supported by the following 
considerations:  
• 
Substantial increases in BMD at the lumbar spine, total hip and femoral neck were 
observed during 12 months of romosozumab administration in the phase 2 
dose-ranging study.  At 12 months, the 210 mg every month (QM) dosing regimen 
resulted in a BMD increase from baseline of 11.3% at the lumbar spine and 4.1% at 
the total hip. 
• 
Increases in bone formation as assessed with bone formation markers were not 
apparent beyond 12 months in the phase 2 dose-ranging study.  For the 
romosozumab 210 mg QM dosing regimen, the median P1NP was 10.2% below 
baseline 1 week after the Month 12 dose; in contrast to an increase of 82.7% above 
baseline 1 week after the Day 1 dose.  Similarly, median BSAP for the romosozumab 
210 mg QM dosing regimen was only 4.0% above baseline at 1 week after the 
Month 12 dose, compared with 17.9% above baseline 1 week after the Day 1 dose.  
Median sCTX was 26.3% below baseline at Month 12. 
• 
Based on Month 18 data available for the 210 mg QM treatment group in the phase 2 
dose-ranging study, beyond Month 12 the BMD appeared to increase more 
gradually, likely primarily due to the antiresorptive effect.   
• 
The results of the modeling using a mechanism-based PK/pharmacodynamic (PD) 
model indicated that the most significant BMD increases occur during the first 
12 months of romosozumab treatment.  
Thus, the intervention with romosozumab will be limited to 12 consecutive months, and it 
is essential to administer a dosing regimen that will achieve maximal effect within this 
12-month treatment duration. 
The 210 mg romosozumab QM dosing regimen was selected based on the following 
data:  
• 
In the phase 2 dose-ranging study, the 210 mg QM romosozumab dosing regimen 
resulted in a greater increase in BMD at the lumbar spine and total hip at 12 months 
compared with other romosozumab dosing groups.  Compared with the 140 mg QM 
romosozumab dosing regimen, the 210 mg QM romosozumab dosing regimen 
resulted in greater gains in lumbar spine BMD (11.3% vs. 9.3% change from 
baseline) and total hip BMD (4.1% vs. 3.5% change from baseline).  The 210 mg QM 
dosing regimen also exhibited a greater increase in BMD at the lumbar spine, total 
hip, and femoral neck compared with the open label active comparators ALN and 
teriparatide. 
• 
The romosozumab 210 mg QM dosing regimen resulted in the largest and most 
prolonged increase in markers of bone formation, including BSAP, P1NP, and OC in 
the phase 2 dose-ranging study.  Median P1NP and OC levels remained above 
baseline up to Months 6 and 9, respectively, and median BSAP levels remained 
above baseline up to Month 12.  In comparison, the 140 mg QM dosing regimen 
increased markers of bone formation for 3 to 6 months. 
 
 
 


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• 
In subjects previously treated with ALN, a 3 mg/kg dose (equivalent to a 210 mg 
fixed dose) in the phase 1b ALN transition study, suggests greater increases in BMD 
and bone formation markers than in subjects previously treated with ALN who 
transitioned to 140 mg QM in the phase 2 dose-ranging study. 
• 
The incidence of adverse events in the phase 2 dose-ranging study was not 
dose-related, and the incidence of neutralizing antibodies against romosozumab was 
low (2%) and similar across QM doses.  Thus, the safety profile of the 210 mg QM 
dosing regimen does not appear to be appreciably different from that of lower doses. 
In addition to the above considerations of the clinical data, PK/PD modeling and 
simulations support the choice of the 210 mg QM dosing regimen.  Conclusions from the 
modeling are as follows: 
• 
There is a robust relationship between PK exposure and BMD gains at the lumbar 
spine; the 210 mg QM dosing regimen is not in the plateau region of the 
exposure-response curve 
• 
Romosozumab 210 mg QM will result in greater BMD gains at both lumbar spine and 
total hip compared with 140 mg QM 
• 
Romosozumab 210 mg QM will result in greater increases in P1NP as compared 
with 140 mg QM 
• 
The rate of BMD increase is greatest during the first 12 months of romosozumab 
treatment 
Based on the above evidence, romosozumab treatments that provide greater systemic 
exposure are expected to result in greater bone formation response and, consequently, 
larger BMD gains. 
In summary, the proposed treatment regimen of 210 mg romosozumab QM for 
12 months is expected to achieve optimal increases in BMD and bone formation markers 
in subjects who are treatment-naïve and in those who have previously received ALN 
without negatively impacting the safety profile of romosozumab.  Thus, a 210-mg QM 
dosing regimen is expected to provide the best risk-benefit profile and enable evaluation 
of the safety, tolerability, and efficacy of romosozumab to prevent fractures in 
postmenopausal women with osteoporosis.   
Refer to the Investigator’s Brochure for a detailed description of data from the phase 2 
dose-ranging study. 
2.4 
Alendronate Background   
Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite 
found in bone.  ALN (Fosamax), a bisphosphonate that acts as an inhibitor of 
osteoclast mediated bone resorption, is indicated for the prevention and treatment of 
osteoporosis in postmenopausal women.  Two trials of three-year duration demonstrated 
 
 
 


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significant increases in BMD at the lumbar spine, femoral neck and hip trochanter in 
response to ALN therapy.  
Results of those trials and those of the Fracture Intervention Trial three- and four-year 
studies demonstrated significant reductions in the incidence of one or more new 
vertebral fractures in women with or without prevalent vertebral fractures at baseline, 
and incidence of hip fractures, and in the incidence of nonvertebral fractures compared 
with placebo (Black et al, 1996; Cummings et al, 1998; Fosamax product insert).  
The Fracture Intervention Trial consisted of two placebo-controlled studies in 
postmenopausal women: a 3-year study of patients with at least one baseline 
radiographic vertebral fracture and a 4-year study of patients with low bone mass but 
without a baseline vertebral fracture (Black et al, 1996; Cummings et al, 1998).  The 
3-year study (in patients with at least one baseline radiographic vertebral fracture) 
demonstrated that treatment with ALN resulted in statistically significant reductions in 
fracture incidence compared with placebo. The incidence of at least one new vertebral 
fracture was decreased from 15.0% to 8.0% (47% RRR). In the 4-year study (in patients 
with low bone mass but without a baseline vertebral fracture) the incidence of at least 
one new vertebral fracture was reduced from 3.8% to 2.1% (44% RRR). 
Additional information is provided in the ALN package insert.  
2.5 
Calcium and Vitamin D Background   
Calcium and vitamin D are important in the formation of bone matrix and for its 
subsequent mineralization where calcium found as calcium hydroxyapatite 
(Ca10[PO4]6[OH]2) provides bones and teeth tissue with its strength.  Calcium and 
vitamin D are therefore considered key components of therapy in the management of 
postmenopausal osteoporosis (PMO) (Dawson-Hughes et al, 2010) and have been 
required as background therapies in all contemporary therapeutic trials in PMO.  
Because of the active bone formation and mineralization that is expected with 
romosozumab, calcium and vitamin D supplementation will be necessary in order to 
achieve and maintain positive bone balance.  The recommended dietary allowance and 
tolerable upper intake level of dietary calcium recommended by the US Institutes of 
Medicine for women over the age of 50 years on a western diet is 1,200 mg and 
2,000 mg per day respectively.  The recommended dietary allowance and tolerable 
upper intake level of dietary vitamin D for women aged 51-70 years is 600 IU and 
4,000 IU per day respectively while the recommended dietary allowance and tolerable 
upper intake level of dietary vitamin D for women over the age of 70 years is 800 IU and 
 
 
 


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4,000 IU per day respectively (IOM 2010; Ross et al, 2011).  The initial loading dose of 
50,000 to 60,000 IU of vitamin D for subjects with vitamin D levels of ≥ 20 ng/mL and 
≤ 40 ng/mL (administered within 1 week of the study day 1 visit) is necessary to provide 
a sufficient calcium pool for the expected and significant increase in bone mass and 
needed for bone mineralization in the first several months after initiation of treatment 
with romosozumab.  This dose has been shown to be safe and well tolerated 
(Giusti et al, 2010; Tucci, 2009).  The daily supplementation required in this study, that at 
a minimum should be in the range of 500 to 1,000 mg elemental calcium and 
600 to 800 IU of vitamin D, is safe and represents commonly used and accepted doses 
for clinical trials in osteoporosis and are consistent with existing treatment practice and 
guidelines (Dawson-Hughes et al, 2010, IOM 2010). 
2.6 
Rationale 
This will be a multicenter, international, randomized, double-blind, alendronate-controlled 
study of romosozumab in postmenopausal women with osteoporosis who have had a 
previous osteoporotic fracture and now require therapy for secondary prevention. 
Choice of control group 
Alendronate was chosen as a control because it permits assessment of effects of 
romosozumab on fracture risk reduction in postmenopausal women with osteoporosis 
compared with the effects of a commonly used therapy for osteoporosis.  Alendronate 
has shown to be effective in reducing vertebral fractures and its safety profile is well 
characterized (Black et al, 1996; Cummings et al, 1998; Fosamax product insert). 
However, in postmenopausal women with osteoporosis, fracture risk remains elevated 
despite continued treatment with alendronate (Black et al, 2006; Schwartz et al, 2010).  
Therefore an alendronate-controlled trial will provide a relevant comparison with a 
commonly used therapy for postmenopausal women with osteoporosis. 
Endpoints 
Primary, secondary, and safety endpoints have been selected to describe the efficacy in 
fracture risk reduction, and the safety profile of romosozumab.  The primary endpoint of 
subject incidence of clinical fracture captures established markers of efficacy for the 
treatment of osteoporosis: nonvertebral fractures and clinical vertebral fractures.  
Nonvertebral fractures and clinical vertebral fractures account for the bulk of significant 
morbidity and mortality related to osteoporosis.  A decrease in the subject incidence of 
clinical fracture will therefore represent an improvement in the clinical burden from 
 
 
 


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osteoporosis.  The primary endpoint of subject incidence of new vertebral fracture 
represents an established endpoint for registration of new osteoporosis therapies. 
The proposed safety endpoints will permit evaluation of the risk/benefit profile of 
romosozumab compared to alendronate in postmenopausal women with osteoporosis 
through the assessment of reported adverse and serious adverse events, vital signs, 
laboratory data and formation of anti-romosozumab antibodies. 
Inclusion criteria  
This study will enroll postmenopausal women with osteoporosis who meet at least one of 
the following BMD and fracture criteria: 
• BMD T-score ≤ -2.50 at the total hip or femoral neck and either at least one 
moderate (SQ2) or severe (SQ3) vertebral fracture or at least 2 mild (SQ1) 
vertebral fractures 
or 
• BMD T-score ≤ -2.00 at the total hip or femoral neck and either at least 
2 moderate (SQ2) or severe (SQ3) vertebral fractures or a fracture of the 
proximal femur that occurred within 3 to 24 months prior to randomization 
The risk of fracture in this study population is high, and the subjects are likely to derive 
significant benefit from a bone forming agent in clinical practice.   
Exclusion criteria  
Since all patients in the study will receive active treatment (either romosozumab or ALN), 
there is no lower threshold of BMD T-score as an exclusion criterion, nor is there an 
exclusion criterion based on higher numbers or severity of prevalent fractures.  
The exclusion criteria for disease state, medical and medication history were chosen to 
minimize the possibility of influencing or confounding the results of the comparative 
assessment of efficacy and safety of two treatments administered in the study.  In 
addition, subjects who have a contraindication to alendronate or unable to take 
alendronate oral tablets in accordance with the package insert are to be excluded. 
ALN study period 
Clinical experience with anabolic agents such as teriparatide and PTH (1-84) strongly 
support the strategy of consolidating gains from anabolic therapy in new bone matrix that 
is either mineralized or in the process of being mineralized with a subsequent period of 
anti-resorptive therapy (Black et al, 2005; Prince et al, 2005).  The sequential therapy 
with ALN following romosozumab treatment for 12 months is justified by the 
 
 
 


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anti-resorptive mechanism of action of ALN and the established clinical paradigms 
currently in use with anabolic agents (Black et al, 2005; Rittmaster et al, 2000; 
National Osteoporosis Foundation 2010).   
Final analysis 
The study will continue beyond the time of primary analysis to allow following of subjects 
for the secondary endpoint of nonvertebral fractures. 
2.7 
Clinical Hypotheses   
The primary clinical hypotheses are that romosozumab treatment for 12 months followed 
by ALN treatment compared with ALN treatment alone is effective in reducing the 
incidence of clinical fracture (nonvertebral fracture and clinical vertebral fracture) and 
new vertebral fracture in postmenopausal women with osteoporosis.  It is expected that 
romosozumab treatment for 12 months followed by ALN treatment will reduce the 
incidence of clinical fractures by 30% and the incidence of new vertebral fractures by 
50% compared with the control group (ALN alone). 
The primary safety hypothesis is that romosozumab treatment for 12 months is well 
tolerated in postmenopausal women with osteoporosis.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 3 multicenter, international, randomized, double-blind, ALN-controlled 
study of romosozumab in postmenopausal women with osteoporosis.  The study is 
designed to evaluate if romosozumab treatment for 12 months followed by ALN 
treatment, compared with ALN treatment alone, is effective in reducing the incidence of 
clinical fracture (nonvertebral fracture and clinical vertebral fracture) and new vertebral 
fracture. 
After signing the informed consent form (ICF), subjects will undergo a screening phase 
to complete eligibility assessments.  Upon confirmation of eligibility, approximately 
4,000 subjects will be randomized 1:1 (approximately 2,000 subjects per arm) to receive 
either 210 mg romosozumab subcutaneous (SC) QM or 70 mg ALN orally (PO) every 
week (QW) in a blinded fashion for the duration of the 12–month double-blind 
ALN-controlled study period.  Randomization will be stratified by age (< 75 years, 
≥ 75 years).  Subjects will also receive matched placebo for either ALN or 
romosozumab.  After the initial 12-month study period, subjects will receive ALN while 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 34 of 118 
CONFIDENTIAL 
 
 
remaining blinded to their initial treatment assignment (romosozumab or ALN).  The 
primary analysis period will end and the primary analysis will be performed when:  
• 
clinical fracture events (nonvertebral fracture or clinical vertebral fracture) have 
been confirmed for at least 330 subjects 
AND 
• 
all subjects have had the opportunity to complete the Month 24 study visit. 
If more than 330 subjects have confirmed clinical fractures at the time each subject has 
completed her Month 24 visit, the primary analysis will be based on all available data, 
which may include more than 330 events. 
Upon completion of the primary analysis period, subjects will continue to be followed for 
the secondary endpoint of nonvertebral fractures.  Subjects and site personnel will 
remain blinded to initial treatment assignments.  The study will proceed in an event-
driven manner.  The final analysis (end of study) will be performed when nonvertebral 
fracture events have been confirmed for at least 440 subjects across the lifetime of the 
study.  The study may be terminated earlier if the primary analysis demonstrates 
superiority of romosozumab treatment for nonvertebral fracture risk reduction (see 
Section 10.2 for details on testing strategy). Study completion constitutes either 
completion of primary analysis if superiority is proven for nonvertebral fractures or when 
at least 440 subjects have experienced a nonvertebral fracture. 
From screening to end of study, subjects will receive daily calcium and vitamin D 
supplementation that at a minimum should be in the range of 500 to 1,000 mg elemental 
calcium and 600 to 800 IU vitamin D.  In addition, subjects with a serum 
25 (OH) vitamin D level of ≥ 20 ng/mL and ≤ 40 ng/mL at screening will receive an initial 
loading dose of 50,000 to 60,000 IU of vitamin D after randomization, preferably by the 
oral route.  Subjects with a serum 25 (OH) vitamin D level of > 40 ng/mL at screening 
may also receive the vitamin D loading dose at the principal investigator’s discretion. 
Approximately 200 subjects at participating centers will be enrolled in an Imaging and 
PK/BTM/Biomarker sub-study.  Within this sub-study, a subset of approximately 
100 subjects will participate in the imaging (DXA, QCT) portion of the sub-study. 
If there is insufficient enrollment into the blood only portion of the sub-study, additional 
sub-study sites will be initiated. Subjects already on trial will be invited to participate and 
consent will be obtained for the use of blood samples from earlier time points for 
sub-study analyses. 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 35 of 118 
CONFIDENTIAL 
 
 
From study start until primary analysis, an external, independent Data Monitoring 
Committee (DMC) will monitor unblinded safety data on an ongoing basis and consider 
efficacy data in order to assess the risk/benefit profile of romosozumab. 
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 
The study endpoints are defined in Section 10.1. 
3.2 
Number of Centers 
Approximately 325 centers in North America, Europe, Central and South America and 
Asia/Pacific will participate in this trial.  Additional regions, countries and/or centers may 
be added. 
Sites that do not enroll subjects within 3 months of site initiation may be closed. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
Approximately 4,000 subjects will be enrolled (approximately 2,000 per arm).  An 
expected annual dropout rate of 10% in the first year and 8% thereafter has been taken 
into account when determining the sample size (refer to Section 10.2).   
3.4 
Estimated Study Duration 
3.4.1 
Study Duration for Participants 
Study duration is event-driven, ie, the end of study visits will occur when nonvertebral 
fracture events have been confirmed by the central imaging vendor for at least 
440 subjects, unless the primary analysis demonstrates superiority of romosozumab 
treatment for nonvertebral fracture risk reduction (see Section 10.2 for details on testing 
strategy). Study completion constitutes either completion of primary analysis if 
superiority is proven for nonvertebral fractures or when at least 440 subjects have 
experienced a nonvertebral fracture.  Enrollment is expected to take approximately 
34 months; however, recruitment is competitive and will stop after approximately 
4,000 subjects are enrolled. 
The estimated study duration for an individual subject, including the screening period, is 
25 to 59 months (if study completion is achieved at primary analysis) or 37 to 71 months 
(if study completion is achieved when at least 440 subjects have experienced a 
nonvertebral fracture), based on projected enrollment and estimated fracture rates.  
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 36 of 118 
CONFIDENTIAL 
 
 
However, actual study duration for individual subjects may be longer, depending on 
actual enrollment and observed fracture rates. 
3.4.2 
End of Study 
Primary Completion: The time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis, ie, when 
clinical fracture events (nonvertebral fracture or clinical vertebral fracture) have been 
confirmed by the central imaging vendor for at least 330 subjects and all subjects have 
had the opportunity to complete the Month 24 study visit. 
End of Trial (end of study):
10.2
 The time when the last subject is assessed or receives an 
intervention for evaluation in the study.  The end of trial will be when nonvertebral 
fracture events have been confirmed for at least 440 subjects across the lifetime of the 
study, unless the primary analysis demonstrates superiority of romosozumab treatment 
for nonvertebral fracture risk reduction (see Section 
 for details on testing strategy). 
Study completion constitutes either completion of primary analysis if superiority is proven 
for nonvertebral fractures or when at least 440 subjects have experienced a nonvertebral 
fracture.   
Early termination (ET) subjects who test positive for neutralizing antibodies to 
romosozumab at the ET study visit will be asked to return for additional follow-up testing 
as described in Section 7.8.4. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate 
(eg, demographic information, eligibility).  Before any study-specific procedure, the 
appropriate written informed consent must be obtained (see Section 11.1).   
4.1 
Inclusion Criteria 
4.1.1 
Ambulatory postmenopausal women, age ≥ 55 to ≤ 90 years at 
randomization.  Postmenopausal status is defined as no vaginal bleeding 
or spotting for 12 consecutive months prior to screening. 
4.1.2 
Subject meets at least one of the following BMD and fracture criteria 
• 
BMD T-score ≤ -2.50 at the total hip or femoral neck 
AND  
EITHER at least one moderate (SQ2) or severe (SQ3) vertebral 
fracture OR at least 2 mild (SQ1) vertebral fractures 
or 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 37 of 118 
CONFIDENTIAL 
 
 
• 
BMD T-score ≤ -2.00 at the total hip or femoral neck 
AND 
EITHER at least 2 moderate (SQ2) or severe (SQ3) vertebral 
fractures OR a fracture of the proximal femur that occurred within 3 to 
24 months prior to randomization 
BMD T-scores at the time of screening will be assessed by the central 
imaging vendor based on DXA scans and using data for Caucasian 
women from the National Health and Nutritional Examination Survey 
(NHANES) 1998.   
Vertebral fractures at the time of screening will be assessed by the 
central imaging vendor based on lateral spine x-rays.   
History of proximal femur fracture will be assessed by the principal 
investigator based on discharge summary, radiology report, or 
comparable documentation of type and date of fracture. 
4.1.3 
At least one hip is evaluable by DXA, as assessed by the principal 
investigator 
4.1.4 
Subject has provided informed consent 
4.2 
Exclusion Criteria 
Use of the following agents affecting bone metabolism (4.2.1 through 4.2.9) 
4.2.1 
Strontium ranelate, or fluoride (for osteoporosis): more than 1 month of 
cumulative use within 5 years prior to randomization 
4.2.2 
Intravenous (IV) bisphosphonates 
• 
Zoledronic acid:  
− 
any dose received within 3 years prior to randomization 
− 
more than 1 dose received within 5 years prior to randomization 
• 
IV ibandronate or IV pamidronate: 
− 
any dose received within 12 months prior to randomization 
− 
more than 3 years of cumulative use, unless last dose received 
≥ 5 years prior to randomization 
4.2.3 
Oral bisphosphonates: 
• 
any dose received within 3 months prior to randomization 
• 
more than 1 month of cumulative use between 3 and 12 months prior 
to randomization 
• 
more than 3 years of cumulative use, unless last dose received 
≥ 5 years prior to randomization 
4.2.4 
Denosumab or any cathepsin K inhibitor, such as odanacatib (MK-0822): 
any dose received within 18 months prior to randomization 
4.2.5 
Teriparatide or any PTH analogs:  
• 
any dose received within 3 months prior to randomization 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 38 of 118 
CONFIDENTIAL 
 
 
• 
more than 1 month of cumulative use between 3 and 12 months prior 
to randomization 
4.2.6 
Systemic oral or transdermal estrogen or SERMs: more than 1 month of 
cumulative use within 6 months prior to randomization 
4.2.7 
Hormonal ablation therapy: more than 1 month of cumulative use within 
6 months prior to randomization 
4.2.8 
Tibolone, cinacalcet, or calcitonin: any dose received within 3 months 
prior to randomization 
4.2.9 
Systemic glucocorticosteroids: ≥ 5 mg prednisone equivalent per day for 
more than 14 days within 3 months prior to randomization 
4.2.10 
History of metabolic or bone disease (except osteoporosis) that may 
interfere with the interpretation of the results, such as sclerosteosis, 
Paget’s disease, osteomalacia, osteogenesis imperfecta, osteopetrosis, 
ankylosing spondylitis, Cushing’s disease, hyperprolactinemia, and 
malabsorption syndrome 
4.2.11 
History of solid organ or bone marrow transplants 
4.2.12 
25 (OH) vitamin D levels < 20 ng/mL, as assessed by the central 
laboratory.  Vitamin D repletion will be permitted and subjects may be 
rescreened once (refer to Section 7.2.2). 
4.2.13 
Current hyper- or hypocalcemia, defined as albumin-adjusted serum 
calcium outside the normal range, as assessed by the central laboratory.  
Serum calcium levels may be retested once in case of an elevated serum 
calcium level within 1.1x the upper limit of normal (ULN) as assessed by 
the central laboratory. 
4.2.14 
Current, uncontrolled hyper- or hypothyroidism, per subject report or chart 
review.  Uncontrolled hyperthyroidism is defined as thyroid-stimulating 
hormone (TSH) and T4 outside the normal range.  Uncontrolled 
hypothyroidism is defined as TSH > 10 
4.2.15 
Current, uncontrolled hyperparathyroidism or history of 
hypoparathyroidism, per subject report or chart review.  Uncontrolled 
hyperparathyroidism is defined as: PTH outside the normal range in 
subjects with concurrent hypercalcemia; or PTH values > 20% above the 
ULN in normocalcemic subjects 
4.2.16 
Possible diagnosis of multiple myeloma or related lymphoproliferative 
disorder, as assessed by serum protein electrophoresis performed by the 
local laboratory (electrophoresis results within 6 months prior to signing 
consent will be acceptable) 
4.2.17 
Exclusion criteria related to contraindications or possible signs of 
intolerance to ALN; contraindications and potential signs of intolerance for 
ALN therapy include:   
• 
Hypocalcemia (as defined in 4.2.13) 
• 
Abnormalities of the esophagus, which delay esophageal emptying 
such as stricture or achalasia 
• 
Inability to stand or sit upright for at least 30 minutes 
• 
Hypersensitivity to ALN or other constituents of ALN tablets 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 39 of 118 
CONFIDENTIAL 
 
 
• 
Pregnancy and lactation 
• 
Other contraindications to ALN based on the country-specific product 
insert applicable to the specific study center 
• 
Significantly impaired renal function (as assessed by the central 
laboratory based on a derived creatinine clearance of < 35 mL/min 
using the Modification of Diet in Renal Disease equation 
[Levey et al, 2006]).  The estimated glomerular filtration rate is 
calculated as follows: estimated glomerular filtration rate 
(mL/min/1.73m2) = 175 x [Serum creatinine (mg/dL)]-1.154 x [Age]-0.203 x 
[0.742 if subject is female] x [1.212 if subject is black]. 
General exclusion criteria (4.2.18 through 4.2.28) 
4.2.18 
Subject is currently enrolled in another investigational device or drug 
study, or less than 30 days since ending another investigational device or 
drug study(s), or receiving other investigational agent(s) 
4.2.19 
Subject has previously entered this study or has previously participated in 
a study with a sclerostin antibody product 
4.2.20 
Other investigational procedures are excluded 
4.2.21 
Malignancy within the last 5 years, except non-melanoma skin cancers, 
cervical or breast ductal carcinoma in situ 
4.2.22 
Subject has known sensitivity to any of the products or components to be 
administered (calcium supplements, vitamin D products, or mammalian 
cell derived products) 
4.2.23 
Subject is pregnant or is planning to become pregnant within 3 months 
after the last dose of investigational product (IP) 
4.2.24 
Subject will not be available for protocol-required study visits or 
procedures, to the best of the subject and investigator’s knowledge 
4.2.25 
Subject has any kind of disorder that, in the opinion of the investigator, 
may compromise the ability of the subject to give written informed 
consent and/or to comply with all required study procedures 
4.2.26 
Subject is known to have human immunodeficiency virus, hepatitis C 
virus, or hepatitis B infection  
4.2.27 
Subject has any condition or illness (acute, chronic, or history), which in 
the opinion of the Investigator might interfere with the evaluation of the 
safety of the study product or may otherwise compromise the safety of 
the subject 
4.2.28 
Subject with reported history of hearing loss associated with cranial nerve 
VIII compression due to excessive bone growth (eg, as seen in conditions 
such as Paget’s disease, sclerosteosis and osteopetrosis) 
4.3 
Inclusion Criteria for the Imaging and PK/BTM/Biomarker Sub-study 
• 
Subject is enrolled at a center participating in this sub-study 
• 
Subject has provided informed consent for participation in this sub-study 
 
 
 


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Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 41 of 118 
CONFIDENTIAL 
 
 
5.1 
Randomization 
Subjects will be randomized 1:1 in a double-blind manner to either the romosozumab or 
the ALN treatment group, based on a randomization schedule prepared by the Amgen 
Central Randomization Group before the start of the study.  A subject may only be 
randomized once, and each randomization number may only be assigned once.   
Randomization will be stratified by age (< 75 years, ≥ 75 years).  There will be no 
stratification by or within clinical center.   
Every attempt should be made for subjects to receive their first injection of IP on the day 
of randomization.  If this is not possible, subjects must receive the first injection of IP 
within 72 hours of randomization.  Similarly, oral IP must be dispensed within 72 hours of 
randomization and must be taken within one week of study Day 1. 
A subject will be considered enrolled once a randomization number is assigned by the 
IVRS.  It is therefore very important to place the randomization call only after the 
subject’s eligibility and willingness to participate has been confirmed, as the subject 
cannot be ‘unenrolled’. 
5.2 
Site Personnel Access to Individual Treatment Assignments 
The identity of IP assigned to subject numbers or to individual packages of IP will be 
contained in the IVRS.  Authorized site staff will be provided with a unique Personal 
Identification Number to access the IVRS to obtain unblinding information.  This 
Personal Identification Number is unique to the individual and must not be shared. 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject.  Unblinding at the study 
site for any other reason will be considered a protocol deviation.  Refer to the 
Investigational Product Instruction Manual (IPIM) for instructions on how to access 
treatment information in the event the blind needs to be broken. 
The principal investigator is strongly encouraged to contact the Amgen study manager 
before unblinding any subject’s treatment assignment, but must do so within 1 working 
day after the event. 
Following the end of the primary analysis period, subjects and site personnel are to 
remain blinded to a subject’s original treatment assignment. 
 
 
 


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Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 43 of 118 
CONFIDENTIAL 
 
 
The first dose of romosozumab/placebo should be administered on the day of 
randomization.  If this is not possible, it must be administered within 72 hours of 
randomization. 
Refer to specific instructions provided by the IVRS vendor for additional information on 
box assignment and to the IPIM for additional information regarding storage and 
preparation of IP. 
Overdose with this product has not been reported.  Neither the effects of overdose of 
romosozumab nor an antidote to overdose are known.  The maximum amount of 
romosozumab that can be safely administered in a single dose has not been 
determined, and there is currently insufficient information to draw any conclusions about 
the safety of doses higher than those studied in clinical trials.  The highest single dose of 
romosozumab tested in clinical trials is 10 mg/kg SC.  Subjects who have received 
higher than protocol-defined doses should be carefully monitored for adverse events. 
6.1.2 
Romosozumab/Placebo Dosage Adjustments 
No dosing adjustments for romosozumab/Placebo will be permitted. 
All efforts should be made to administer romosozumab/placebo within the defined study 
visit windows (refer to Section 7).  In case of an out-of-window visit, 
romosozumab/placebo can be administered ± 2 weeks of the target visit date, 
ie, calculated from the Day 1 visit as described in Section 7.1.1.  If 
romosozumab/placebo cannot be administered ± 2 weeks of the target visit date, the 
dose has to be considered missed. 
6.1.3 
Guidance on Hepatotoxicity Stopping and Rechallenge Rules for 
Romosozumab/Placebo 
A US Food and Drug Administration (FDA) Guidance exists for drug-induced liver injury 
(DILI) (Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, July 2009).  This guidance is general for all investigational products, and its 
recommendations can be found in Appendix B.  It provides criteria for withholding 
romosozumab/placebo in the event that a subject develops signs or symptoms of 
hepatitis during a clinical trial.  These guidelines provided in Appendix B apply to all 
centers in all regions. 
6.2 
ALN / Matched Placebo and Open-label ALN  
ALN and matched placebo will also be used in this study and will be considered 
non-Amgen investigational products.   
 
 
 


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Blinded ALN will be manufactured by Merck & Co Inc., packaged by Patheon Inc., and 
labeled and distributed using Amgen clinical study drug distribution procedures.  Blinded 
ALN will be presented as a blister pack containing 10 tablets.   
Placebo to ALN will be presented in identical containers and stored/packaged the same 
as ALN. 
Open-label ALN will be manufactured and packaged by Merck & Co Inc., and labeled 
and distributed using Amgen clinical study drug distribution procedures.  Open-label ALN 
will be presented as a blister pack containing 4 tablets. 
Additional detail regarding these IPs is provided in the IPIM. 
6.2.1 
ALN/Placebo and ALN Dosage, Administration, and Schedule 
During the 12-month double-blind ALN-controlled study period, subjects will be 
dispensed a 2-month supply (ie, 1 blister pack containing 10 tablets) of ALN or matched 
placebo at the Day 1, Month 2, Month 4, Month 6, Month 8, and Month 10 visits.  One 
70 mg tablet will be taken orally once a week and will be self-administered by the 
subjects.  At the Month 2, Month 4, Month 6, Month 8, Month 10, and Month 12 visits, 
subjects will be asked to bring in all used and unused packages to facilitate collection of 
unused ALN/placebo and assessment of compliance.  The investigational site staff will 
count the number of returned tablets and capture this information on drug accountability 
forms and in the electronic case report form (eCRF). 
The first 2-month supply of ALN/placebo should be dispensed on the day of 
randomization.  If this is not possible, it must be dispensed within 72 hours of 
randomization.  The first dose of ALN/placebo must be taken within one week of study 
Day 1. 
Following the 12-month double-blind ALN-controlled study period, subjects will be 
dispensed a 6-month supply (ie, 7 blister packs with 4 tablets each of open-label ALN) at 
the Month 12 study visit and every 6 months thereafter.  One 70 mg tablet will be taken 
orally once a week and will be self-administered by the subjects.  At the Month 18 study 
visit and every six months thereafter until the end of study, subjects will be asked to 
bring in all used and unused packages to facilitate collection of unused ALN and 
assessment of compliance.  The investigational site staff will count the number of 
returned tablets and capture this information on drug accountability forms and in the 
eCRF.  During the end of primary analysis period phone call and the end of study phone 
 
 
 


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call, subjects will be asked to verbally document their ALN compliance since the last 
study visit. 
Refer to specific instructions provided by the IVRS vendor for additional information on 
box assignment and to the IPIM for additional information regarding storage of IP. 
Unused alendronate at the time of end of study should be returned to the sites 
(Please refer to study IPIM for details). 
ALN is a marketed product.  For further information, including information on treatment 
of overdose, the package insert should be referenced.  
6.2.2 
Dosage Adjustments 
No dosing adjustments for ALN/placebo or ALN will be permitted. 
If a subject misses a scheduled dose of the oral investigational product, the dose should 
be taken as soon as possible as long as it is before the next scheduled dose, and should 
be resumed at the same dose (70 mg once weekly).  Double or extra doses should not 
be taken.   
6.3 
Other Protocol-required Therapies 
All other protocol-required drugs (ie, vitamin D and calcium supplements) that are 
commercially available are not provided by Amgen except under special circumstances 
(eg, if required by local regulation or due to availability issues).  The investigator will be 
responsible for obtaining supplies of these drugs.  Sites will be reimbursed for both 
calcium and vitamin D supplements. 
From screening to end of study, subjects will receive daily calcium and vitamin D 
supplementation that at a minimum should be in the range of 500 to 1,000 mg elemental 
calcium and 600 to 800 IU vitamin D.  In addition, subjects with a serum 
25 (OH) vitamin D level of ≥ 20 ng/mL and ≤ 40 ng/mL at screening will receive an initial 
loading dose of 50,000 to 60,000 IU vitamin D after randomization, preferably by the oral 
route.  Subjects with a serum 25 (OH) vitamin D level of > 40 ng/mL at screening may 
also receive the vitamin D loading dose at the principal investigator’s discretion.  The 
initial vitamin D loading dose is to be administered within 1 week of the study day 1 visit.  
However, if the vitamin D loading dose is missed in this timeframe, it should be given as 
soon as possible thereafter.   
Where available, vitamin D3 preparations should be used; if vitamin D3 is not available, 
use of vitamin D2 preparations is acceptable. 
 
 
 


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If a subject develops hypercalcemia over the course of the study, the principal 
investigator may use his/her medical judgment and reduce the calcium and/or vitamin D 
supplementation to maintain serum calcium concentration within the normal range.   
If a subject develops hypocalcemia over the course of the study, appropriate additional 
supplementation should be instituted as deemed acceptable by local guidelines, to 
maintain serum calcium concentration within the normal range.   
If a subject is unable to tolerate the daily calcium or vitamin D supplementation, the 
formulation may be changed or the dose lowered.  The intolerance as well as the 
resolution (ie, change in formulation or dosage) should be documented in the subject 
chart. 
Additional details regarding calcium and vitamin D supplements are provided in the IPIM. 
6.4 
Concomitant Therapy  
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.5.   
6.5 
Excluded Treatments During Study Period   
Medications listed below will be proscribed during the study, including the use of other 
investigational products and medications known or suspected to affect bone 
metabolism: 
• 
Strontium (including strontium ranelate and over-the-counter strontium preparations) 
• 
Fluoride (for treatment of osteoporosis) 
• 
Vitamin K and vitamin K analogs (for treatment of osteoporosis) 
• 
Activated vitamin D (1,25-di(OH) vitamin D or 1-(OH) vitamin D) 
• 
IV bisphosphonates 
• 
Oral bisphosphonates, except ALN as study medication (cumulative dosing regimens 
of ≤ 1 month are acceptable) 
• 
Denosumab 
• 
Teriparatide or any PTH analogs 
• 
Systemic oral or transdermal estrogen (cumulative dosing regimens of ≤ 1 month are 
acceptable, vaginal preparations and estrogen creams will be allowed at any time) 
• 
SERMs (cumulative dosing regimens of ≤ 1 month are acceptable) 
• 
Calcitonin (cumulative dosing regimens of ≤ 1 month are acceptable) 
• 
Tibolone (cumulative dosing regimens of ≤ 1 month are acceptable) 
• 
Cinacalcet 
 
 
 


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• 
Prolonged (ie, > 3 months) oral glucocorticoid therapy at a prednisone equivalent 
dose of ≥ 5.0 mg/day (tapering glucocorticoid courses of < 1 month duration are 
permitted regardless of dose; inhaled or topical glucocorticoids are permitted) 
• 
Hormonal ablation therapy 
If a subject receives any IV bisphosphonate therapy or oral bisphosphonate therapy 
equivalent to > 1 month of therapy (except ALN as study medication) while being 
on-study, IP (ie, romosozumab/placebo, blinded ALN/placebo, or open-label ALN) must 
be discontinued.  However, every effort should be made to have the subject continue 
participation in the study and complete all scheduled assessments.  
If a subject discontinues IP and begins an approved alternative osteoporosis therapy, 
every effort should be made to have the subject continue participation in the study and 
complete all scheduled assessments (ie, withdrawal of partial consent, see Section 8.1). 
7. 
STUDY PROCEDURES 
7.1 
General Study Procedures  
Study assessments and procedures will be performed only after written informed 
consent is obtained.   
During the primary analysis period, PRO/ClinRO questionnaires should preferably be 
completed before any other study procedure is performed.  During the 12-month 
double-blind ALN-controlled study period, at visits where a nonvertebral or suspected 
clinical vertebral fracture is reported, the postfracture PRO/ClinRO assessments should 
be completed immediately after the nonvertebral fracture or suspected clinical vertebral 
fracture is reported by the subject.  During the 3 subsequent monthly study visits, up to 
the Month 12 study visit, the postfracture PRO/ClinRO assessments should preferably 
be completed before any other study procedure is performed.   
IP administration must be the last procedure after all other study visit procedures have 
been completed.   
Any other procedures that must be performed in a specific order are clearly indicated in 
Section 7.3.   
7.1.1 
Study Visit Definitions 
The screening date is defined as the date the ICF is signed.  The enrollment date is 
defined as the date of randomization.  Randomization must be completed within 35 days 
of the screening date, or if the subject is rescreened per Section 7.2.2 or Section 7.2.3, 
within 35 days of the rescreening date.  
 
 
 


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Day 1 is defined as the day the first dose of romosozumab/placebo is administered.  All 
on-study (post Day 1) visits are to be calculated from the Day 1 visit.  If a subject’s visit 
is delayed, their subsequent visit date is not to be shifted, and is always to be calculated 
from the Day 1 visit.  Month is defined as a calendar month.  
7.1.2 
Study Windows 
Study visit windows differ based on the type of visit and are clearly identified in the 
description of study visits in Section 7.3.  All monthly study visits during the 12-month 
double-blind ALN-controlled study period have a ± 7-day window (see Section 6.1.2 for 
romosozumab/placebo dosing window).  Following the 12-month double-blind 
ALN-controlled study period, study visits have a ± 14-day window.  The window for the 
monthly phone contact in between clinic visits throughout the study is ± 7 days. The 
window for the end of primary analysis period phone call is −14 days to end of 
primary analysis.  Unscheduled follow-up clinic visits after the monthly phone contact 
have a + 21-day window.  The window for the end of study phone contact is −14 days to 
+ 7 days. 
Study procedures for a specific visit may be completed on multiple days as long as all 
the procedures are completed within the visit window.   
7.2 
Screening and Rescreening 
7.2.1 
Screening 
The screening period begins on the date that the ICF is signed.  Screening procedures 
may be performed on multiple days but must be completed within a 35-day screening 
window.  From start of screening through randomization, all subjects are required to take 
daily calcium and vitamin D supplementation that at a minimum should be in the range of 
500 to 1,000 mg elemental calcium and 600 to 800 IU vitamin D.  The screening 
procedures are: 
• 
Informed consent 
• 
Medical and medication history (including clinical fracture history, and bone-specific 
medications) 
• 
Assessment of and instructions for daily calcium and vitamin D supplementation 
• 
Physical examination  
• 
Vital signs: blood pressure, temperature, and pulse 
• 
Height and weight 
• 
Blood samples for serum chemistry, hematology, and 25 (OH) vitamin D 
 
 
 


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• 
Blood sample for serum protein electrophoresis to assess possible diagnosis of 
multiple myeloma or related lymphoproliferative disorder, performed by the local 
laboratory (electrophoresis results within 6 months prior to signing consent will be 
acceptable) 
• 
Lateral spine x-rays (lumbar and thoracic), submitted to the central imaging vendor 
as soon as possible following the visit 
Note: To have vertebrae previously treated with vertebroplasty or kyphoplasty included in the 
eligibility assessment, lateral spine x-rays obtained prior to the procedure must be submitted 
to the central imaging vendor.  The central imaging vendor will use these x-rays to document 
the presence and severity of the vertebral fracture before vertebroplasty or kyphoplasty.  In 
addition, current lateral spine x-rays, taken after the vertebroplasty or kyphoplasty procedure, 
must be obtained, either during the screening period or within 35 days prior to the beginning 
of the screening period as outlined below. 
• 
DXA scan of the proximal femur, submitted to the central imaging vendor as soon as 
possible following the visit 
Note: To facilitate subject scheduling, the Day 1/baseline lumbar spine DXA scan may be 
taken with the proximal femur DXA scan performed during screening. 
Note: For screening and Day 1 purposes, lateral spine x-rays and DXA scans of the lumbar 
spine and proximal femur taken up to 35 days prior to the beginning of the screening period 
may be used if all of the following criteria are met: 
a. Images were obtained as part of the routine standard of care, for the purposes of another 
clinical research study following appropriate informed consent procedures, or as part of 
community outreach efforts 
b. Images were obtained by a trained technician, using the parameters specified by the 
central imaging vendor for this study (refer to the appropriate imaging manuals provided 
by the central imaging vendor) 
c. DXA images were obtained using the same DXA scanner that will be used for this study 
• 
Serious adverse event reporting 
During the screening period, serum calcium levels may be retested once in case of an 
elevated serum calcium level within 1.1x ULN as assessed by the central laboratory 
(refer to exclusion criterion 4.2.13).  To enroll subjects after retesting of serum calcium 
levels, an eligible serum calcium level must be confirmed by the central laboratory, and 
the subject must be randomized within the 35-day screening window. 
7.2.2 
Partial Rescreening for low Vitamin D 
Partial rescreening will be allowed only for subjects who fail to meet the serum 
25 (OH) vitamin D criterion.  Subjects who fail for any other reason may enter full 
rescreening as defined in Section 7.2.3.   
Informed consent obtained at the beginning of the screening period also covers the 
partial rescreening for low vitamin D; therefore reconsenting is not required.  
 
 
 


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Subjects with a serum 25 (OH) vitamin D level < 20 ng/mL may be rescreened according 
to the following procedure: 
• 
Subject will be logged as a screen failure into the IVRS and immediately entered as 
a rescreen.  Subjects not entered into IVRS as a rescreen will not be eligible for 
randomization. 
• 
The 35-day rescreening period will commence at this time. 
• 
Subject must be repleted for vitamin D, as confirmed by a serum 25 (OH) vitamin D 
level ≥ 20 ng/mL assessed by the central laboratory. 
• 
Subject must be randomized within the new 35-day screening window.   
• 
Subject may enter partial rescreening for low vitamin D only once after screening 
(Section 7.2.1) and only once after full rescreening (Section 7.2.3, if applicable). 
During partial rescreening for low vitamin D, blood samples for assessment of serum 
25 (OH) vitamin D may be sent to the central laboratory more than once.  To enroll 
subjects after partial rescreening for low vitamin D, an eligible vitamin D level must be 
confirmed by the central laboratory, and the subject must be randomized within the 
35-day rescreening window. 
Initial screening assessments performed during the screening period (eg, lateral spine 
x-rays, DXA scans, or physical examination) may be used for subjects who have been 
rescreened for low vitamin D, and those assessments do not need to be repeated.  
However, any lateral spine x-rays obtained prior to the beginning of the screening period 
(see Section 7.2.1) must be repeated and submitted to the central imaging vendor as 
soon as possible after rescreening commences. 
7.2.3 
Full Rescreening 
Full rescreening will be allowed for any subject who has previously failed screening if in 
the opinion of the investigator the reason for the initial screen failure has been resolved 
or is not applicable anymore.  The 35-day rescreening period begins on the date that the 
ICF is signed.  Full rescreening will be performed according to the following procedure: 
• 
Subject informed consent must be obtained. 
• 
Subject will be entered into the IVRS as a full rescreen with the same subject 
identification number as assigned during the initial screening.  Subjects not entered 
into IVRS as a full rescreen will not be eligible for randomization. 
• 
Subject may only be entered into full rescreening once. 
 
 
 


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• 
During full rescreening, all screening procedures have to be performed as defined in 
Section 7.2.1. 
• 
Subjects who fail to meet the serum 25 (OH) vitamin D criterion during the full 
rescreening may still enter the partial rescreening for low vitamin D as defined in 
Section 7.2.2. 
7.3 
Study Visits 
7.3.1 
Study Day 1/Baseline 
• 
PRO/ClinRO questionnaires: OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain (should 
preferably be completed before any other study procedures are performed) 
For all subjects 
• 
Blood sample for serum chemistry, hematology, and anti-romosozumab antibody 
• 
DXA scans of lumbar spine, submitted to the central imaging vendor as soon as 
possible following the visit 
Note: DXA scans of the lumbar spine may also be obtained during the screening period prior to 
Day 1 to facilitate subject scheduling. 
• 
Adverse event and concomitant medications data collection 
• 
If applicable, vitamin D loading dose of 50,000 to 60,000 IU, preferably by the oral 
route.  The initial vitamin D loading dose is to be administered within 1 week of the 
study day 1 visit.  However, if the vitamin D loading dose is missed in this timeframe, 
it should be given as soon as possible thereafter.   
• 
Oral IP (ALN/placebo) dispensation (blinded, 2-month supply) 
• 
IP (romosozumab/placebo) injection (must be the last procedure)   
Note: If the vitamin D loading dose is given by SC injection, vitamin D and IP should not be 
administered in the same anatomical location. 
• 
Blood sample for romosozumab levels 
For subjects participating in the Imaging and PK/BTM/Biomarker sub-study 
• 
Fasting blood sample for P1NP, sCTX, BSAP, and OC 
• 
Blood sample for sclerostin and iPTH 
• 
Blood sample (serum and plasma) for novel biomarker development 
• 
For subjects also participating in the imaging components: QCT of the spine, 
submitted to the central imaging vendor as soon as possible following the visit 
7.3.2 
Month 1 (± 7 Days) 
• 
Vital signs: blood pressure, temperature, and pulse 
For all subjects 
• 
Blood sample for serum chemistry, hematology, and anti-romosozumab antibody 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
• 
Adverse event and concomitant medications data collection 
• 
IP (romosozumab/placebo) injection (must be the last procedure) 
 
 
 


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For subjects who have reported nonvertebral or suspected clinical vertebral fractures at 
this study visit
7.12
  
(PRO/ClinRO questionnaires should preferably be completed before any other study 
procedures are performed or immediately after a fracture is reported; refer to 
Section 
) 
• 
Postfracture PRO/ClinRO assessments: OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain 
• 
Blood sample for romosozumab levels 
For subjects participating in the Imaging and PK/BTM/Biomarker sub-study 
• 
Fasting blood sample for P1NP, sCTX, BSAP, and OC 
• 
Blood sample for sclerostin and iPTH 
• 
Blood sample (serum and plasma) for novel biomarker development 
7.3.3 
Month 2 (± 7 Days) 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
For all subjects 
• 
Adverse event and concomitant medications data collection 
• 
Oral IP (ALN/placebo) dispensation (blinded, 2-month supply) 
• 
Unused oral IP (ALN/placebo) collection (blinded) 
• 
IP (romosozumab/placebo) injection (must be the last procedure) 
For subjects who have reported nonvertebral or suspected clinical vertebral fractures at 
the Month 1 or Month 2 study visit
7.12
  
(PRO/ClinRO questionnaires should preferably be completed before any other study 
procedures are performed or immediately after a fracture is reported; refer to 
Section 
) 
• 
Postfracture PRO/ClinRO assessments: OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain 
7.3.4 
Month 3 (± 7 Days) 
• 
Blood sample for serum chemistry, hematology, and anti-romosozumab antibody 
For all subjects 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
• 
Adverse event and concomitant medications data collection 
• 
IP (romosozumab/placebo) injection (must be the last procedure) 
 
 
 


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For subjects who have reported nonvertebral or suspected clinical vertebral fractures at 
the Month 1, 2, or 3 study visits
7.12
  
(PRO/ClinRO questionnaires should preferably be completed before any other study 
procedures are performed or immediately after a fracture is reported; refer to 
Section 
) 
• 
Postfracture PRO/ClinRO assessments: OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain 
• 
Blood sample for romosozumab levels 
For subjects participating in the Imaging and PK/BTM/Biomarker sub-study 
• 
Fasting blood sample for P1NP, sCTX, BSAP, and OC 
• 
Blood sample for sclerostin and iPTH 
• 
Blood sample (serum and plasma) for novel biomarker development 
7.3.5 
Month 4 (± 7 Days) 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
For all subjects 
• 
Adverse event and concomitant medications data collection 
• 
Oral IP (ALN/placebo) dispensation (blinded, 2-month supply) 
• 
Unused oral IP (ALN/placebo) collection (blinded) 
• 
IP (romosozumab/placebo) injection (must be the last procedure) 
For subjects who have reported nonvertebral or suspected clinical vertebral fractures at 
the Month 1 to 4 study visits
7.12
  
(PRO/ClinRO questionnaires should preferably be completed before any other study 
procedures are performed or immediately after a fracture is reported; refer to 
Section 
) 
• 
Postfracture PRO/ClinRO assessments: OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain 
7.3.6 
Month 5 (± 7 Days) 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
For all subjects 
• 
Adverse event and concomitant medications data collection 
• 
IP (romosozumab/placebo) injection (must be the last procedure) 
 
 
 


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For subjects who have reported nonvertebral or suspected clinical vertebral fractures at 
the Month 2 to 5 study visits
7.12
  
(PRO/ClinRO questionnaires should preferably be completed before any other study 
procedures are performed or immediately after a fracture is reported; refer to 
Section 
) 
• 
Postfracture PRO/ClinRO assessments: OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain 
7.3.7 
Month 6 (± 7 Days) 
• 
PRO/ClinRO questionnaires: OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain (should 
preferably be completed before any other study procedures are performed) 
For all subjects 
• 
Vital signs: blood pressure, temperature, and pulse 
• 
Height and weight 
• 
Blood sample for serum chemistry, hematology, and anti-romosozumab antibody 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
• 
Adverse event and concomitant medications data collection 
• 
Oral IP (ALN/placebo) dispensation (blinded, 2-month supply) 
• 
Unused oral IP (ALN/placebo) collection (blinded) 
• 
IP (romosozumab/placebo) injection (must be the last procedure) 
• 
Blood sample for romosozumab levels 
For subjects participating in the Imaging and PK/BTM/Biomarker sub-study 
• 
Fasting blood sample for P1NP, sCTX, BSAP, and OC 
• 
Blood sample for sclerostin and iPTH 
• 
Blood sample (serum and plasma) for novel biomarker development 
• 
For subjects also participating in the imaging components:  
• 
QCT of the spine, submitted to the central imaging vendor as soon as possible 
following the visit 
• 
DXA scans of lumbar spine and proximal femur, submitted to the central imaging 
vendor as soon as possible following the visit 
7.3.8 
Month 7 (± 7 Days) 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
For all subjects 
• 
Adverse event and concomitant medications data collection 
• 
IP (romosozumab/placebo) injection (must be the last procedure) 
 
 
 


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For subjects who have reported nonvertebral or suspected clinical vertebral fractures at 
the Month 4 to 7 study visits
7.12
  
(PRO/ClinRO questionnaires should preferably be completed before any other study 
procedures are performed or immediately after a fracture is reported; refer to 
Section 
) 
• 
Postfracture PRO/ClinRO assessments: OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain 
7.3.9 
Month 8 (± 7 Days) 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
For all subjects 
• 
Adverse event and concomitant medications data collection 
• 
Oral IP (ALN/placebo) dispensation (blinded, 2-month supply) 
• 
Unused oral IP (ALN/placebo) collection (blinded) 
• 
IP (romosozumab /placebo) injection (must be the last procedure) 
For subjects who have reported nonvertebral or suspected clinical vertebral fractures at 
the Month 5 to 8 study visits
7.12
  
(PRO/ClinRO questionnaires should preferably be completed before any other study 
procedures are performed or immediately after a fracture is reported; refer to 
Section 
) 
• 
Postfracture PRO/ClinRO assessments: OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain 
7.3.10 
Month 9 (± 7 Days) 
• 
Blood sample for serum chemistry and hematology 
For all subjects 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
• 
Adverse event and concomitant medications data collection 
• 
IP (romosozumab/placebo) injection (must be the last procedure) 
For subjects who have reported nonvertebral or suspected clinical vertebral fractures at 
the Month 6 to 9 study visits
7.12
  
(PRO/ClinRO questionnaires should preferably be completed before any other study 
procedures are performed or immediately after a fracture is reported; refer to 
Section 
) 
• 
Postfracture PRO/ClinRO assessments: OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain 
 
 
 


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• 
Blood sample for romosozumab levels 
For subjects participating in the Imaging and PK/BTM/Biomarker sub-study 
• 
Fasting blood sample for P1NP, sCTX, BSAP, and OC 
• 
Blood sample for sclerostin and iPTH 
• 
Blood sample (serum and plasma) for novel biomarker development 
7.3.11 
Month 10 (± 7 Days) 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
For all subjects 
• 
Adverse event and concomitant medications data collection 
• 
Oral IP (ALN/placebo) dispensation (blinded, 2-month supply) 
• 
Unused oral IP (ALN/placebo) collection (blinded) 
• 
IP (romosozumab/placebo) injection (must be the last procedure) 
For subjects who have reported nonvertebral or suspected clinical vertebral fractures at 
the Month 7 to 10 study visits
7.12
  
(PRO/ClinRO questionnaires should preferably be completed before any other study 
procedures are performed or immediately after a fracture is reported; refer to 
Section 
) 
• 
Postfracture PRO/ClinRO assessments: OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain 
7.3.12 
Month 11 (± 7 Days) 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
For all subjects 
• 
Adverse event and concomitant medications data collection 
• 
IP (romosozumab/placebo) injection (must be the last procedure) 
For subjects who have reported nonvertebral or suspected clinical vertebral fractures at 
the Month 8 to 11 study visits
7.12
  
(PRO/ClinRO questionnaires should preferably be completed before any other study 
procedures are performed or immediately after a fracture is reported; refer to 
Section 
) 
• 
Postfracture PRO/ClinRO assessments: OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain 
 
 
 


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7.3.13 
Month 12 (± 7 Days) / Early Termination for the 12-month 
Double-blind ALN-controlled Study Period 
• 
PRO/ClinRO questionnaires: OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain (should 
preferably be completed before any other study procedures are performed) 
For all subjects 
• 
Physical examination  
• 
Vital signs: blood pressure, temperature, and pulse 
• 
Height and weight 
• 
Blood sample for serum chemistry, hematology, and anti-romosozumab antibody 
• 
Lateral spine x-rays (lumbar and thoracic), submitted to the central imaging vendor 
as soon as possible following the visit 
• 
DXA scans of lumbar spine and proximal femur, submitted to the central imaging 
vendor as soon as possible following the visit 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
• 
Adverse event and concomitant medications data collection 
• 
Unused oral IP (ALN/placebo) collection (blinded) 
• 
ALN dispensation (open-label, 6-month supply) 
• 
Blood sample for romosozumab levels 
For subjects participating in the Imaging and PK/BTM/Biomarker sub-study 
• 
Fasting blood sample for P1NP, sCTX, BSAP, and OC 
• 
Blood sample for sclerostin and iPTH 
• 
Blood sample (serum and plasma) for novel biomarker development 
• 
For subjects also participating in the imaging components: QCT of the spine, 
submitted to the central imaging vendor as soon as possible following the visit 
Note:  If a subject terminates early from the study between the Day 1 and Month 12 visits, the 
Month 12 procedures except open-label ALN dispensation are to be completed at that time.  DXA 
scans and lateral spine x-rays should be performed if at least 6 weeks have elapsed since the 
previous one. 
7.3.14 
Month 15 (± 14 Days) for Sub-study Subjects Only 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
For subjects participating in the Imaging and PK/BTM/Biomarker sub-study 
• 
Adverse event and concomitant medications data collection 
• 
Fasting blood sample for P1NP and sCTX 
• 
Blood sample for sclerostin and iPTH 
• 
Blood sample (serum and plasma) for novel biomarker development 
 
 
 


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7.3.15 
Month 18 (± 14 Days) 
• 
PRO/ClinRO questionnaires: OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain (should 
preferably be completed before any other study procedures are performed) 
For all subjects 
• 
Vital signs: blood pressure, temperature, and pulse 
• 
Height and weight 
• 
Blood sample for serum chemistry and hematology 
• 
Blood sample for anti-romosozumab antibody 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
• 
Adverse event and concomitant medications data collection 
• 
ALN dispensation (open-label, 6-month supply) 
• 
Unused ALN collection (open-label) 
• 
Fasting blood sample for P1NP and sCTX 
For subjects participating in the Imaging and PK/BTM/Biomarker sub-study 
• 
Blood sample for sclerostin and iPTH 
• 
Blood sample (serum and plasma) for novel biomarker development 
• 
For subjects participating in the imaging components: DXA scans of lumbar spine 
and proximal femur, submitted to the central imaging vendor as soon as possible 
following the visit 
7.3.16 
Month 24 (± 14 Days) / Early Termination for Month 12 to Month 24 of 
the Primary Analysis Period 
• 
PRO/ClinRO questionnaires: OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain (should 
preferably be completed before any other study procedures are performed) 
For all subjects 
• 
Physical examination  
• 
Vital signs:  blood pressure, temperature, and pulse 
• 
Height and weight 
• 
Blood sample for serum chemistry, hematology, and anti-romosozumab antibody 
• 
Lateral spine x-rays (lumbar and thoracic), submitted to the central imaging vendor 
as soon as possible following the visit 
• 
DXA scans of lumbar spine and proximal femur, submitted to the central imaging 
vendor as soon as possible following the visit 
• 
Nonvertebral and suspected clinical vertebral fracture reporting 
• 
Adverse event and concomitant medications data collection 
• 
ALN dispensation (open-label, 6-month supply) 
• 
Unused ALN collection (open-label) 
 
 
 


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• 
Fasting blood sample for P1NP and sCTX 
For subjects participating in the Imaging and PK/BTM/Biomarker sub-study 
• 
Blood sample for sclerostin and iPTH 
• 
Blood sample (serum and plasma) for novel biomarker development 
• 
For subjects participating in the imaging components: QCT of the spine, submitted to 
the central imaging vendor as soon as possible following the visit 
Note:  If a subject terminates early from the study between the Month 12 and Month 24 visits, 
Month 24 procedures except ALN dispensation are to be completed at that time.  DXA scans and 
lateral spine x-rays should be performed if at least 6 weeks have elapsed since the previous one. 
7.3.17 
Month 30 (± 14 Days) 
• 
PRO/ClinRO questionnaires: OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain (should 
preferably be completed before any other study procedures are performed) (primary 
analysis period only) 
For all subjects 
• 
Vital signs: blood pressure, temperature, and pulse 
• 
Height and weight 
• 
Blood sample for serum chemistry and hematology (to be processed and sent to the 
central laboratory during the primary analysis period; to be analyzed at local 
laboratories following the primary analysis period, See Section 7.8.1) 
• 
Nonvertebral fracture reporting 
• 
Suspected clinical vertebral fracture reporting (primary analysis period only) 
• 
Adverse event and concomitant medications data collection 
• 
ALN dispensation (open-label, 6-month supply) 
• 
Unused ALN collection (open-label) 
7.3.18 
Month 36 and Subsequent Clinic Visits  (± 14 Days) to End of 
Primary Analysis Period 
For all subjects, at Month 36 and every 6 months thereafter
• 
PRO/ClinRO questionnaires: OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain (should 
preferably be completed before any other study procedures are performed) (primary 
analysis period only) 
 until the end of the primary 
analysis period 
• 
Physical examination  
• 
Vital signs: blood pressure, temperature, and pulse 
• 
Height and weight 
• 
Blood sample for serum chemistry and hematology (to be processed and sent to the 
central laboratory during the primary analysis period) 
• 
Nonvertebral fracture reporting 
 
 
 


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 
Suspected clinical vertebral fracture reporting (primary analysis period only) 
 
Adverse event and concomitant medications data collection 
 
ALN dispensation (open-label, 6-month supply) 
 
Unused ALN collection (open-label) 
For all subjects, at Month 36 and every 12 months thereafter until the end of the 
primary analysis period 
 
Lateral spine x-rays (lumbar and thoracic), submitted to the central imaging vendor 
as soon as possible following the visit (primary analysis period only) 
 
DXA scans of lumbar spine and proximal femur, submitted to the central imaging 
vendor as soon as possible following the visit (primary analysis period only) 
For subjects participating in the Imaging and PK/BTM/Biomarker sub-study, at Month 36 
or until end of the primary analysis period, whichever comes first 
 
Fasting blood sample for P1NP and sCTX 
 
Blood sample for sclerostin and iPTH 
 
Blood sample (serum and plasma) for novel biomarker development 
Note:  If a subject terminates early from the study between the Month 24 and the end of the 
primary analysis period, the Month 36 procedures are to be completed at that time (except ALN 
dispensation).  DXA scans and lateral spine x-rays should be performed if at least 6 weeks have 
elapsed since the previous one.   
7.3.19 
Clinical Visits After the Primary Analysis Period to End of Study 
For all subjects, at every 6-month clinic visit thereafter  
 
Physical examination  
 
Vital signs: blood pressure, temperature, and pulse 
 
Height and weight 
 
Blood sample for serum chemistry and hematology (to be analyzed at local 
laboratories following the primary analysis period, chloride, bicarbonate, and 
calculated adjusted calcium assessments are optional after primary analysis. 
(See Section 7.8.1) 
 
Nonvertebral fracture reporting 
 
Adverse event and concomitant medications data collection 
 
ALN dispensation (open-label, 6-month supply) 
 
Unused ALN collection (open-label) 
 
 
 


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7.3.20 
Monthly Telephone Contacts in Between Clinic Visits (± 7 Days) Until 
end of Study 
• 
Nonvertebral fracture reporting 
For all subjects 
• 
Adverse event and concomitant medications data collection 
When nonvertebral fractures are reported during the monthly telephone contacts, the 
same process as for nonvertebral fracture reporting at clinic visits should be followed.  
No unscheduled follow-up clinic visit or further unscheduled assessments will be 
required.  The event should be recorded on the respective eCRF and copies of 
radiographs or other diagnostic images and/or a copy of the radiology report, surgical 
report, or discharge summary should be obtained, included in the subject’s study records 
and submitted to the central imaging vendor. 
Procedure for reporting of nonvertebral fractures during monthly telephone contacts:   
When back pain is reported during the monthly telephone contacts, the back pain (but 
not a vertebral fracture) will be recorded as an adverse event, and the subject will be 
asked to complete an unscheduled follow-up clinic visit as soon as possible but no later 
than 21 days after reporting of the back pain (refer to Section 7.3.21).   
For the primary analysis period only: Procedure for reporting of an adverse event of back 
pain during monthly telephone contacts:  
Refer to Section 7.11.1 and Section 7.11.2 for general information about nonvertebral 
and suspected clinical vertebral fracture reporting procedures.  
7.3.21 
Unscheduled Follow-up Clinic Visit (+ 21 Days After Monthly Phone 
Contact) (Primary Analysis Period Only) 
• 
Suspected clinical vertebral fracture reporting 
For subjects who have reported back pain as an adverse event during the monthly 
telephone contact: 
• 
Lateral spine x-rays (lumbar and thoracic), submitted to the central imaging vendor 
as soon as possible following the visit 
For subjects for whom the previously reported back pain is considered to be possibly 
due to a new or worsening vertebral fracture: 
 
 
 


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Procedure for reporting of suspected clinical vertebral fractures during the unscheduled 
follow-up clinic visit:  
Unscheduled follow-up clinic visits will only be completed if back pain is reported during 
the monthly phone contact.  The follow-up clinic visit has to be completed as soon as 
possible after the phone call but no later than 21 days after reporting of the back pain. 
At the unscheduled follow-up clinic visit, the investigator will evaluate if the back pain is 
possibly due to a new or worsening vertebral fracture, and the respective eCRF will be 
completed.  If the investigator considers the back pain to be possibly due to a new or 
worsening vertebral fracture, a confirmatory lateral spine x-ray will be taken and 
submitted to the central imaging vendor as soon as possible following the visit. 
7.3.22 
Telephone Contact at “End of Primary Analysis Period” (−14 Days to 
end of Primary Analysis Period)  
For all subjects 
 
Nonvertebral fracture reporting 
 
Adverse event and concomitant medications data collection 
 
ALN compliance reporting (open-label) 
The procedure for reporting of nonvertebral fractures during the end of primary analysis 
period telephone contact is the same as for the monthly telephone contacts (refer to 
Section 7.3.19). 
If back pain is reported during the end of primary analysis period telephone contact, the 
back pain (but not a vertebral fracture) will be recorded as an adverse event.  The 
subject will not be asked to complete an unscheduled follow-up clinic visit. 
Note: If all the data required for an end of primary analysis telephone call has already been 
obtained during the 14 days prior to the end of the primary analysis period, no additional 
end of primary analysis period telephone call will be necessary.  
7.3.23 
End of Study Telephone Contact (−14 to + 7 Days) 
For all subjects   
 
Adverse event and concomitant medications data collection 
 
ALN compliance reporting (open-label) 
Note: The end of study telephone contact will not be necessary for subjects who have had 
a clinic visit or have been contacted during this timeframe if all data required for the end of 
study telephone contact have been collected.  The subjects, however, may be contacted 
after this time for additional safety information, follow-up, or possible follow on study 
opportunities. 
 
 
 


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If a nonvertebral fracture is reported during the end of study telephone contact, the 
fracture will be recorded as an adverse event.  Copies of the radiographs, diagnostic 
images and/or radiology report, surgical report, clinical notes, or discharge summary 
need not be obtained. 
7.4 
Medical History 
The subject’s complete medical history will be obtained prior to enrollment and recorded 
in the eCRF.  History of fractures after the age of 45 will also be obtained, and will 
include date of fracture, anatomical site(s) of fracture(s), and degree of trauma involved.   
Detailed information will also be collected about the history of hearing disorders and 
cancer history. 
7.5 
Medication History 
Information on all medications administered within the month before study Day 1 will be 
recorded in the eCRF.  For all bone-specific medications, information on administration 
during the 5 years prior to screening will be recorded. 
7.6 
Physical Examination 
The physical examination will include height (using a stadiometer, to be measured 
without shoes) and weight.  A pelvic, breast, or rectal examination will not be required for 
the screening or on-study physical examinations unless specific evaluation is deemed 
necessary by the principal investigator.   
7.7 
Vital Signs 
Vital signs will include temperature, blood pressure, and pulse obtained in the sitting 
position after the subject has sat quietly for at least 5 minutes.   
7.8 
Laboratory Assessments  
7.8.1 
General 
All applicable screening and all on-study blood samples during the primary analysis 
period will be processed and sent to the central laboratory.  Depending on the 
assessment, the central laboratory will be responsible for either performing the assays, 
or shipping samples to Amgen or a specialty laboratory for assay.   
The central laboratory will be responsible for all screening and on-study serum 
chemistry, hematology, and serum 25 (OH) vitamin D tests. The central laboratory will 
provide a study manual that outlines handling, labeling, and shipping procedures for all 
serum samples.   
 
 
 


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Blood samples for BTMs, romosozumab levels, and anti-romosozumab antibodies will 
be processed by the central laboratory, sent to an appropriate secondary laboratory or 
sent to Amgen for analysis or further distribution to other laboratories.  
Following the end of primary analysis period, all applicable on-study blood samples will 
be processed and analyzed at a local laboratory.  Local laboratories will use the local 
laboratory’s normal ranges.  Local laboratory results will be monitored by the principal 
investigator and any adverse events supported by local laboratory results should be 
reported as an adverse event (please see Section 9.1.2). 
All blood samples will be obtained by venipuncture before IP administration, when 
applicable, at the time points outlined in the Schedules of Assessments (Appendix A).  
The date and time of blood collection will be recorded in the subject’s medical record.  
Samples for assessment of BTMs must be obtained from subjects in the fasted state as 
indicated in Section 7.8.2.  
Table 1 outlines the specific analytes for the serum chemistry and hematology 
assessments, as well as other assessments to be conducted on blood samples.   
Chloride, bicarbonate, and calculated adjusted calcium assessments are optional 
after primary analysis. 
On-study (ie, after baseline/Day 1) laboratory results for serum calcium, 
albumin-adjusted calcium, phosphorus, and alkaline phosphatase (ALP), will not be 
reported to any study-related personnel in order to maintain the integrity of the study 
blind up until primary analysis.  These laboratory results will not be blinded after 
primary analysis (refer to Section 10.3 for information on access to individual subject 
treatment assignments by Amgen).  However, in the event of an abnormal value of 
clinical relevance (panic value) obtained in the central laboratory during the primary 
analysis period, sites will be notified of the unblinded value by the central laboratory.  In 
addition, laboratory results for romosozumab levels, sclerostin, BTMs (P1NP, BSAP, 
OC, and sCTX), iPTH, and anti-romosozumab antibodies will not be reported to any 
personnel responsible for study-related management (including the sites).  When a panic 
alert is issued for serum calcium, albumin-adjusted calcium levels, phosphorus, or ALP, 
the sites may perform additional follow-up blood draws for local analysis as required to 
support subject medical care. 
 
 
 


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Table 1.  Blood Sample Analyte Listing 
Serum Chemistry 
Hematology 
BTMs 
Other 
Sodium 
RBC 
P1NPa 
Romosozumab levelsa 
Potassium 
Hemoglobin 
sCTXa 
Sclerostina 
Chlorideb 
 
BSAPa 
25 (OH) vitamin D 
Bicarbonateb 
Platelets 
OCa 
iPTHa 
Total Protein 
WBC 
 
Anti-romosozumab antibodya 
Albumin 
• 
Differential 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
Biomarker sample 
Calciuma 
 
Magnesium 
Phosphorusa 
Glucose 
BUN 
Creatinine 
TBL 
ALPa 
ALT (SGPT) 
AST (SGOT) 
Albumin-adjusted 
Calciuma,b 
ALP = alkaline phosphatase; ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic 
transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
BSAP = bone specific alkaline phosphatase; BTM = bone turnover marker; BUN = blood urea nitrogen; 
iPTH = intact parathyroid hormone; OC = osteocalcin; P1NP = procollagen type 1 N-telopeptide;  
RBC = red blood cell; sCTX = serum type-1 collagen C-telopeptide; TBL = total bilirubin;  
WBC = white blood cell 
a Until the end of the primary analysis period, results of post Day 1 assessments will be blinded to any 
study-related personnel (including the sites) except for serum calcium, albumin-adjusted calcium, 
phosphorus or alkaline phosphatase in the event of a panic value.   
b.Chloride, bicarbonate, and calculated adjusted calcium assessments are optional after primary 
analysis. 
Any blood or tissue samples collected according to the Schedule of Assessments 
(Appendix A may be analyzed for any of the tests outlined in the protocol and for any 
tests necessary to ensure subject safety.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This may 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 
If informed consent is provided by the subject, Amgen may do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
bone metabolic diseases, the dose response and/or prediction of response to 
 
 
 


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romosozumab or other protocol-specified therapy, as required, characterize antibody 
response, and characterize aspects of the molecule (eg, metabolites).  Results from this 
analysis will be documented and maintained, but may not be reported as part of this 
study.   
Additional subjects will be invited to participate in the blood only portion of the sub-study 
at the time of enrollment and in the case of insufficient enrollment, additional blood only 
sub-study sites will be initiated and subjects already on trial will be invited to participate 
with consent for blood collected earlier in the study to be used for sub-study analyses. 
7.8.2 
Bone Turnover Markers 
Subjects participating in the Imaging and PK/BTM/Biomarker sub-study will have blood 
drawn at visits specified in Section 7.3 and the Schedule of Assessments (Appendix A) 
for analysis of BTMs (P1NP, sCTX, BSAP, and OC).    
Blood draws for BTMs must be obtained from subjects in fasting stage and before noon.  
Fasting stage is defined as overnight fasting.  If overnight fasting is not feasible, at a 
minimum 8 hours fasting is required. 
Results from BTM assessments are considered potentially unblinding and will not be 
reported to study-related personnel post Day 1/baseline. 
7.8.3 
Romosozumab Levels and Sclerostin 
Subjects participating in the Imaging and PK/BTM/Biomarker sub-study will have blood 
drawn at visits specified in Section 7.3 and in the Schedule of Assessments 
(Appendix A) for analysis of romosozumab and sclerostin levels.   
Results from romosozumab and sclerostin assays are considered potentially unblinding 
and will not be reported to study-related personnel post Day 1/baseline. 
7.8.4 
Antibody Testing Procedures 
Blood samples will be collected from all subjects for anti-romosozumab antibody testing 
procedures; however only samples from subjects exposed to romosozumab will be 
analyzed to test for anti-romosozumab binding antibodies.  Samples testing positive for 
binding antibodies will also be tested for neutralizing antibodies and may be further 
characterized for quantity/titer, isotype, affinity, and presence of immune complexes.  
Additional blood samples may be obtained to rule out anti-romosozumab antibodies 
during the study.   
 
 
 


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Subjects who test positive for neutralizing antibodies to romosozumab at the ET visit will 
be asked to return for additional follow-up testing.  This testing should occur 
approximately every 3 months starting from when the site has been notified of the 
positive result, until:  (1) neutralizing antibodies are no longer detectable or (2) the 
subject has been followed for a period of at least 1 year (± 4 weeks) after the last dose 
of romosozumab.  More frequent testing (eg, every month) or testing for a longer period 
of time may be requested in the event of safety-related concerns.  Follow-up testing will 
not be required where it is established that the subject did not receive romosozumab. 
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-romosozumab antibody 
response may also be asked to return for additional follow-up testing. 
Sites will only be contacted if additional follow-up testing is needed after an ET visit.  No 
notifications will be sent before an ET visit or for subjects testing negative for antibodies 
to romosozumab. 
7.9 
Adverse Event Data Collection and Adjudication 
Any adverse events occurring after the first dose of IP will be recorded in the subjects’ 
records and on the appropriate eCRFs.  Recording of serious adverse events begins 
after signing of the informed consent form.  Refer to Section 9.1 and Section 9.2 for 
more details.   
Additional information will be collected for certain adverse events of interest. 
The following events will be adjudicated by independent adjudication committees: 
Potential Osteonecrosis of the Jaw (ONJ) Events 
Cases of ONJ have been reported in association with anti-resorptive use.  ONJ may be 
associated with pain and/or infection of the jaw bone, teeth or gums resulting in a 
non-healing area of exposed bone in the mouth.  How this happens is poorly 
understood.  One hypothesized mechanism involves interference with bone remodeling 
as a result of decreased osteoclast activity.  In this study all events reported as ONJ, or 
those coded to pre-specified terms potentially indicative of ONJ, will be reviewed by an 
independent adjudication committee. 
Potential Atypical Femoral Fracture Events 
Cases of atypical femoral fracture have been reported in patients with osteoporosis in 
association with anti-resorptive use.  Some case series have reported a possible 
 
 
 


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association between atypical femoral fracture and long-term alendronate therapy 
(Odvina et al, 2010; Lenart et al, 2008; Odvina et al, 2005), while others have not 
(Abrahamsen et al, 2009).  All events reported as atypical femoral fractures, or those 
events relating to pre-specified events potentially indicative of atypical femoral fractures, 
will be reviewed by an independent adjudication committee. 
Potential Cardiovascular Events 
In order to carefully evaluate cardiovascular events during the trials, all deaths, and 
serious adverse events that are deemed by the investigator to be of potential 
cardiovascular origin or etiology, will be submitted to an independent committee for 
adjudication.  Serious adverse events with terms mapping to a pre-defined preferred 
term list potentially indicative of cardiovascular etiology will also be adjudicated. 
7.10 
Concomitant Medication Data Collection 
All concomitant medications, including over-the-counter products, administered while the 
subject is enrolled in the study must be recorded on the eCRF, listing generic name or 
trade name, indication, quantity administered, and date(s) of administration.   
7.11 
Clinical Fracture Recording 
7.11.1 
Suspected Clinical Vertebral Fractures (Primary Analysis Period) 
Information on suspected clinical vertebral fractures will be recorded until clinical fracture 
events (nonvertebral fracture or clinical vertebral fracture) have been confirmed for at 
least 330 subjects AND all subjects have had the opportunity to complete the Month 24 
study visit.  If, during the primary analysis period, a subject reports back pain that is 
considered by the investigator to be possibly due to a new or worsening vertebral 
fracture, a confirmatory lateral spine x-ray will be taken and the back pain (but not a 
vertebral fracture) will be recorded as an adverse event.  The lateral spine x-rays as well 
as copies of other diagnostic images (computerized tomography or magnetic resonance 
imaging) and/or radiology report, surgical report, or discharge summary will be submitted 
to the central imaging vendor for confirmation of fracture (refer to Section 7.14).  To 
confirm a clinical vertebral fracture, at least one new or one worsening (ie, change by at 
least 1 SQ grade) vertebral fracture have to be identified by the central imaging vendor 
on lateral spine x-rays.  The central imaging vendor will inform the sites of any new or 
worsening vertebral fractures; however x-rays taken upon reporting of back pain may 
also be read locally if necessary to support subject medical care.  Only clinical vertebral 
fractures confirmed by the central imaging vendor will be included for the statistical 
analysis.   
 
 
 


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Postfracture PRO/ClinRO assessments will be triggered by the investigator’s decision to 
order the confirmatory lateral spine x-ray (refer to Section 7.12) after reporting of a 
suspected clinical vertebral fracture.  However, only responses corresponding to clinical 
vertebral fractures confirmed by the central imaging vendor will be included for the 
statistical analysis. 
7.11.2 
Nonvertebral Fractures 
Information about any nonvertebral fractures and level of trauma causing the fracture 
while on study will be recorded.  A copy of radiographs or other diagnostic images such 
as computerized tomography or magnetic resonance imaging confirming the fracture, 
and/or a copy of the radiology report, surgical report, or discharge summary should be 
obtained and included in the subject’s study records.  Copies of the radiographs, 
diagnostic images and/or radiology report, surgical report, clinical notes, or discharge 
summary will be submitted to the central imaging vendor for confirmation of fracture.  If 
the radiograph or diagnostic image is not available, then, at minimum, a copy of the 
radiology report, surgical report, clinical notes, or discharge summary should be 
submitted to the central imaging vendor.  Additional information about nonvertebral 
fractures will be entered into the eCRF, eg, details regarding the type of fracture and 
other pertinent data.   
Postfracture PRO/ClinRO assessments will be triggered by the reporting of nonvertebral 
fractures (refer to Section 7.12), except for fractures of the skull, face, fingers, and toes, 
which are typically not associated with osteoporosis and do not require postfracture 
PRO/ClinRO assessments.  However, only responses corresponding to nonvertebral 
fractures confirmed by the central imaging vendor will be included for the statistical 
analysis. 
7.12 
Patient Reported and Clinician Reported Outcomes 
PRO and ClinRO assessments are to be completed before any other study procedures 
are performed.  All subjects will complete the OPAQ SV, EQ-5D-5L, LAD, and BPI worst 
pain questionnaires every 6 months during the primary analysis period (refer to the 
Schedule of Assessments, Appendix A).  Subjects who have reported a nonvertebral or 
a suspected clinical vertebral fracture during the 12-month double-blind ALN-controlled 
study period (ie, up to the Month 12 study visit) will start postfracture PRO/ClinRO 
assessments.  These subjects will be asked to complete the OPAQ SV, EQ-5D-5L, LAD, 
and BPI worst pain questionnaires.  Postfracture PRO/ClinRO assessments will be 
performed at the visit during which the nonvertebral fracture or suspected clinical 
 
 
 


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vertebral fracture has been reported and at the 3 consecutive monthly study visits.  
Subsequent nonvertebral or suspected clinical vertebral fractures will trigger a new cycle 
of postfracture PRO/ClinRO assessments.  Postfracture PRO/ClinRO assessments will 
only be performed up to the Month 12 study visit; data collection is not required beyond 
Month 12 even if the fracture has been reported at the Month 10, Month 11, or Month 12 
study visits.   
7.12.1 
OPAQ SV 
The OPAQ SV evaluates the impact of vertebral and nonvertebral fractures on physical 
function, emotional status and back pain.  Support for the reliability and validity of the 
OPAQ SV has been reported in published literature (Silverman, 2000). 
7.12.2 
EQ-5D-5L 
The EQ-5D-5L, developed in 1990, is a widely used generic patient reported 
health-related quality of life instrument that allows for estimation of utility (Brooks, 1996).  
The EQ-5D-5L is comprised of 2 components: a health state index and a general health 
visual analog scale.  The EQ-5D-5L health state index is comprised of 5 questions which 
address the following dimensions: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression.  The responses will be reported as one of five levels of severity 
(no problems/slight problems/moderate problems/severe problems/extreme problems) 
within a particular EQ-5D dimension. 
7.12.3 
Limited Activity day Survey   
The LAD is a modification of the Back Pain and LAD questionnaire.  The LAD captures 
subjects' limited activity, hospitalization, and bed rest experience (yes/no), and the 
number of days of limited activity, hospitalization, and bed rest due to health-related 
reasons (eg, back pain, fracture) over the last 30 days.   
The LAD will be administered as a ClinRO questionnaire. 
7.12.4 
BPI Worst Pain 
The BPI short form is a validated, widely used questionnaire developed to assess the 
severity of pain and the impact of pain on daily functions (Mendoza et al, 2006).  Data in 
several disease areas, including osteoarthritis, indicate that the modified BPI short form, 
much like the original scale, was internally reliable, consistent over time, and had good 
construct, as well as convergent and predictive validity in assessment of patients 
suffering from conditions of chronic pain.  The modified BPI short form, like the parent 
scale, is a valid and reliable tool for situations in which pain is assessed daily and 
 
 
 


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minimizes the burden placed on patients to record information necessary for scientific 
investigations. 
To minimize burden for respondents, only one item extracted from the BPI-short form will 
be used to assess the worst fracture-related pain over the last 24 hours.  This item will 
be referred to as “BPI worst pain”.  Pain and the limitations due to pain related to day to 
day osteoporosis will be captured by the OPAQ SV and EQ-5D-5L. 
7.13 
Dual-energy X-ray Absorptiometry 
Bone density measurements will be performed by DXA.  Only Lunar or Hologic bone 
densitometers will be allowed for the study.  The same DXA machine must be used for 
all study procedures for a particular subject for the duration of the study.  All DXA scans 
will be submitted to and analyzed by the central imaging vendor.  A separate procedure 
manual provided by the central imaging vendor will give specific instructions for 
acquisition of scans as well as performance of Instrument Quality Control.   
For all subjects, bone density will be measured at the lumbar spine and the proximal 
femur.  Lumbar spine scans must include L1 through L4.  Detailed instructions for scan 
acquisition can be found in the separate manual provided by the central imaging vendor. 
For proximal femur, the left side should be used for all scans at all study visits.  If the 
right side must be used (eg, due to implants) or is inadvertently used at baseline, then it 
must be used consistently throughout the study.  If a subject fractures the hip that has 
been scanned during the study up to the time of fracture, no further scans will be 
obtained.   
7.13.1 
Screening BMD Assessment 
To determine eligibility based on BMD T-score, proximal femur DXA scans will be 
analyzed by the central imaging vendor.  To facilitate subject scheduling, the 
Day 1/baseline lumbar spine DXA scan may be taken with the proximal femur DXA scan 
performed during screening. 
Data from the screening DXA scans will be electronically transferred to the central 
imaging vendor as soon as possible following acquisition.  Sites unable to submit data 
electronically can submit on CD or other media as specified in the DXA Procedural 
Manual, but electronic submission is preferred.   
7.13.2 
On-study BMD Assessments 
In order to maintain the blind, all DXA scans performed after the baseline assessment 
must not be analyzed by site staff.  All DXA scan data will be submitted electronically to 
 
 
 


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the central imaging vendor for analysis.  Sites unable to submit data electronically can 
submit on CD or other media as specified in the DXA Procedural Manual, but electronic 
submission is preferred.   
The results from the central imaging vendor will be used as the final data for statistical 
analysis.   
After analysis by the central imaging vendor, the study site may be asked to re-acquire a 
scan due to malpositioning or other technical reasons.  The investigative sites must 
comply with the requests from the central imaging vendor.  Repeat scans must be 
performed as soon as possible after the request is received.   
DXA BMD data are considered potentially unblinding and will not be reported to 
study-related personnel (including sites) post Day 1/baseline. 
7.13.3 
Monitoring of BMD Decreases 
BMD changes for individual subjects will be monitored by the central imaging vendor 
during the primary analysis period.  Investigators will be alerted if a subject experiences 
a BMD loss from baseline of 7% or more at the total hip and/or at the lumbar spine at 
any time during the study. 
7.14 
Lateral Spine X-ray Assessments 
X-rays of the lateral thoracic and lumbar spine will be acquired according to specific 
instructions provided by the central imaging vendor per the schedule outlined in 
Appendix A.   
For assessment of prevalent vertebral fractures at screening/baseline, which will be 
performed by a radiologist at the central imaging center, a visual semiquantitative 
grading scale will be used (Genant et al, 1993):  
• 
SQ grade 0 (SQ0) = no fracture 
• 
SQ grade 1 (SQ1) = mild fracture, 20 to 25% reduction in vertebral height (anterior, 
middle, or posterior) 
• 
SQ grade 2 (SQ2) = moderate fracture, 25 to 40% reduction in height 
• 
SQ grade 3 (SQ3) = severe fracture, greater than 40% reduction in height  
For assessment of incident vertebral fracture, x-rays will be scored blinded to treatment 
but not to sequence.  The semiquantitative grading scale will be used.  New vertebral 
fractures are defined as fractures in previously undeformed vertebrae.  Worsening of 
pre-existing vertebral fractures will also be assessed.  Worsening is defined as an 
 
 
 


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increase of at least 1 grade on the semiquantitative scale.  Investigators will be alerted 
by the central imaging vendor when a new or worsening vertebral fracture is identified. 
If a subject presents with acute back pain likely related to a new vertebral fracture at a 
time point other than when a scheduled lateral spine x-ray is obtained during the primary 
analysis period, and occurrence of a vertebral fracture is suspected, unscheduled lateral 
spinal x-rays will be obtained for submission to the central imaging facility for evaluation 
(refer to Section 7.11.1).  The central imaging vendor will inform the sites if a new or 
worsening vertebral fracture is identified; however these x-rays may also be read locally 
if necessary to support the subject’s medical care.  Only fractures confirmed by the 
central imaging vendor will be included for the analyses.  
7.15 
Quantitative Computed Tomography (QCT) 
A subset of the subjects participating in the Imaging and PK/BTM/Biomarker sub-study 
will undergo QCT scans of the spine at visits specified in Section 7.3 and the Schedule 
of Assessments (Appendix A).   
The same QCT scanner must be used for all scans for a particular subject.  All QCT 
scans will be collected by a trained technician and submitted to the central imaging 
vendor for analysis.  QCT data are considered potentially unblinding and will not be 
reported to study-related personnel (including sites) post Day 1/baseline.  Detailed 
instructions for scan acquisition are provided in a separate manual by the central 
imaging vendor.   
7.16 
Biomarker Development  
7.16.1 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  Biomarker development may be useful in developing markers to identify 
disease subtypes, guide therapy, and/or predict disease severity.   
Amgen may attempt to develop blood tests designed to identify subjects most likely to 
respond positively or negatively to romosozumab.  Biomarker development may be 
pursued by use of advanced biochemical analyses, such as proteomic methods or 
ribonucleic acid transcript profiling. 
If informed consent is provided by the subject, blood samples will be collected for 
biomarker development at the time points specified in the Schedule of Assessments 
(Appendix A).   
 
 
 


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Refer to the laboratory manual for detailed collection and handling procedures for 
biomarker development samples. 
7.16.2 
Sample Storage and Destruction  
Biomarker development blood samples and any other components from the cells, as well 
as any other unused samples may be stored for up to 20 years from the end of the study 
to research scientific questions related to osteoporosis in postmenopausal women 
and/or romosozumab.  The subject retains the right to request that the sample material 
be destroyed at any time by contacting the principal investigator.  The sponsor will be 
the exclusive owner of any data, discoveries, or derivative materials from the sample 
materials and is responsible for the destruction of the sample(s) at the request of the 
subject through the principal investigator or at the end of the storage period or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  Following the request from the subject, the 
principal investigator will provide the sponsor with the required study and subject 
numbers so that any remaining blood samples and any other components from the cells 
can be located and destroyed.  If a commercial product is developed from this research 
project, the sponsor will own the commercial product.  The subject will have no 
commercial rights to such product and will have no commercial rights to the data, 
information, discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
8. 
REMOVAL AND REPLACEMENT OF SUBJECTS 
8.1 
Removal of Subjects 
Subjects have the right to withdraw fully or partially from the study at any time and for 
any reason without prejudice to his or her future medical care by the physician or at the 
institution. 
Withdrawal of full consent for a study means that the subject does not wish to receive 
further investigational treatment and does not wish to or is unable to continue further 
study participation; subject data and samples obtained up to withdrawal of consent will 
be included in the analysis of the study.  Any subject may withdraw full consent to 
participate in the study at any time during the study.  The investigator will discuss with 
the subject appropriate procedures for withdrawal from the study.   
Withdrawal of partial consent for a study means that the subject does not wish to take 
investigational product(s) or other protocol-required therapies any longer but is still 
willing to collaborate in providing further data by continuing on study (eg, participate in all 
 
 
 


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subsequent study visits or procedures).  Subjects may decline to continue receiving 
investigational product(s) or other protocol-required therapies at any time during the 
study.  If this occurs, the investigator will discuss with the subject appropriate procedures 
for withdrawal from investigational product(s) or other protocol-required therapies.  
These subjects, as well as those who have stopped receiving investigational product(s) 
or other protocol-required therapies for other reasons (eg, investigator or sponsor 
concern) should continue the schedule of study observations.   
Should a subject (or a legally acceptable representative) request or decide to withdraw 
from the study, all efforts will be made to complete and report the observations as 
thoroughly as possible up to the date of withdrawal.  All information should be reported 
on the applicable eCRFs.   
Reasons for removal from protocol required products or observation might include: 
• 
partial withdrawal of consent 
• 
withdrawal of full consent 
• 
administrative decision by the investigator or Amgen 
• 
pregnancy in a female subject (report on Pregnancy Notification Worksheet; see 
Appendix C).  
• 
ineligibility 
• 
significant protocol deviation 
• 
subject noncompliance 
• 
adverse event 
• 
disease progression 
• 
other safety concern by the investigator or Amgen  
• 
death 
• 
lost to follow-up 
If a subject experiences BMD reduction of ≥ 7% from baseline at the total hip and/or 
lumbar spine at any time during the primary analysis period, the investigator is required 
to discuss implications for individual fracture risk, alternative treatment options and 
options for continuing in the study with the subject, and to document that discussion.  If a 
decision is made to begin alternative treatment, IP must be discontinued and every effort 
should be made to complete all remaining study visits, regardless of any alternative 
treatment chosen by the subject. 
8.2 
Replacement of Subjects 
Subjects will not be replaced on this study. 
 
 
 


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9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates the pre-existing medical condition (eg, diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration, and/or has an 
association with a significantly worse outcome.  A pre-existing condition that has not 
worsened during the study, and involves an intervention such as elective cosmetic 
surgery or a medical procedure while on study is not considered an adverse event.     
9.1.2 
Reporting Procedures for Adverse Events 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of IP through the 
end of study are reported using the applicable eCRF (eg, Adverse Event Summary 
eCRF).  For subjects who discontinue the study early, adverse events will be reported 
through 30 days after the last dose of IP. 
The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution, 
• 
Severity (and/or toxicity per protocol), 
• 
Assessment of relatedness to IP, and 
• 
Action taken. 
The adverse event toxicity grading scale used will be the Common Terminology Criteria 
for Adverse Events (CTCAE) version 3.0.  The toxicity grading scale used in this study is 
described in Appendix B. 
The investigator must assess whether the adverse event is possibly related to the IP 
and/or other study drugs.  This relationship is indicated by a “yes” or “no” response to 
the question:  Is there a reasonable possibility that the event may have been caused by 
the IP and/or other study drugs?   
 
 
 


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The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated screening procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may be 
related to screening procedures?” 
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity or procedure.  This relationship is indicated by a “yes” or “no” 
response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”? 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) should not be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) should be recorded as the adverse 
event. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility. 
The investigator’s clinical judgment will be used to determine whether a subject should 
be removed from treatment or from the study due to an adverse event.  A subject, or 
subject’s parent/legal guardian, may also voluntarily withdraw from treatment due to an 
adverse event.  If the subject withdraws full consent, the subject should be encouraged 
to undergo, at a minimum, an end-of-study assessment.   
9.2 
Serious Adverse Events 
9.2.1 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
 
 
 


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An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix B for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
9.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after the last dose of IP are recorded in the subject’s medical 
record and are submitted to Amgen.  For subjects who discontinue the study early, 
serious adverse events will be reported through 30 days after the last dose of IP.  The 
serious adverse event must be submitted to Amgen within 24 hours following the 
investigator’s knowledge of the event.  If the electronic data capture (EDC) system is 
unavailable to the site staff to report the Serious Adverse Event, the information is to be 
reported to Amgen via an electronic Serious Adverse Event (eSAE) Contingency Report 
Form within 24 hours of the investigator’s knowledge of the event.  See Appendix D for a 
sample of the Serious Adverse Event Worksheet/eSAE Contingency Report Form.  
Where the first notification of a Serious Adverse Event is reported to Amgen via the 
eSAE Contingency Report Form, the data must be entered into the EDC system when 
the system is again available. 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
In addition to the attributes listed in Section 9.1.2, the investigator must also complete 
the SAE section of the Adverse Event Summary CRF. 
After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events.  However, if the 
investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event to Amgen within 24 hours following 
the investigator’s knowledge of the event.  SAEs reported outside of the 
 
 
 


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protocol-required reporting period will be captured within the safety database as clinical 
trial cases for the purposes of expedited reporting.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following the investigator’s knowledge of the new information.  
The investigator may be asked to provide additional follow-up information, which may 
include a discharge summary or extracts from the medical record.  Information provided 
about the serious adverse event must be consistent with that recorded on the applicable 
eCRF (eg, Adverse Event Summary eCRF). 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/ECs in 
compliance with all reporting requirements according to local regulations and good 
clinical practice (GCP).  
The investigator is to notify the appropriate IRB/EC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes.   
9.3 
Pregnancy Reporting 
If a pregnancy occurs in a subject while the subject is taking protocol-specified product 
and for 3 months after end of treatment with romosozumab (ie, 3 months after the 
Month 11 visit) the pregnancy should be reported to Amgen’s global Pregnancy 
Surveillance Program.   
Report pregnancy on the Pregnancy Notification Worksheet (Appendix C). 
 
 
 


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10. 
STATISTICAL CONSIDERATIONS   
10.1 
Study Endpoints, Subsets, and Covariates 
10.1.1 
Primary Endpoints 
During the primary analysis period 
• 
Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral 
fracture) at primary analysis 
• 
Subject incidence of new vertebral fracture through Month 24 
10.1.2 
Secondary Endpoints 
The secondary efficacy endpoints include the following:  
During the primary analysis period 
• 
Subject incidence of nonvertebral fracture at primary analysis 
• 
Subject incidence of all fractures (nonvertebral fracture and new or worsening 
vertebral fracture) at primary analysis 
• 
Subject incidence of new or worsening vertebral fracture through Month 24 
• 
Subject incidence of major nonvertebral fracture (pelvis, distal femur, proximal tibia, 
ribs, proximal humerus, forearm, and hip) at primary analysis 
• 
Subject incidence of hip fracture at primary analysis  
• 
Subject incidence of multiple new or worsening vertebral fractures through Month 24 
• 
Subject incidence of clinical fracture (nonvertebral fracture and clinical 
vertebral fracture) through Month 24 
• 
Subject incidence of nonvertebral fracture through Month 24 
• 
Subject incidence of hip fracture through Month 24 
• 
Subject incidence of clinical vertebral fracture through Month 24 
• 
Percent change from baseline in BMD at the lumbar spine, total hip, and femoral 
neck at Months 24, and 36 
During the 12-month double-blind ALN-controlled study period 
• 
Subject incidence of clinical fracture (nonvertebral fracture and clinical vertebral 
fracture) through Month 12 
• 
Subject incidence of new vertebral fracture through Month 12 
• 
Subject incidence of all fractures (nonvertebral fracture and new or worsening 
vertebral fracture) through Month 12 
• 
Subject incidence of nonvertebral fracture through Month 12 
• 
Subject incidence of hip fracture through Month 12 
• 
Subject incidence of major osteoporotic fracture (hip, forearm, humerus, and 
clinical vertebral) through Month 12 
• 
Subject incidence of clinical vertebral fracture through Month 12 
 
 
 


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• 
Percent change from baseline in BMD at the lumbar spine, total hip, and femoral 
neck at Month 12 
For the overall study period  
• 
Subject incidence of nonvertebral fractures at final analysis 
• 
Subject incidence of major nonvertebral fracture (pelvis, distal femur, proximal 
tibia, ribs, proximal humerus, forearm, and hip) at final analysis 
• 
Subject incidence of hip fracture at final analysis 
10.1.3 
Exploratory Endpoints 
The exploratory endpoints include the following: 
During the 12-month double-blind ALN-controlled study period 
• 
Subject incidence of new or worsening vertebral fracture through Month 12 
• 
Subject incidence of major nonvertebral fracture (pelvis, distal femur, proximal tibia, 
ribs, proximal humerus, forearm, and hip) through Month 12 
• 
Subject incidence of multiple new or worsening vertebral fractures through Month 12 
• 
Actual value in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, and BPI 
worst pain) at Months 6 and 12 
• 
Change from baseline in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, 
and BPI worst pain) at Months 6 and 12 
• 
Actual value in PRO and ClinRO measures after experiencing a nonvertebral or 
clinical vertebral fracture (OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain) at 
reporting of the nonvertebral or clinical vertebral fracture and at 1, 2 and 3 months 
after the fracture 
• 
Change from pre-fracture baseline in PRO and ClinRO measures after experiencing 
a nonvertebral or clinical vertebral fracture (OPAQ SV, EQ-5D-5L, LAD, and BPI 
worst pain) at reporting of the nonvertebral or clinical vertebral fracture and at 1, 2 
and 3 months after the fracture 
• 
Proportion of subjects with a clinically meaningful improvement in worst pain (defined 
as a 2-point improvement in the BPI worst pain scale compared with the fracture 
reporting visit) at 1, 2, and 3 months after reporting of a nonvertebral or clinical 
vertebral fracture 
• 
Change from baseline in height at Month 12 
During the primary analysis period 
• 
Subject incidence of major osteoporotic fracture (hip, forearm, humerus, and clinical 
vertebral) at primary analysis 
• 
Actual value in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, and BPI 
worst pain) at Months 18, 24, 30, and 36 
• 
Change from baseline in PRO and ClinRO measures (OPAQ SV, EQ-5D-5L, LAD, 
and BPI worst pain) at Months 18, 24, 30, and 36 
• 
Change from baseline in height at Month 24 
 
 
 


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During the month 12 to 24 ALN study period 
• 
Subject incidence of new vertebral fractures between Month 12 and Month 24 
• 
Subject incidence of clinical fracture (nonvertebral fracture and clinical 
vertebral fracture) between Month 12 and Month 24 
• 
Subject incidence of nonvertebral fracture between Month 12 and Month 24 
• 
Subject incidence of hip fracture between Month 12 and Month 24 
• 
Subject incidence of clinical vertebral fracture between Month 12 and Month 24 
10.1.4 
Safety Endpoints 
The safety endpoints include the following: 
During the 12-month double-blind ALN-controlled study period 
• 
Subject incidence of adverse events by system organ class and preferred term 
• 
Changes from baseline in laboratory assessments (serum chemistry and 
hematology) and the shifts from baseline to the worst value between baseline and 
Month 12 
• 
Changes from baseline in vital signs 
• 
Subject incidence of anti-romosozumab antibodies 
During the primary analysis period 
• 
Subject incidence of adverse events by system organ class and preferred term 
• 
Changes from baseline in laboratory assessments (serum chemistry and 
hematology) and the shift from baseline to the worst value between baseline and 
primary analysis  
• 
Changes from baseline in vital signs 
• 
Subject incidence of anti-romosozumab antibodies 
During the overall study period 
• 
Subject incidence of adverse events by system organ class and preferred term 
• 
Changes from baseline in vital signs  
10.1.5 
Imaging and PK/BTM/Biomarker Sub-study Endpoints 
During the 12-month double-blind ALN-controlled study period 
• 
Romosozumab serum concentrations at Day 1, Months 1, 3, 6, 9, and 12 
• 
Percent change from baseline in P1NP, BSAP, OC, and sCTX at Months 1, 3, 6, 9, 
and 12 
• 
Percent change from baseline in iPTH and sclerostin at Months 1, 3, 6, 9, and 12 
 
 
 


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• 
For subjects participating in the imaging components:  
• 
Percent change from baseline in integral (total) and trabecular vBMD at the 
lumbar spine by QCT at Months 6, and 12 
• 
Percent change from baseline in lumbar spine strength as assessed by FEA at 
Months 6, and 12 
• 
Percent change from baseline in DXA BMD at the lumbar spine, total hip, and 
femoral neck at Month 6 
During the primary analysis period 
• 
Percent change from baseline in P1NP and sCTX at Months 15, 18, 24, and 36 
• 
Percent change from baseline in iPTH and sclerostin at Months 15, 18, 24, and 36 
• 
For subjects participating in the imaging components: 
• 
Percent change from baseline in integral (total) and trabecular vBMD at the 
lumbar spine by QCT at Month 24 
• 
Percent change from baseline in lumbar spine strength as assessed by FEA at 
Month 24 
• 
Percent change from baseline in DXA BMD at the lumbar spine, total hip, and 
femoral neck at Month 18 
10.1.6 
Analyses Subsets 
10.1.6.1 
Primary Efficacy Analysis Set for Vertebral Fracture 
This analysis set includes all randomized subjects who have a baseline and 
≥ 1 post-baseline evaluation of vertebral fracture at or before the time point under 
consideration.  Subjects in this subset will be analyzed according to their randomized 
treatment assignments, regardless of treatment received. This analysis set will be used 
as the primary analysis set for the following endpoints: new, new or worsening, and 
multiple new or worsening vertebral fractures. 
10.1.6.2 
Full Analysis Set 
This analysis set includes all randomized subjects.  Subjects in the full analysis set will 
be analyzed according to their randomized treatment assignments, regardless of 
treatment received.  The full analysis set will be used as the primary analysis set for the 
following endpoints: nonvertebral fracture, clinical fracture, major nonvertebral fracture, 
all fracture, major osteoporotic fracture, and hip fracture.   
10.1.6.3 
Per-protocol Analysis Set 
The per-protocol analysis set will only be used to analyze the following endpoints: 
subject incidence of clinical fracture, new vertebral fracture through Month 24, and 
nonvertebral fracture as sensitivity analyses for the primary analysis period and 
nonvertebral fracture for the overall study period.  The per-protocol analysis set includes 
 
 
 


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subjects who are defined in Section 10.1.6.1 (for new vertebral fractures in the primary 
analysis period) or Section 10.1.6.2 (for clinical fracture and nonvertebral fracture in the 
primary or overall study analysis period) and receive the active investigational product 
with no major protocol violations in the corresponding analysis period.  The major 
protocol violations will be defined in the Statistical Analysis Plan (SAP), and will be 
identified prior to study unblinding.  Subjects in the per-protocol set will be analyzed 
according to their randomized treatment assignments. 
10.1.6.4 
Primary Efficacy Analysis Set for BMD, Height, and PRO/ClinRO 
Endpoints for the Double-blind ALN-controlled Study Period and 
Primary Analysis Period 
This analysis set includes all randomized subjects who have a baseline and ≥ 1 post 
baseline evaluation at or before the time point under consideration.  The efficacy 
analysis set may vary for different endpoints due to missing data.  Subjects in the 
analysis set will be analyzed according to their randomized treatment assignments, 
regardless of treatment received. 
10.1.6.5 
Safety Analysis Set for the Double-blind ALN-controlled Study 
Period, Primary Analysis Period, and Overall Study Period 
The safety analysis set includes all randomized subjects who receive ≥ 1 dose of 
investigational product in the 12-month of double-blind ALN-controlled study period.  
These subjects will be analyzed according to their actual treatment received, where 
subjects who received ≥ 1 dose of romosozumab will be analyzed in the romosozumab 
treatment group regardless of the randomized treatment.   
10.1.6.6 
Analysis Set for Imaging and PK/BTM/Biomarker Sub-study 
The analysis set for BTM/Biomarker includes all randomized subjects who undergo 
BTM/biomarker sampling during the study.  Subjects will be analyzed according to their 
randomized treatment assignments.  The analysis set for imaging includes all 
randomized subjects who undergo additional imaging procedures during the study.  
Subjects will be analyzed according to their randomized treatment assignments.  The PK 
analysis set includes all randomized subjects who undergo PK sampling during the study 
and who have received ≥ 1 dose of romosozumab. 
10.1.7 
Covariates 
All analyses assessing treatment effect of clinical fracture or nonvertebral fracture will 
include the stratification factor age (< 75 or ≥ 75 years), presence or absence of severe 
vertebral fracture at baseline, and baseline total hip BMD T-score as main covariates in 
the model.  Additional covariates will be analyzed separately and simultaneously, if 
 
 
 


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appropriate, as exploratory analyses.  The additional covariates of interest include the 
following: 
• 
baseline body mass index (BMI) 
• 
years since menopause at baseline  
• 
prior nonvertebral osteoporotic fracture (yes, no)  
• 
geographic region 
• 
race/ethnicity  
• 
prior use of bone-specific therapeutic agents (yes, no) 
• 
10-year probability of major osteoporotic fracture with BMD (as calculated by a 
third-party vendor) 
All analyses assessing treatment effect on new vertebral fracture endpoints will include 
the stratification factor age (< 75 or ≥ 75 years), presence or absence of severe vertebral 
fracture at baseline, and baseline total hip BMD T-score as main covariates in the 
model.  The new vertebral fracture endpoint assessed through Month 24 will also be 
analyzed adjusting for each of the additional covariates, as stated above, separately and 
simultaneously, if appropriate, as exploratory analyses.  
10.2 
Sample Size Considerations 
The study is designed to evaluate the effectiveness of romosozumab treatment for 
12 months followed by ALN (romosozumab/ALN) treatment compared with ALN 
treatment alone in reducing the subject incidence of clinical fracture (nonvertebral 
fracture or clinical vertebral fracture), subject incidence of vertebral fracture through 
Month 24, and subject incidence of nonvertebral fracture in postmenopausal women with 
osteoporosis. The total sample size of approximately 4,000 subjects (2,000:2,000 
equally allocated between the treatment groups) is determined based on the clinical 
fracture and new vertebral fracture endpoints.   
The dropout rate is assumed 10% for the first year and 8% per year thereafter.  The 
enrollment is expected to complete in 34 months. 
Because study design requires all subjects to complete the Month 24 visit for the 
ascertainment of the new vertebral fracture endpoint, the minimum follow-up on an 
individual subject is at least 24 months.  Additionally, all subjects will be followed until at 
least 440 subjects have confirmed nonvertebral fracture events for the final analysis, 
unless superiority of the nonvertebral fracture endpoint is achieved at the primary 
analysis.  The minimum follow-up time (24 months) and event-driven components of this 
study add complexity to the sample size calculation and power estimates.  To address 
 
 
 


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this complexity and the added complexity of using Hochberg’s method (Hochberg, 1988) 
to adjust for the multiplicity of the primary endpoints, a simulation was performed to 
derive the sample size and power for the clinical fracture and nonvertebral fracture 
endpoints. 
New vertebral fracture assumptions 
The one-year incidence of new vertebral fractures in untreated subjects in the population 
defined in this study is expected to be 5.5% (Black et al, 1996; Cummings et al, 2009).  
Assuming ALN treatment decreases this incidence by 60%, the new vertebral fracture 
incidence in the ALN group is expected to be 2.2% in one year and 4.4% in two years.  
Romosozumab/ALN treatment is expected to decrease the incidence of new vertebral 
fractures by 80%.  This represents a risk reduction of 50% compared to ALN treatment 
alone.   
Nonvertebral fracture assumptions 
The one-year incidence rate of nonvertebral fractures in the population defined in this 
study is expected to be 5.5% (Black et al, 2000).  Based on the ALN treatment 
assumption, 25% risk reduction, the one-year nonvertebral incidence rate is expected to 
be approximately 4% when treated by ALN.  Romosozumab/ALN is assumed to reduce 
the risk by 45% when compared to no treatment.  The combination of the 25% assumed 
reduction for ALN and the 45% assumed reduction for romosozumab /ALN leads to the 
assumption of a 27% reduction in fracture risk when comparing romosozumab /ALN to 
ALN.  
Clinical fracture assumptions 
Clinical fracture is the combination of nonvertebral fractures and clinical vertebral 
fractures.  Clinical vertebral fractures are expected to account for at 1/3 
(Black et al, 2000) of new vertebral fractures.  In the FREEDOM study, in the untreated 
population, the one-year incidence rate was 0.5% for clinical vertebral fracture and 3.5% 
for clinical fracture (Amgen, data on file).  Therefore, it is expected that clinical fractures 
are composed of approximately 85% nonvertebral fractures and 15% clinical vertebral 
fractures.  By pooling the treatment effects of nonvertebral and clinical vertebral 
fractures in the natural log-scale, with 85% and 15% as weights, then taking the 
exponential, romosozumab/ALN treatment compared with ALN alone reduces the risk of 
clinical fractures by approximately 30% (ie, exp(0.15*ln(1-50%) + 0.85*ln(1-27%))=69%, 
approximately 30% risk reduction). This estimation of risk reduction was further 
supported in the simulation.  Under the assumption that romosozumab/ALN will reduce 
 
 
 


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the risk by 30% compared to ALN, we would need to follow subjects until the 
330th subject had a confirmed clinical fracture to achieve a 90% power to detect the 
treatment effect using a 2-sided log-rank test at an overall significance level of 0.05.  The 
power calculation was performed using software EAST 5.4. 
DXA BMD assumptions 
The assumptions of mean percent change in DXA BMD and standard deviation for 
ALN at Month 12 and Month 24 are summarized in Table 2 (Schnitzer et al, 2000; 
Greenspan et al, 2002).  Using the FRAME study, the assumptions of mean 
percent change in DXA BMD and standard deviation for romosozumab at 
Month 12 are summarized in Table 3 (Amgen, data on file).  It is further assumed 
that at Month 24, romosozumab/ALN will maintain the BMD increase achieved at 
Month 12. 
Table 2.  Mean Percent Change From Baseline in BMD for Alendronate 
 
Mean % Change from 
Baseline 
Standard Deviation 
Lumbar spine at Month 12 
5.1 
3.5 
Total hip at Month 12 
2.9 
3.5 
Femoral neck at Month 12 
2.3 
4.6 
Lumbar spine at Month 24 
6.3 
4.9 
Total hip at Month 24a 
4.7 
6.3 
Femoral neck at Month 24 
3.1 
4.8 
a The mean of percent change from baseline at hip trochanter is used as the assumption for total hip.  
Table 3.  Mean Percent Change From Baseline in BMD at Month 12 for 
Romosozumab 
 
Mean % Change from 
Baseline 
Standard Deviation 
Lumbar spine at Month 12 
13.1 
6.0 
Total hip at Month 12 
6.0 
4.2 
Femoral neck at Month 12 
5.5 
4.6 
Simulation parameters 
The assumed distributions for nonvertebral fractures and new vertebral fractures are 
exponential with the yearly rates specified previously.  A binomial distribution with 
probability of 1/3 is assumed for the likelihood of a new vertebral fractures being a 
clinical vertebral fracture.  Additionally, the censoring distribution is assumed exponential 
 
 
 


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with a rate of 10% for the first year and a yearly rate of 8% thereafter.  Enrollment is 
assumed to be completed in 34 months.  As stated previously, the minimum follow-up is 
24 months and all subjects will be followed until the 330th subject has a clinical fracture.  
A log-rank test is used for the clinical and nonvertebral fracture endpoints and a Χ2 (no 
continuity correction) test is used for the new vertebral fracture endpoint. Results are 
based on 10,000 iterations. 
Power 
The power for the clinical fracture and new vertebral fracture endpoint after accounting 
for the multiplicity adjustment are 94% and 95%.  There is 91% power that both primary 
endpoints will be significant at the 5% level (2-sided) after accounting for multiplicity.  
Based on the simulation, the median time of the primary analysis is after the last enrolled 
subject completes the Month 24 visit.  The median number of subjects having clinical 
fractures in the simulation at the time of the primary analysis is 396.  Note that the 
number of clinical fractures at the time of the primary analysis will exceed 330 when 
330 subjects with confirmed clinical fractures occur before the Month 24 analysis. 
If both primary endpoints are significant under the Hochberg procedure, each of the 
following secondary DXA BMD endpoints will be tested hierarchically at 0.05 
according to the following sequence: percent change from baseline in BMD at 
lumbar spine at Month 24, percent change from baseline in BMD at total hip at 
Month 24, percent change from baseline in BMD at femoral neck at Month 24, 
percent change from baseline in BMD at lumbar spine at Month 12, percent 
change from baseline in BMD at total hip at Month 12, and percent change from 
baseline in BMD at femoral neck at Month 12. The power for each DXA BMD 
endpoints is > 99% using the 2-sample t-test.  
If all preceding endpoints are significant, the nonvertebral fracture endpoint will be 
tested using a group sequential approach at the primary analysis and the final analysis 
based on a 1-sided test (α = 0.025).  The Lan-DeMets alpha spending function (Lan and 
DeMets,1983) that approximates a Pocock boundary (Pocock, 1977), 
(0.025*LN(1+(EXP(1) -1)*information fraction)), will be used to determine the 
significance level at the time of the primary analysis.  Based on the number of subjects 
with nonvertebral fractures at the time of the primary analysis out of the total 
440 planned, which represents the information fraction in the alpha spending function, 
the significance level will be calculated at the time of primary analysis.  For example, if 
the information fraction is 80% at time of the primary analysis, the significance level is 
 
 
 


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0.0216.  Based on the simulation, the power for nonvertebral fracture and both primary 
endpoints and DXA BMD endpoints at Month 12 and Month 24 being significant is 
approximately 78% at the primary analysis.  
If the significance of nonvertebral fracture is not demonstrated at the time of the primary 
analysis, the nonvertebral fracture endpoint will be tested again using a 1-sided test at 
the time of the final analysis.  Based on the alpha level spent at the primary analysis, the 
significance level at final will be determined.  For example, if the information fraction is 
80% at the primary analysis (ie, the significance level is 0.0216 at primary), the 
significance level at the final analysis will be 0.0119 using software EAST 5.4 or R 
gsDesign package.  Based on the simulation, the power for nonvertebral fracture being 
significant at the primary or final analysis and both primary endpoints and DXA BMD 
endpoints at Month 12 and Month 24 being significant at primary analysis is 
approximately 84%. 
Monitoring of Blinded Fracture Rates 
The sponsor will monitor the pooled clinical fracture rate; if it is lower than expected, the 
sample size may be modified.    
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Staff from Amgen’s Biological Sample Management, Pharmacokinetics & Drug 
Metabolism, and Clinical Immunology and Molecular Sciences departments perform 
analyses during this double-blind study.  Therefore, the staff will not be blinded to the 
treatment assignments in this study.  However, these individuals will not have access to 
subject level clinical data apart from the samples they are assaying and analyzing during 
the course of the study.  They will ensure potentially unblinding data are not distributed 
to blinded individuals until the primary analysis. Roles and/or groups authorized to 
access restricted data elements during study (including at primary analysis) will be 
pre-specified to ensure the integrity of the trial. 
10.4 
Interim Analysis and Early Stopping Guidelines 
No interim analysis is planned for this study prior to the evaluation of the primary 
endpoints.   
An external, independent DMC will monitor unblinded safety data on an ongoing basis 
throughout the study and consider efficacy data in order to assess the risk/benefit profile 
of romosozumab.  No type I error adjustment is necessary for the evaluation of primary 
endpoints.  The DMC will not stop the trial early for efficacy or futility. DMC members will 
 
 
 


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have access to treatment assignments if knowledge of treatment assignment at the 
individual level is essential to evaluate safety.  To minimize the potential introduction of 
bias, these individuals will not have direct contact with the study site personnel or 
subjects.  An independent statistical service provider will generate unblinded reports for 
review by the DMC.  If at any time there are safety concerns, the DMC will communicate 
the concerns to a representative from Amgen senior management.  The DMC will 
convene approximately every 3 to 6 months.  The start date will depend on subject 
accrual rates.  Roles and groups requiring access to restricted and interim data at the 
time of the primary analyses and any time before initial database lock will be pre-
specified to ensure the integrity of the trial. 
10.5 
Planned Methods of Analysis 
10.5.1 
General Approach/Considerations 
The analytical approach for this study will be to use inferential testing to evaluate the 
following: 
• 
the effect of romosozumab treatment for 12 months followed by ALN treatment on 
fracture outcome as compared with ALN alone 
• 
the effect of romosozumab treatment for 12 months on fracture outcome as 
compared with ALN alone 
All efficacy analyses will be performed by randomized treatment, regardless of treatment 
received. 
At primary analyses, to maintain the overall significance level of 0.05, Hochberg’s 
method will be used to evaluate the primary endpoints: 
• 
Subject incidence of clinical fracture at primary analysis 
• 
Subject incidence of new vertebral fracture through Month 24 
If both the primary endpoints are significant at the 0.05 level (2-sided), each of the 
following secondary DXA BMD endpoints will be tested hierarchically at 0.05 
(2-sided). If all preceding endpoints are significant, the nonvertebral fracture at the 
primary analysis will be evaluated based on a 1-sided test at the significance level 
determined by the alpha spending function specified in Section 10.2.  All remaining 
secondary and exploratory efficacy endpoints will be tested at significance level of 0.05. 
 If superiority of the nonvertebral fracture endpoint is achieved at the primary analysis 
and the study is stopped after the primary analysis has been performed, all data, 
including the additional safety and nonvertebral fracture data, collected after the primary 
analysis will be summarized descriptively and not be included in confirmatory testing. 
 
 
 


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Study completion constitutes either completion of primary analysis if superiority is proven 
for nonvertebral fractures or when at least 440 subjects have experienced a nonvertebral 
fracture. 
Continuous parameters will be summarized using descriptive statistics, which include the 
mean, standard deviation, minimum, 25th percentile, median (50th percentile), 
75th percentile, maximum, and number of non-missing observations (n).  Nominal and 
ordinal categorical variables will be summarized using frequencies and percentages.  
For time-to-event parameters, the event rate at particular time point will be estimated 
using Kaplan-Meier method. 
10.5.2 
Analysis of Key Study Endpoints 
10.5.2.1 
Efficacy Endpoints 
Clinical Fractures  
Clinical fractures include nonvertebral fractures and clinical vertebral fracture (with 
≥ 1 grade increase from the previous grade in any vertebra from T4 to L4) that are 
associated with signs and/or symptoms indicative of a fracture.  All nonvertebral 
fractures confirmed by the central imaging vendor, except those of the skull, face, 
fingers, and toes, which are typically not associated with osteoporosis, will be included in 
analyses.  However, fractures associated with high trauma severity or pathologic 
fractures will be excluded.  
Subject incidence of clinical fracture at pre-specified time points will be estimated for 
each treatment group using Kaplan-Meier method. The treatment effect on clinical 
fractures will be assessed based on the hazard ratio, corresponding 95% confidence 
interval, and the p-value of the score test from a Cox proportional hazards model 
controlling for stratification factor age (< 75 or ≥ 75 years), presence or absence of 
severe vertebral fracture at baseline, and baseline total hip BMD T-score.  For subjects 
who have one or more clinical fractures from randomization to a pre-specified time point, 
the first event is used to define time to first clinical fracture.  Subjects who do not have 
clinical fractures from randomization to a pre-specified time point will be censored at the 
date of last evaluation for clinical fractures prior to the pre-specified time point.  
Graphical representations of the clinical fracture incidence over time will also be 
displayed using Kaplan-Meier curves. 
 
 
 


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Vertebral Fracture Endpoints 
Lateral spine x-rays will be obtained at screening (baseline) then annually, until primary 
analysis, and at visits when a clinical vertebral fracture is suspected.  A new vertebral 
fracture is identified when there is ≥ 1 grade increase from the previous grade of 0 in any 
vertebra from T4 to L4. 
The subject incidence of new vertebral fracture will be calculated as the ratio of the 
number of subjects experiencing at least one new vertebral fracture during the time 
period of interest to the number of subjects evaluable for new vertebral fracture during 
the time period of interest (See Section 10.1.6.1).  The number of subjects reporting at 
least one new vertebral fracture and the incidence rates will be summarized by treatment 
group.   
Subject incidence of new vertebral fracture at pre-specified time points will be compared 
between treatment groups using a logistic regression model adjusting for stratification 
factor age (< 75 or ≥ 75 years), presence or absence of severe vertebral fracture at 
baseline, and baseline total hip BMD T-score.  The odds ratio of vertebral fracture for 
subjects randomized to romosozumab as compared with subjects randomized to ALN, 
the corresponding 95% confidence interval, and the p-value using a score test will be 
reported.  
The subject incidence of new or worsening vertebral fractures and subject incidence of 
multiple new or worsening vertebral fractures will be analyzed using the same approach 
as described for subject incidence of new vertebral fractures. 
Nonvertebral Fractures  
Nonvertebral fractures will be analyzed using the same approach as described for 
clinical fractures.   
Other Fractures Endpoints at Specific Time Points 
Major nonvertebral fractures, all fractures, major osteoporotic fractures, clinical 
vertebral fractures, and hip fractures at specific time points will be analyzed using the 
same approach as described for clinical fractures.   
Fracture Endpoints Between Month 12 and Month 24 
Subject incidence of new vertebral fractures between Month 12 and Month 24 will 
be described. 
 
 
 


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Subject incidence of clinical fracture, nonvertebral fracture, hip fracture, and 
clinical vertebral fracture between Month 12 and Month 24 will be summarized 
descriptively as for the clinical fracture endpoint.  
Bone Mineral Density by DXA  
For a body site (lumbar spine, total hip and femoral neck), percent changes of BMD from 
baseline to Month 12 will be compared between treatment groups using an ANCOVA 
model with treatment group, stratification factor (age), presence or absence of severe 
vertebral fracture at baseline, baseline BMD at the same body site as the endpoint, 
machine type, interaction of baseline BMD and machine type as independent variables.  
Any missing BMD value at Month 12 will be imputed by the last post-baseline BMD value 
that is prior to Month 12. 
Percent changes of BMD from baseline to Month 24 and 36 during the primary analysis 
period will be analyzed using the same ANCOVA approach.  Any missing values at 
Months 24 or 36 will be imputed by the last post-Month 12 value that is prior to the time 
point of interest.   
Patient and Clinician Reported Outcome 
The actual values and changes from baseline in PRO and ClinRO measures (OPAQ SV, 
EQ-5D-5L, LAD, and BPI worst pain) will be summarized by visit within each treatment 
group for all subjects.  The change from baseline in PRO and ClinRO measures at 
Months 6 and 12 will be described and compared between treatment groups using 
non-parametric methods. 
After experiencing an on-study clinical fracture during the primary analysis period, the 
actual values and the changes from the pre-fracture baseline in PRO and ClinRO 
measures (OPAQ SV, EQ-5D-5L, LAD, and BPI worst pain) will be summarized by visit 
since the reporting of the clinical fracture within each treatment group and both treatment 
groups combined.  The change from pre-fracture baseline in PRO measures will be 
compared between treatment groups by visit since the reporting of the clinical fracture 
using regression models adjusting for fracture location and potentially other factors 
impacting the PRO as per the statistical analysis plan.  Pre-fracture baseline is defined 
as the last PRO or ClinRO measurement before the reporting of the clinical fracture.  
The proportion of subjects with a clinically meaningful improvement in worst pain 
(defined as a 2-point improvement in the BPI worst pain scale compared with the 
fracture reporting visit) at months 1, 2 and 3 after experiencing a clinical fracture will be 
 
 
 


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analyzed using a logistic regression model adjusting for fracture location and potentially 
other factors impacting the pain score as per the statistical analysis plan. 
Change from Baseline in Height 
The changes from baseline in height at Months 12 and 24 will be summarized by visit 
within each treatment group using the full analysis set and analyzed using a 
non-parametric method.   
BTM and Biomarkers in the Sub-study 
The changes from baseline in BTMs and biomarkers will be summarized by visit within 
each treatment group using the analysis set for the Imaging and PK/BTM/Biomarker 
sub-study and will be analyzed using a non-parametric method.  
Lumbar Spine BMD by DXA and BMD and estimated bone strength by QCT in the 
Sub-study 
Lumbar spine BMD and estimated bone strength measured in the sub-study will 
be summarized by visit using the same approach as described for the main study. 
10.5.2.2 
Safety Endpoints 
Adverse Events 
Subject incidence rates of adverse events in the 12-month double-blind study period will 
be tabulated by system organ class and preferred term.  Summaries of deaths, events of 
interest, serious, and investigational product related adverse events, adverse events 
leading to early withdrawals from investigational product or study in the 12-month 
double-blind study period, will also be provided.  
The adverse events in the primary analysis period and in the overall study period will be 
summarized using the same approach as described for the 12-month double-blind study 
period. 
Laboratory Assessments 
The actual values and changes from baseline by visit will be summarized descriptively 
for each laboratory parameters in the 12-month double-blind study period. Laboratory 
parameters will also be summarized showing the shift in CTCAE toxicity grades from 
baseline to the ‘worst’ on-study value in the 12-month double-blind ALN-controlled study 
period.   
The actual values and changes from baseline by visit will be summarized descriptively 
for each laboratory parameters for the primary analysis period.  Laboratory parameters 
 
 
 


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will also be summarized showing the shift in CTCAE toxicity grades from baseline to the 
‘worst’ on-study value in the primary analysis period.  Graphical representation showing 
central tendency and dispersion of the actual values and/or changes from baseline of 
laboratory parameters over time will be provided. 
Vital Signs 
The actual values and changes from baseline in vital signs by visit will be summarized 
descriptively in the 12-month double-blind study period, the primary analysis period, and 
the overall study period.   
Anti-romosozumab Antibodies 
The frequencies and percentages of subjects exhibiting anti-romosozumab antibodies at 
any time in the 12-month double-blind study period will be tabulated.  This analysis will 
be repeated to further include all testing results from samples collected during the rest of 
the primary analysis period. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial generic ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the template will be communicated 
by letter from the Amgen study manager to the investigator.  The written informed 
consent document should be prepared in the language(s) of the potential patient 
population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational products are administered.   
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have her primary care physician informed of 
the subject’s participation in the clinical study.  If the subject agrees to such notification, 
the investigator shall inform the subject’s primary care physician of the subject’s 
participation in the clinical study.  If the subject does not have a primary care physician 
and the investigator will be acting in that capacity, the investigator should document 
such in the subject’s medical record.  The acquisition of informed consent and the 
subject’s agreement or refusal of her notification of the primary care physician should be 
documented in the subject’s medical records, and the informed consent form should be 
 
 
 


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signed and personally dated by the subject and by the person who conducted the 
informed consent discussion.  The original signed informed consent form should be 
retained in accordance with institutional policy, and a copy of the signed consent form 
should be provided to the subject. 
If a potential subject is illiterate or visually impaired, the investigator must provide an 
impartial witness to read the informed consent form to the subject and must allow for 
questions.  Thereafter, both the subject and the witness must sign the informed consent 
form to attest that informed consent was freely given and understood.   
11.2 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IEC/IRB for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IEC/IRB 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator should notify the IEC/IRB of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator will be responsible for obtaining annual IEC/IRB approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IEC/IRB continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained:   
• 
On the eCRFs or other documents submitted to Amgen, subjects should be identified 
by a subject identification number only, with a complete and accurate date of birth on 
the demographics eCRF.   
• 
For Serious Adverse Events reported to Amgen, subjects should be identified by 
their initials, date of birth, and a subject identification number.   
• 
Documents that are not for submission to Amgen (eg, signed informed consent 
forms) should be kept in strict confidence by the investigator. 
In compliance with Federal regulations/International Conference on Harmonization (ICH) 
GCP Guidelines, it is required that the investigator and institution permit authorized 
representatives of the company, of the regulatory agency(s), and the IEC/IRB direct 
 
 
 


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access to review the subject’s original medical records for verification of study-related 
procedures and data.  Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study.  
The investigator is obligated to inform and obtain the consent of the subject to permit 
named representatives to have access to her study-related records, including personal 
information, without violating the confidentiality of the subject. 
11.4 
Investigator Signatory Obligations 
Each clinical study report should be signed by the coordinating investigator. 
The coordinating investigator, identified by Amgen, will either be: 
• 
a recognized expert in the therapeutic area 
• 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the investigator must be obtained.  The 
IEC/IRB must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IEC/IRB to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the investigator’s participation in the study 
according to the study contract.  The investigator should notify the IEC/IRB in writing of 
the study’s completion or ET and send a copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product by 
an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product, and by what mechanism, after 
termination of the trial and before it is available commercially. 
12.2 
Study Documentation and Archive 
The investigator should maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 
 
 
 


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and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
In this study, the Electronic Trial Operations System captures the following data points 
and these are considered source data:  protocol number, site number, subject ID, 
gender, date of birth, date informed consent was signed, sub-study participation, 
treatment group assignment, screen failure reason, randomization date, randomization 
number and IP box ID assignment. 
eCRF entries may be considered source data if the eCRF is the site of the original 
recording (ie, there is no other written or electronic record of data).   
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  Elements should include: 
• 
Subject files containing informed consent forms, and subject identification list 
• 
Study files containing the protocol with all amendments, investigator’s brochure, 
copies of prestudy documentation, and all correspondence to and from the IEC/IRB 
and Amgen 
• 
If kept, proof of receipt, Investigational Product Accountability Record, Return of 
Investigational Product for Destruction, Final Investigational Product Reconciliation 
Statement (if applicable), and all drug-related correspondence 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen monitor is responsible for verifying the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the eCRFs. 
 
 
 


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The investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing eCRFs, 
are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, drug storage areas, laboratories) 
and review of study-related records will occur to evaluate the study conduct and 
compliance with the protocol, ICH GCP, and applicable regulatory requirements. 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the eCRFs must be maintained and 
readily available. 
• 
Updates to eCRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review will be performed on subject data received at Amgen.  During 
this review, subject data will be checked for consistency, omissions, and any 
apparent discrepancies.  In addition, the data will be reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or site notifications will be created in 
the EDC system database for site resolution and closed by Amgen reviewer. 
• 
The principal investigator signs only the Investigator Verification Form for this EDC 
study.  This signature will indicate that the principal investigator inspected or 
reviewed the data on the eCRF, the data queries, and the site notifications, and 
agrees with the content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit—week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.   
12.4 
Language 
eCRFs must be completed in English.  TRADENAMES (if used) for concomitant 
medications may be entered in the local language. 
 
 
 


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All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  Consult the 
country-specific requirements for language requirements. 
12.5 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several principal investigators and appropriate 
Amgen staff, the governance and responsibilities of which are set forth in a Publication 
Charter.  The committee is expected to solicit input and assistance from other 
investigators and to collaborate with authors and Amgen staff as appropriate as defined 
in the Publication Charter.  Membership on the committee (both for investigators and 
Amgen staff) does not guarantee authorship—the criteria described below should be met 
for every publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; (4) agreement to be accountable for all aspects of the work 
in ensuring that questions related to the accuracy or integrity of any part of the work 
are appropriately investigated and resolved.  Authors should meet conditions 1, 2, 3, 
and 4. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical 
Study Agreement among the institution, principal investigator, and Amgen will detail the 
procedures for, and timing of, Amgen’s review of publications. 
 
 
 


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12.6 
Compensation  
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent.  If 
permitted under applicable regional laws or regulatory guidelines, subjects may be 
compensated for other inconveniences not associated with study-related injuries 
(eg, travel costs). 
 
 
 


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13. 
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Balemans W, Ebeling M, Patel N, et al.  Increased bone density in sclerosteosis is due 
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Black DM, Delmas PD, Eastell R, et al.  Once-yearly zoledronic acid for treatment of 
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Black DM, Schwartz AV, Ensrud KE, et al.  Effects of continuing or stopping alendronate 
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Black DM, Bilezikian JP, Ensrud KE et al.  One year of alendronate after one year of 
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Black DM, Thompson DE, Bauer DC et al.  Fracture risk reduction with alendronate in 
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2000;85: 4118–4124. 
Black DM, Cummings SR, Karpf DB, et al.  Randomised trial of effect of alendronate on 
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Borggrefe J, Graeff C, Nickelsen TN, Marin F, Glüer CC.  Quantitative computed 
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EUROFORS study.  J Bone Miner Res.  2010;Mar;25(3):472-81. 
Brooks R.  EuroQoL: the current state of play.  Health Policy.  1996;37(1):53-72. 
Brunkow ME, Gardner JC, Van Ness J, et al.  Bone dysplasia sclerosteosis results from 
loss of the SOST gene product, a novel cystine knot-containing protein.  Am J Hum 
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Canalis E.  Update in new anabolic therapies for osteoporosis.  J Clin Endocrinol Metab.  
2010;95(4):1496-1504. 
Chestnut III CH, Skag A, Christiansen C et al.  Effects of oral Ibandronate administered 
daily or intermittently on fracture risk in postmenopausal Osteoporosis.  J Bone Miner 
Res.  2004;(8):1241-1249. 
Chestnut III CH, Silverman S, Andriano K, et al.  A randomized trial of nasal spray 
salmon calcitonin in postmenopausal women with established osteoporosis: the prevent 
recurrence of osteoporotic fractures study (PROOF).  PROOF Study Group.  Am J Med.  
2000;109:267-276. 
Cree MW, Juby AG, Carriere KC.  Mortality and morbidity associated with osteoporosis 
drug treatment following hip fracture.  Osteoporos Int.  2003;14(9):722-727. 
Cummings SR, San Martin J, McClung MR, et al.  Denosumab for prevention of 
fractures in postmenopausal women with osteoporosis.  N Engl J Med.  
2009;361(8):756-765. 
Cummings SR, Black DM, Thompson DE, et al.  Effect of alendronate on risk of fracture 
in women with low bone density but without vertebral fractures: results from the Fracture 
Intervention Trial.  JAMA.  1998;280(24):2077-2082. 
 
 
 


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Dawson-Hughes B, Mithal A, Bonjour JP et al.  IOF position statement: vitamin D 
recommendations for older adults.  Osteoporos Int.  2010;21:1151–1154. 
Ettinger B, Black DM, Mitlak BH, et al.  Reduction of vertebral fracture risk in 
postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year 
randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) 
Investigators.  JAMA.  1999;282(7):637-645. 
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Giusti A, Barone A, Pioli G et al.  Heterogeneity in serum 25-hydroxy-Vitamin D 
response to Cholecalciferol in elderly women with Secondary Hyperparathyroidism and 
Vitamin D deficiency.  J Am Geriatr Soc.  2010;58:1489–1495. 
Greenblatt D.  Treatment of postmenopausal osteoporosis.  Pharmacotherapy.  
2005;25(4):574-584. 
Greenspan SL, Schneider DL, McClung MR, et al.  Alendronate improves bone 
mineral density in elderly women with osteoporosis residing in long-term care 
facilities.  A randomized, double-blind, placebo-controlled trial.  Ann Intern Med. 
2002;136:742-746. 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009. 
Hamersma H, Gardner J, Beighton P.  The natural history of sclerosteosis.  Clin Genet.  
2003;63(3):192-197. 
Harris ST, Watts NB, Genant HK, et al.  Effects of risedronate treatment on vertebral and 
nonvertebral fractures in women with postmenopausal osteoporosis: a randomized 
controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group.  
JAMA.  1999;282(14):1344-1352. 
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance.  
Biometrika.  1988;(74):800-802. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2006.  http://www.icmje.org/. 
IOM Report.  Dietary Reference Intakes for Vitamin D and Calcium (2010).  
http://books.nap.edu/openbook.php?record_id=13050. Accessed May 19th 2011. 
Kanis JA, Dawson A, Oden A, Johnell O, De Laet C, Jonsson B.  Cost-effectiveness of 
preventing hip fracture in the general female population.  Osteoporosis Int.  
2001a;12;356-362. 
Kanis JA, Oden A, Johnell O, Jonsson B, de Laet C, Dawson A.  The burden of 
osteoporotic fractures: a method for setting intervention thresholds.  Osteoporosis Int.  
2001b;12;417-427. 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-663. 
Lenart BA, Lorich DG, Lane JM.  Atypical fractures of the femoral diaphysis in 
postmenopausal women taking alendronate.  N Engl J Med.  2008;358:1304-1306. 
 
 
 


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Levey AS, Coresh J, Greene T, et al.  Chronic Kidney Disease Epidemiology 
Collaboration.  Using standardized serum creatinine values in the modification of diet in 
renal disease study equation for estimating glomerular filtration rate.  Ann Intern Med.  
2006;145(4):247–54. 
Li X, Ominsky MS, Warmington KS, et al.  Sclerostin antibody treatment increases bone 
formation, bone mass, and bone strength in a rat model of postmenopausal 
osteoporosis.  J Bone Miner Res.  2009;24(4):578-588. 
Li X, Warmington KS, Niu Q, et al.  Bone formation without increasing bone resorption in 
aged male rats.  J Bone and Mineral Res.  2007a;22(suppl.1):S36.   
Li X, Warmington KS, Niu QT, et al.  Treatment with an anti-sclerostin antibody directly 
stimulates bone formation in a dose-dependent manner in ovariectomized rats with 
established osteopenia.  J Bone Miner Res.  2007b;22(Suppl 1):S65. 
McClung MR, Geusens P, Miller PD, et al.  Effect of risedronate on the risk of hip 
fracture in elderly women (HIP Study).  Hip Intervention Program Study Group.  N Engl J 
Med.  2001;344(5):333-340. 
Mendoza T, Mayne T, Rublee D, Cleeland C.  Reliability and validity of a modified Brief 
Pain Inventory short form in patients with osteoarthritis.  Eur J Pain.  2006;10(4):353-61. 
National Osteoporosis Foundation.  Clinician’s Guide to Prevention and Treatment of 
Osteoporosis.  Washington, DC:  National Osteoporosis Foundation.  2010:24. 
Neer RM, Arnaud CD, Zanchetta JR, et al.  Effect of parathyroid hormone (1-34) on 
fractures and bone mineral density in postmenopausal women with osteoporosis.  N 
Engl J Med.  2001;344(19):1434-1441. 
NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and 
Therapy.  Osteoporosis prevention, diagnosis, and therapy.  JAMA.  2001;285:785-795. 
Odvina CV, Levy S, Rao S, Zerwekh JE, Rao DS.  Unusual mid-shaft fractures during 
long-term bisphosphonate therapy.  Clin Endocrinol (Oxf).  2010;72:161-168. 
Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY.  Severely 
suppressed bone turnover: a potential complication of alendronate therapy.  J Clin 
Endocrinol Metab.  2005;90:1294-1301. 
Ominsky MS, Li CY, Li X, et al.  Inhibition of sclerostin by monoclonal antibody enhances 
bone healing and improves bone density and strength of non-fractured bones.  J Bone 
Miner Res.  Published online December 2, 2010a;doi:10.1002/jbmr.307. 
Ominsky MS, Niu QT, Kurimoto P, Ke HZ.  Tissue level mechanism of increased bone 
formation by sclerostin antibody in male cynomolgus monkeys.  J Bone Miner Res.  
2010b:25(Suppl. 1):S53. 
Papapoulos S, Makras P.  Selection of antiresorptive or anabolic treatments for 
postmenopausal osteoporosis.  Nature Clin Practice Endocrinology & Metabolism.  
2008;4(9) 514-523. 
Pocock SJ. Group sequential methods in the design and analysis of clinical trials.  
Biometrika 1977; 64:191-199. 
Poole KE, van Bezooijen RL, Loveridge N, et al.  Sclerostin is a delayed secreted 
product of osteocytes that inhibits bone formation.  FASEB J.  2005;19(13):1842-1844. 
Prince R, Sipos A, Hossain A et al.  Sustained Nonvertebral Fragility Fracture Risk 
Reduction After Discontinuation of Teriparatide Treatment.  J Bone Miner Res.  
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Reginster JY, Burlet N.  Osteoporosis:  a still increasing prevalence.  Bone.  
2006;38(2 suppl 1):S4-S9. 
Rittmaster RS, Bolognese M, Ettinger MP, et al.  Enhancement of bone mass in 
osteoporotic women with parathyroid hormone followed by alendronate.  
J Clin Endocrinol Metab.  2000;85:2129-2134. 
Romosozumab (AMG 785) Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
Ross AC, Taylor CL, Yaktine AL, Del Valle HB (Editors)/Committee to Review Dietary 
Reference Intakes for Vitamin D and Calcium.  Dietary Reference Intakes for Calcium 
and Vitamin D: The National Academies Press;  2011. 
Schnitzer T, Bone HG, Crepaldi G, et al.  Therapeutic equivalence of alendronate 
70 mg once weekly and alendronate 10 mg daily in the treatment of osteoporosis.  
Aging Clin Exp Res.  2000;12:1-12. 
Schwartz AV, Bauer DC, Cummings SR, et al.  Efficacy of continued alendronate for 
fractures in women with and without prevalent vertebral fracture: the FLEX trial.  J Bone 
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Silverman SL.  The osteoporosis assessment questionnaire (OPAQ): a reliable and valid 
disease-targeted measure of health-related quality of life in osteoporosis.  
Quality of Life Research.  2000; 9:767-774.  
Tucci JR.  Vitamin D therapy in patients with primary hyperparathyroidism and 
hypovitaminosis D.  Europ J Endocr.  2009;161:189–193. 
van Bezooijen RL, Roelen BA, Visser A, et al.  Sclerostin is an osteocyte-expressed 
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2004;199(6):805-814. 
Vanhoenacker FM, Balemans W, Tan GJ, et al.  Van Buchem disease: lifetime evolution 
of radioclinical features.  Skeletal Radiol.  2003;32(12):708-718. 
Winkler DG, Sutherland MK, Geoghegan JC, et al.  Osteocyte control of bone formation 
via sclerostin, a novel BMP antagonist.  EMBO J.  2003;22(23):6267-6276. 
World Health Organization.  WHO Scientific Group on the Assessment of Osteoporosis 
at Primary Health Care Level (Summary Meeting Report, Brussels, Belgium, 5-7 May 
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World Health Organization.  Assessment of fracture risk and its application to screening 
for postmenopausal osteoporosis.  World Health Organization.  Geneva, Switzerland.  
1994:1-129. 
 
 
 


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14. 
APPENDICES 
 
 
 


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Appendix A.  Schedule of Assessments 
 
 
 


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1. 
During Screening and Full Rescreening, serious adverse event reporting only; no adverse event reporting or concomitant medication data collection. 
2. 
PROs/ClinROs should preferably be the first procedure at each applicable visit, IP injection must be the last procedure at each applicable visit. 
3. 
Blood draws will continue approximately every three months for subjects testing positive for neutralizing antibodies at ET visit. 
4. 
The initial vitamin D loading dose is to be administered within 1 week of the study day 1 visit. However, if the vitamin D loading dose is missed in this timeframe, it 
should be given as soon as possible thereafter. 
5. 
Additional lateral spine X-rays may be taken in cases of a suspected clinical vertebral fracture. 
6. 
Post-fracture Month 12. Data collection will occur only up to the Month 12 study visit and is not required after Month 12 even if the fracture has been reported at 
the Month 10, Month 11, or Month 12 study visits. 
7. 
Following Month 36, clinic visits will continue every 6 months until end of study (440 nonvertebral fractures) including all assessments listed unless otherwise 
noted. 
8. 
End of primary analysis period phone contacts will occur when clinical fracture events (nonvertebral fracture or clinical vertebral fracture) have been confirmed by 
the central imaging vendor for at least 330 subjects and all subjects have had the opportunity to complete their Month 24 study visit. 
9. 
End of study telephone contacts will be performed after nonvertebral fracture events have been confirmed for at least 440 subject. 
10. Performed by local laboratory; electrophoresis results within 6 months prior to signing consent will be acceptable. 
11. Blood draws for BTMs must be obtained from subjects in fasting stage and before noon.  Fasting stage is defined as overnight fasting.  If overnight fasting is not 
feasible, at a minimum 8 hours is required. 
 
 
 
 


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12. SAE reporting to continue through 30 days after the last dose of IP. 
13. Monthly contacts begin at M13.  Contact will be initiated by a phone call. During the primary analysis period, if back pain is reported during the phone call, it will 
be recorded as an adverse event and the subject will be asked to complete an unscheduled follow-up clinic visit as soon as possible but no later than 21 days 
after reporting of the back pain for evaluation of a suspected clinical vertebral fracture. 
14. Lateral spine x-ray will only be taken at the unscheduled follow-up clinic visit if the investigator considers the back pain previously reported during the monthly 
phone contact to be possibly due to a new or worsening vertebral fracture. 
15. To facilitate subject scheduling, the Day 1/baseline lumbar spine DXA scan may be taken with the proximal femur DXA scan performed during screening. For 
Screening and Day 1 purposes, lateral spine x-rays and DXA scans of the lumbar spine and proximal femur taken up to 35 days prior to the beginning of the 
screening period may be used if all of the criteria outlined in Section 7.2.1 are met. 
16. In a subset of subjects. 
17. To be processed and sent to the central laboratory during the primary analysis period; to be analyzed at local laboratories following the primary analysis period. 
18. To be performed in the primary analysis period only. 
19. To be performed at month 36 and then every 12 months thereafter during the primary analysis period only. 
20. For subjects in the sub-study only. 
Notes: 
a) 
To maintain the blind of the study, the following on-study (after Day 1/baseline) data will not be reported to any study-related personnel: serum calcium, albumin-
adjusted calcium, phosphorus, alkaline phosphatase, romosozumab levels, Sclerostin, BTMs, iPTH, anti-romosozumab antibodies, and DXA results. However, in 
the case of a panic value for either serum calcium, albumin-adjusted calcium, phosphorus or alkaline phosphatase the central laboratory will notify the study site. 
When a panic alert is issued for serum calcium, albumin-adjusted calcium levels, phosphorus, or ALP, the sites may perform additional follow-up blood draws for 
local analysis as required to support subject medical care.  After primary analysis, the chemistry and hematology labs will be unblinded as these will be done by 
local lab. 
b) 
Phone contact to occur monthly in between clinic visits following the 12-month, double-blind, ALN-controlled study period until the end of study. When a 
nonvertebral fracture is reported:  Event to be recorded in eCRF, copies of radiographs or other diagnostic images and/or a copy of the radiology report, surgical 
report, or discharge summary should be obtained, included in the subject’s study records and submitted to the central imaging vendor. When back pain is 
reported (until clinical fracture events have been confirmed by the central imaging vendor for at least 330 subjects and all subjects have had the opportunity to 
complete their Month 24 study visit): back pain (but not a vertebral fracture) will be recorded as an adverse event. The subject will be asked to complete an 
unscheduled follow-up clinic visit as soon as possible but no later than 21 days after reporting of the back pain. If at the unscheduled clinic visit, the investigator 
considers the back pain to be possibly due to a new or worsening vertebral fracture, a confirmatory lateral spine x-ray will be taken. 
c) 
Visit windows are ±7 days for the monthly study visits during the 12-month double-blind ALN-controlled study period, ± 14 days for clinic visits during the rest of 
the study. The window for the monthly phone contact in between clinic visits and the end of primary analysis period phone contact  is ± 7 days. The window for 
the end of study contact is -14 to +7 days. 
d) 
If a subject terminates early from the study between Day 1 and Month 12, the Month 12 procedures (except ALN dispensation) are to be completed at that time.  
If a subject terminates early between Month 12 and Month 24, the Month 24 procedures (except ALN dispensation) are to be completed at that time. If a subject 
terminates early from the study between Month 24 and the end of the primary analysis period, the Month 36 procedures are to be completed at that time (except 
ALN dispensation; DXA scans and lateral spine x-rays should be performed if at least 6 weeks have elapsed since the previous one). If a subject terminates early 
from the study following the end of primary analysis period, the end of primary analysis period phone contact procedures are to be completed at that time. 
e) 
Study visits and phone contacts after Month 24 are required until the end of study phone contact has been completed. 
 
 
 
 
 


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Appendix B.  Additional Safety Assessment Information 
For grading of adverse events, the Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 is to be used.  
Adverse Event Toxicity Grading Scale 
Grade 
CTCAE version 3.0 
1 
MILD ADVERSE EVENTS 
2 
MODERATE ADVERSE EVENTS 
3 
SEVERE ADVERSE EVENTS 
4 
LIFE-THREATENING OR DISABLING ADVERSE EVENTS 
5 
DEATH RELATED to ADVERSE EVENTS 
Go to 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf to 
access a full version of CTCAE version 3.0 
As noted in Section 
United States FDA Guidance on Hepatotoxicity Stopping and Rechallenge Rules 
6.1.3 an FDA Guidance exists for DILI (Guidance for Industry 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009).  This guidance 
is general for all investigational and marketed products, and is synopsized here as a 
reference.  It provides criteria for reporting and withholding investigational product in the 
event that a subject develops signs or symptoms of hepatotoxicity during a clinical trial.  
For the purpose of this study, these FDA guidelines apply to all centers in all countries. 
Criteria for Permanent Withholding of IP due to Potential Hepatotoxicity 
IP should be discontinued permanently and the subject should be followed for possible 
DILI, if ALL of the criteria below are met:  
• 
TBL>2x ULN or international normalized ratio >1.5 
• 
AND increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
<ULN 
>3x ULN 
 
 
 


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CONFIDENTIAL 
 
 
• 
AND no other cause for the combination of laboratory abnormalities is immediately 
apparent; important potential causes for abnormal AST/ALT or TBL values include, 
but are not limited to: 
− 
Obstructive gall bladder or bile duct disease 
− 
Viral or alcoholic hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, 
cytomegalovirus, Herpes Simplex Virus, Varicella, etc) 
− 
Progression of malignancy involving the liver (note that metastatic disease to the 
liver, by itself, should not be used as an explanation for significant AST/ALT 
elevations) 
− 
Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right sided heart failure 
− 
Concomitant administration of other hepatotoxins, including drugs that inhibit 
bilirubin glucuronidation (eg, indinavir, atazanavir, irinotecan) or herbal or dietary 
supplements 
− 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome); 
alpha-one antitrypsin deficiency 
− 
Autoimmune hepatitis 
− 
Nonalcoholic Steatohepatitis (NASH) or other “fatty liver disease” 
It should be noted that some of the circumstances above may nevertheless warrant 
discontinuation of romosozumab (Section 8) without requiring assessment for 
drug-induced liver injury. 
Criteria for Conditional Withholding of IP due to Potential Hepatotoxicity 
For subjects that do not meet the criteria for permanent withholding of investigational 
product outlined above, IP should be withheld if ANY of the following criteria are met, 
and the subject should be evaluated for DILI:   
• 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation 
Any 
> 8x ULN at any time 
Any 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
Any 
> 5x ULN but < 8x ULN and unable to adhere to enhanced 
monitoring schedule 
• 
OR: clinical signs or symptoms that are, in the opinion of the investigator, consistent 
with hepatitis (such as right upper quadrant pain/tenderness, fever, nausea, 
vomiting, jaundice, rash or eosinophilia > 5%).  If such signs or symptoms are 
coupled with ALT or AST elevations > 3x ULN, investigational product should be 
withheld.  
• 
OR: TBL > 3x ULN at any time 
• 
OR: ALP > 8x ULN at any time 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 113 of 118 
CONFIDENTIAL 
 
 
IP should be withheld pending investigation into alternative causes of DILI.  If IP is 
withheld, the subject should be followed according to recommendations above for 
possible DILI.  Rechallenge may be considered if an alternative cause, such as acute 
Hepatitis B infection, is discovered and the laboratory abnormalities resolve to normal or 
baseline.  
Criteria for Rechallenge of IP after Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, Principal Investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then IP should be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation 
should never be rechallenged. 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST/ALT and 
TBL elevation that require permanent withholding of IP require the following: 
• 
The event should be reported to Amgen as a serious adverse event within 24 hours 
of discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate CRF (eg, Adverse Event CRF) that captures information necessary 
to facilitate the evaluation of treatment-emergent liver abnormalities should be 
completed and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI should be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2. 
Additional Clinical Assessments and Observation 
All subjects in whom IP is withheld (either permanently or conditionally) due to potential 
DILI or who experience AST/ALT elevations >3x ULN should undergo a period of “close 
observation” until abnormalities return to normal or to the subject’s baseline levels.  
Assessments that should be performed during this period include:  
• 
Repeat liver chemistries within 24-48 hours (ALT, AST, ALP, TBL); in cases of  
TBL >2x ULN or AST/ALT much greater than 3x ULN, retesting should be performed 
within 24 hours  
− 
Subjects should be monitored at least twice weekly; testing frequency may 
decrease to once per week or less if laboratory abnormalities stabilize or the 
investigational product has been discontinued AND the subject is asymptomatic 
• 
Obtain PT/international normalized ratio, fractionated bilirubin and any other 
potentially relevant laboratory evaluations of liver function or disease  
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 114 of 118 
CONFIDENTIAL 
 
 
• 
Obtain complete blood count  with differential to assess for eosinophilia 
• 
Obtain appropriate blood sampling for PK analysis if this has not already been 
collected  
• 
Obtain a more detailed history of:  
− 
Prior and/or concurrent diseases or illness 
− 
Exposure to environmental and/or industrial chemical agents  
− 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
− 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
− 
Concomitant medications (including non-prescription medicines & herbal and 
dietary supplements)  
• 
Initiate full viral and autoimmune hepatitis evaluation (serologies for hepatitis A,B,C, 
D, E, Epstein-Barr Virus, Herpes Simplex Virus, etc); evaluate for other potential 
causes of DILI including but not limited to: Nonalcoholic Steatohepatitis, 
hypoxic/ischemic hepatopathy, and biliary tract disease  
• 
Obtain gastroenterology or hepatology consult  
• 
Perform appropriate liver imaging or biopsy if clinically indicated; strongly consider 
these tests in cases of concurrent transaminase and TBL elevation that require 
permanent withholding of investigational product  
• 
Follow the subject until all laboratory abnormalities return to baseline or normal.  The 
“close observation period” should continue for a minimum of 4 weeks after drug 
discontinuation. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding eCRFs. 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 115 of 118 
CONFIDENTIAL 
 
 
Appendix C.  Pregnancy Notification Worksheet 
 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 116 of 118 
CONFIDENTIAL 
 
 
Appendix D.  eSAE Contingency Report Form 
 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 117 of 118 
CONFIDENTIAL 
 
 
 
 
 


Product:  Romosozumab 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 118 of 118 
CONFIDENTIAL 
 
 
 
 
 
 


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Product:  Romosozumab 
 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 8 of 28 
CONFIDENTIAL 
 
 
0.05 level, the nonvertebral fracture endpoint will be tested using a group sequential 
approach at the primary analysis and the final analysis based on a 1-sided test 
(α = 0.025).  The Lan-Demets alpha spending function that approximates a Pocock 
boundary will be used to determine the significance level at the time of the primary 
analysis. 
Subject incidence of clinical fractures will be compared between treatment groups using 
a Cox proportional hazards model controlling for age (< 75 years,  75 years), presence 
or absence of severe vertebral fracture at baseline, and baseline total hip BMD T-score.  
Nonvertebral fractures, major nonvertebral fractures, hip fractures, and all fractures will 
be analyzed using the same approach as for clinical fractures.  The Kaplan-Meier 
method will be used to summarize the cumulative fracture incidence at pre-specified 
time points.   
Subject incidence of new vertebral fracture at a pre-specified time point will be compared 
between treatment groups using a logistic regression model adjusting for age 
(< 75 years, ≥ 75 years), presence or absence of severe vertebral fracture at baseline, 
and baseline total hip BMD T-score.  Subject incidence of new or worsening vertebral 
fractures and multiple new or worsening vertebral fractures will be analyzed using the 
same approach as for new vertebral fractures. 
With: 
In order to maintain the overall significance level at 0.05, the primary endpoints will be 
assessed using Hochberg’s procedure.  If both primary endpoints are significant at the 
0.05 level, each of the following secondary DXA BMD endpoints will be tested 
hierarchically at 0.05 according to the following sequence: percent change from 
baseline in BMD at lumbar spine at Month 24, percent change from baseline in 
BMD at total hip at Month 24, percent change from baseline in BMD at femoral 
neck at Month 24, percent change from baseline in BMD at lumbar spine at 
Month 12, percent change from baseline in BMD at total hip at Month 12, and 
percent change from baseline in BMD at femoral neck at Month 12.  If all preceding 
endpoints are significant, the nonvertebral fracture endpoint will be tested using a 
group sequential approach at the primary analysis and the final analysis based on a 
1-sided test (α = 0.025).  The Lan-Demets alpha spending function that approximates a 
Pocock boundary will be used to determine the significance level at the time of the 
primary analysis. 
 
 
 


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Product:  Romosozumab 
 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 17 of 28 
CONFIDENTIAL 
 
 
(P1NP, BSAP, OC, and sCTX), iPTH, and anti-romosozumab antibodies will not be 
reported to any personnel responsible for study-related management (including the 
sites).  When a panic alert is issued for serum calcium, albumin-adjusted calcium levels, 
phosphorus, or ALP, the sites may perform additional follow-up blood draws for local 
analysis as required to support subject medical care. 
With: 
Table1 outlines the specific analytes for the serum chemistry and hematology 
assessments, as well as other assessments to be conducted on blood samples.   
Chloride, bicarbonate, and calculated adjusted calcium assessments are optional 
after primary analysis. 
On-study (ie, after baseline/Day 1) laboratory results for serum calcium, 
albumin-adjusted calcium, phosphorus, and alkaline phosphatase (ALP), will not be 
reported to any study-related personnel in order to maintain the integrity of the study 
blind up until primary analysis.  These laboratory results will not be blinded after 
primary analysis (refer to Section 10.3 for information on access to individual subject 
treatment assignments by Amgen).  However, in the event of an abnormal value of 
clinical relevance (panic value) obtained in the central laboratory during the primary 
analysis period, sites will be notified of the unblinded value by the central laboratory.  In 
addition, laboratory results for romosozumab levels, sclerostin, BTMs (P1NP, BSAP, 
OC, and sCTX), iPTH, and anti-romosozumab antibodies will not be reported to any 
personnel responsible for study-related management (including the sites).  When a panic 
alert is issued for serum calcium, albumin-adjusted calcium levels, phosphorus, or ALP, 
the sites may perform additional follow-up blood draws for local analysis as required to 
support subject medical care. 
Section: 7.8.1 General 
Table 1 
Replace 
Chloride 
 
BSAPa 
25 (OH) vitamin D 
Bicarbonate 
Platelets 
OCa 
iPTHa 
Albumin-adjusted Calciuma 
 
 
 
a Results of post Day 1 assessments will be blinded to any study-related personnel (including the sites) 
except for serum calcium, albumin-adjusted calcium, phosphorus or alkaline phosphatase in the event of a 
panic value.   
 
 
 
 


Product:  Romosozumab 
 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 18 of 28 
CONFIDENTIAL 
 
 
With: 
Chlorideb 
 
BSAPa 
25 (OH) vitamin D 
Bicarbonateb 
Platelets 
OCa 
iPTHa 
Albumin-adjusted 
Calciuma,b 
 
 
 
a Until the end of the primary analysis period, results of post Day 1 assessments will be blinded to any 
study-related personnel (including the sites) except for serum calcium, albumin-adjusted calcium, 
phosphorus or alkaline phosphatase in the event of a panic value.   
b.Chloride, bicarbonate, and calculated adjusted calcium assessments are optional after primary 
analysis. 
Section:  7.8.1 General 
Replace: 
If informed consent is provided by the subject, Amgen may do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
bone metabolic diseases, the dose response and/or prediction of response to 103 
romosozumab or other protocol-specified therapy, as required, characterize antibody 
response, and characterize aspects of the molecule (eg, metabolites).  Results from this 
analysis will be documented and maintained, but may not be reported as part of this 
study. 
With: 
If informed consent is provided by the subject, Amgen may do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
bone metabolic diseases, the dose response and/or prediction of response to 103 
romosozumab or other protocol-specified therapy, as required, characterize antibody 
response, and characterize aspects of the molecule (eg, metabolites).  Results from this 
analysis will be documented and maintained, but may not be reported as part of this 
study. 
Section:  10.1.2 Secondary Endpoints 
During the Primary Analysis Period 
Add: 
 
Subject incidence of clinical fracture (nonvertebral fracture and clinical 
vertebral fracture) through Month 24 
 
Subject incidence of nonvertebral fracture through Month 24 
 
Subject incidence of hip fracture through Month 24 
 
Subject incidence of clinical vertebral fracture through Month 24 
 
 
 


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Product:  Romosozumab 
 
Protocol Number:  20110142 
Date:  14 September 2016 
Page 28 of 28 
CONFIDENTIAL 
 
 
Replace 
b) 
Phone contact to occur monthly in between clinic visits following the 12-month, double-blind, ALN-controlled study period. When a nonvertebral fracture is 
reported:  Event to be recorded in eCRF, copies of radiographs or other diagnostic images and/or a copy of the radiology report, surgical report, or discharge 
summary should be obtained, included in the subject’s study records and submitted to the central imaging vendor. When back pain is reported (until clinical 
fracture events have been confirmed by the central imaging vendor for at least 330 subjects and all subjects have had the opportunity to complete their Month 24 
study visit): back pain (but not a vertebral fracture) will be recorded as an adverse event. The subject will be asked to complete an unscheduled follow-up clinic 
visit as soon as possible but no later than 21 days after reporting of the back pain. If at the unscheduled clinic visit, the investigator considers the back pain to be 
possibly due to a new or worsening vertebral fracture, a confirmatory lateral spine x-ray will be taken. 
With  
b) 
Phone contact to occur monthly in between clinic visits following the 12-month, double-blind, ALN-controlled study period until the end of study. When a 
nonvertebral fracture is reported:  Event to be recorded in eCRF, copies of radiographs or other diagnostic images and/or a copy of the radiology report, surgical 
report, or discharge summary should be obtained, included in the subject’s study records and submitted to the central imaging vendor. When back pain is reported 
(until clinical fracture events have been confirmed by the central imaging vendor for at least 330 subjects and all subjects have had the opportunity to complete 
their Month 24 study visit): back pain (but not a vertebral fracture) will be recorded as an adverse event. The subject will be asked to complete an unscheduled 
follow-up clinic visit as soon as possible but no later than 21 days after reporting of the back pain. If at the unscheduled clinic visit, the investigator considers the 
back pain to be possibly due to a new or worsening vertebral fracture, a confirmatory lateral spine x-ray will be taken. 
 
Replace 
c) 
Visit windows are ±7 days for the monthly study visits during the 12-month double-blind ALN-controlled study period, ± 14 days for clinic visits during the rest of the 
study. The window for the monthly phone contact in between clinic visits and the end of primary analysis period phone contact is ± 7 days. The window for the end 
of study contact is -14 to +7 days. 
 
With 
c) 
Visit windows are ±7 days for the monthly study visits during the 12-month double-blind ALN-controlled study period, ± 14 days for clinic visits during the rest of the 
study. The window for the monthly phone contact in between clinic visits and the end of primary analysis period phone contact is ± 7 days. The window for the end 
of study contact is -14 to +7 days.