Denosumab (DMAB) Discontinuation And Switching In Glucocorticoid-Induced Osteoporosis (GIOP): A Pilot Study
Phase: PHASE4
Conditions: Osteoporosis
Sponsor: University of Alabama at Birmingham

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Title: 
DENOSUMAB DISCONTINUATION AND SWITCHING IN GLUCOCORTICOID-
INDUCED OSTEOPOROSIS: A PILOT STUDY 
NCT number: 
NCT04177940 
Version date: 
31MAR2026 
 
 
 

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DENOSUMAB DISCONTINUATION AND SWITCHING IN 
GLUCOCORTICOID-INDUCED OSTEOPOROSIS: A PILOT STUDY 
Version 4.3; 260331 
 
Summary of Changes: 
Protocol 
Affected Section(s) 
Summary of Revisions 
Made 
Rationale 
Version 4.3, 260331 
Section 6.1- Primary 
outcome 
Updated the primary 
outcome description  
Primary outcome 
description was incorrectly 
documented in the 
protocol.  
Version 4.2; 201005 
Summary Page, 6, 7, 8, 
Table 1, Figure 1 
Updated site list to include 
University of Verona and 
NoordWest 
Ziekenhuisgroep (NWZ), 
updated visit naming 
conventions, and updated 
inclusion/exclusion criteria 
Addition to 2 new sites and 
removal of Vrije University. 
Updated visit names to 
limit confusion/easier to 
follow, time since most 
recent dose of 
denosumab, and clarified 
timing of screening DXA 
Version 4.1; 200507 
Summary page 
Updated name to 
ReumaClinic 
Typo 

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Version 4; 200421 
Table1. Schedule of visits 
and evaluations 
 
Updated HR-pQCT 
location to ReumaClinic 
Updated procedure 
location to match previous 
update 
Version 3; 200327 
2,8,12,14,15 
Updated investigational 
sites 
Updated Maastricht 
University to Reumaclinic, 
Genk, Belgium.  
 
1 
Contents 
2 
Summary .................................................................................................................................................... 6 
3 
Background ................................................................................................................................................ 7 
4 
Rationale for the Study .............................................................................................................................. 7 
5 
Research Strategy ..................................................................................................................................... 7 
5.1 
Study Design .......................................................................................................................................... 7 
5.2 
Rationale for Study Design ..................................................................................................................... 8 
6 
Outcomes ................................................................................................................................................... 8 
6.1 
Primary Outcome ................................................................................................................................... 8 
6.2 
Secondary Outcomes ............................................................................................................................. 8 
6.3 
Safety Outcomes .................................................................................................................................... 9 
6.4 
Exploratory Outcomes ............................................................................................................................ 9 
7 
Patient Population ...................................................................................................................................... 9 
7.1 
Inclusion Criteria ..................................................................................................................................... 9 
7.2 
Exclusion Criteria ................................................................................................................................... 9 
8 
Study Procedures and Assessments ....................................................................................................... 11 
8.1 
Screening Visit (V1, 2 weeks prior to the first denosumab dose or to randomization among prevalent 
users who have received 2-4 prior doses of denosumab) .............................................................................. 11 
8.2 
Visit 2 (V2) [for new denosumab users] ............................................................................................... 12 
8.3 
Visit 3 (V3) [for individuals with one prior dose of denosumab and new denosumab users seen at V2]
 
12 
8.4 
Visit 4 (V4) Randomization visit ............................................................................................................ 13 
8.5 
Visit 5 (V5) (3 months post-randomization) .......................................................................................... 14 
8.6 
Visit 6 (V6) (6 months post-randomization) .......................................................................................... 14 
8.7 
Visit 7 (V7) (End of Study Visit; 12 months post-randomization) .......................................................... 15 
8.8 
Post-study assessment ........................................................................................................................ 15 
9 
Informed Consent (IC) Procedures .......................................................................................................... 15 
10 
Study Medications .................................................................................................................................... 16 
10.1 
Denosumab .......................................................................................................................................... 16 

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10.1.1 
Packaging and Labeling of Clinical Supplies ................................................................................ 16 
10.1.2 
Storage and Return of Clinical Supplies ....................................................................................... 18 
10.1.3 
Denosumab Preparation and Administration ................................................................................ 18 
10.2 
Zoledronic acid ..................................................................................................................................... 18 
10.2.1 
Packaging and Labeling of Clinical Supplies ................................................................................ 18 
10.2.2 
Storage and Return of Clinical Supplies ....................................................................................... 18 
10.2.3 
Zoledronic Acid Preparation and Administration ........................................................................... 19 
10.3 
Alendronate .......................................................................................................................................... 19 
10.3.1 
Packaging and Labeling of Clinical Supplies ................................................................................ 19 
10.3.2 
Storage and Return of Clinical Supplies ....................................................................................... 19 
10.3.3 
Alendronate Preparation and Administration ................................................................................ 19 
10.4 
Concomitant Medications ..................................................................................................................... 19 
11 
Statistical Considerations ......................................................................................................................... 20 
11.1 
Sample Size Justification ..................................................................................................................... 20 
11.2 
Data Management ................................................................................................................................ 21 
11.3 
Interim Analyses ................................................................................................................................... 22 
12 
Safety Officer ........................................................................................................................................... 22 
12.1 
Responsibilities .................................................................................................................................... 22 
12.2 
Review Process .................................................................................................................................... 23 
12.3 
Meeting Format .................................................................................................................................... 23 
12.4 
Meeting Materials ................................................................................................................................. 23 
12.5 
Reports ................................................................................................................................................. 23 
12.6 
Confidentiality ....................................................................................................................................... 24 
13 
Adverse Events (AE) ................................................................................................................................ 24 
13.1 
Serious AE (SAE) ................................................................................................................................. 24 
13.2 
Suspected Unexpected Serious Adverse Reaction (SUSARs). ........................................................... 24 
13.3 
AE Severity ........................................................................................................................................... 24 
13.3.1 
Mild AE .......................................................................................................................................... 25 
13.3.2 
Moderate AE ................................................................................................................................. 25 
13.3.3 
Severe AE ..................................................................................................................................... 25 
13.4 
Adverse Event (AE) Classifications ...................................................................................................... 25 
13.4.1 
Expected AE ................................................................................................................................. 25 
13.4.2 
Unexpected AE ............................................................................................................................. 25 
13.4.3 
Related to the research ................................................................................................................. 26 
13.4.4 
Unrelated to the research .............................................................................................................. 26 

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13.4.5 
Unanticipated Problems Involving Risks to Participants or Others (Unanticipated Problems) ...... 26 
13.5 
Relationship to Study Drugs ................................................................................................................. 26 
13.5.1 
Probably Related to Study Drug .................................................................................................... 26 
13.5.2 
Possibly Related to Study Drug .................................................................................................... 26 
13.5.3 
Unlikely Related to Study Drug ..................................................................................................... 26 
14 
Investigational Study Sites ....................................................................................................................... 26 
14.1 
Site Recruitment ................................................................................................................................... 26 
14.2 
Participant Recruitment and Consent ................................................................................................... 27 
14.3 
Site Monitoring ..................................................................................................................................... 27 
15 
Institutional Review Board (IRB) .............................................................................................................. 28 
16 
Administrative Procedures ....................................................................................................................... 28 
16.1 
Protocol Amendments .......................................................................................................................... 28 
16.2 
Compliance with Law, Audit, and Debarment ...................................................................................... 28 
16.3 
Compliance with Financial Disclosure Requirements .......................................................................... 29 
16.4 
Confidentiality and Privacy ................................................................................................................... 29 
16.5 
Study Reports ....................................................................................................................................... 29 
16.6 
Publication of results ............................................................................................................................ 29 
16.7 
Changes in study personnel ................................................................................................................. 29 
 
 
 
 

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2 
Summary  
Title: Denosumab discontinuation and switching in glucocorticoid-induced osteoporosis: a pilot study 
Duration: 4 years  
Study Site(s): University of Alabama at Birmingham (US), ReumaClinic (Belgium),University of Verona (Italy), 
and NoordWest Ziekenhuisgroep (NWZ) (Netherlands) 
Approximate number of participants: 45 
Investigators: Kenneth G. Saag MD, MSc, Gary Cutter PhD, Maria I. Danila, MD, MSc, MSPH, Piet Geusens 
MD, Willem Lems MD, Davide Gatti, MD, Giovanni Adami, MD, and Henry G. Raterman, MD.  
Methodology: Open-label randomized multicenter pilot trial to evaluate the efficacy of different bisphosphonate 
strategies to attenuate the rebound effect of bone turnover markers after denosumab discontinuation in 
glucocorticoid-induced osteoporosis.  
 
List Abbreviations, Tables, and Figures 
Abbreviations : 
AE 
Adverse Event 
ALN                     Alendronate 
BMD 
Bone Mineral Density 
CBC                    Complete Blood Count  
CC  
Coordinating Center 
CFR 
Code of Federal Regulation 
CMP                    Complete Metabolic Profile 
CRF                    Case Report Form 
CTX 
Sum C-Terminal Telopeptide 
DHHS  
Department of Health and Human Services 
DXA                    Dual Energy X-ray Absorptiometry 
eCRF                  Electronic Case Report Form 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
GIOP                   Glucocorticoid-induced Osteoporosis 
HR-pQCT            High Resolution peripheral Quantitative Computed Tomography 
IC 
Informed Consent 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV                         Intravenous 
LVA                      Lateral Vertebral Assessment  
OHRP 
  Office of Human Research Protections 
OPG 
  Osteoprotegerin 
ONJ                     Osteonecrosis of the Jaw 
PHI 
  Personal Health Information 
PI 
  Principal Investigator 
P1NP                   Procollagen type 1 Amino-terminal   Propeptide 
PFS                     Pre-filled Syringe 
PTH                     Parathyroid Hormone 
OHRP                 Office of Human Research Protections 
RANKL  
Receptor Activator Of Nuclear Factor Kappa-B Ligand 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOP 
Standard Operating Procedure 
SAE                     Serious Adverse Event 
SUSARs              Suspected Unexpected Serious Adverse Reaction 
USDA                  United States Department of Agriculture 
Tables: 
Table 1. Schedule of 
visits and evaluations 
Table 2. Descriptive 
statistics for CTX data 
from the DAPS study 
used for sample size 
calculation 
 
Figures:  
Figure 1. Study 
Design 
 

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Zol                       Zoledronic Acid 
3 
Background  
Denosumab (Prolia) is a fully human monoclonal antibody with a high affinity (Kd 3 x 10(-12) M) for RANKL 
that can bind and neutralize the activity of human RANKL similar to the action of endogenous osteoprotegerin 
(OPG). Denosumab-induced decrease in bone breakdown is rapidly reversed after discontinuation.1 A rapid 
rebound of bone turnover markers (e.g. Serum C-Terminal Telopeptide (CTX) and Procollagen type 1 Amino-
terminal Propeptide (P1NP)) after denosumab discontinuation may lead to an increased risk of vertebral 
fractures.2 It is less certain if this is a concern in the setting of glucocorticoid-induced osteoporosis (GIOP), 
where the exposure to denosumab may be less acute but where shorter courses of glucocorticoids may lead to 
limited denosumab exposure.3,4 In a previous study, 6-months after discontinuation of denosumab, serum CTX 
increased by +63% and P1NP by +47% compared to baseline (before the initiation of denosumab).1 In the 
same study, denosumab discontinuation was associated with a decrease of lumbar spine and total hip bone 
mineral density (BMD) as early as 1 year since the last denosumab dose.1 In addition, it has been suggested 
that the decrease of BMD after denosumab discontinuation may not be related to previous treatment duration 
in some studies but not in others including a small sample of patients who received denosumab along with 
glucocorticoids for rheumatoid arthritis management.5-7 
 
4 
Rationale for the Study  
While prompt anti-resorptive treatment after denosumab discontinuation has been recommended,8 recently 
published studies created a controversy around the timing and route of bisphosphonate administration 
following denosumab discontinuation in post-menopausal osteoporosis. In such patients, alendronate, an oral 
bisphosphonate administered weekly, did not stop bone loss and did not prevent the development of vertebral 
fractures.9 A potent intravenous (IV) bisphosphonate (i.e., zoledronic acid) administered immediately after 
denosumab discontinuation was found to only partly mitigate the rebound in bone turnover.10,11 In another 
small observational study, delayed administration of zoledronic acid (approximately 3-months after the 
cessation of denosumab activity) was found to be more efficacious in preventing bone loss.12 We will test the 
hypothesis that an increase in bone turnover markers (e.g. CTX and P1NP) in patients currently taking chronic 
glucocorticoids will be attenuated more in those who switch from denosumab to "late" zoledronic acid (9 
months after last denosumab dose) compared to participants randomized to "early" zoledronic acid (6 months 
after last denosumab dose) or weekly alendronate (6 months after last denosumab dose).  
 
5 
Research Strategy  
5.1 
Study Design  
This is an open-label, randomized, parallel-group pilot clinical trial in which Denosumab users will be assigned 
in a 1:1:1 allocation to one the following groups: 
 
• 
Switch from Denosumab 60 mg administered subcutaneously (SC) to weekly oral alendronate (70 
mg; started 6 months after last denosumab dose) 
OR 
• 
Switch from Denosumab 60 mg administered subcutaneously (SC) to one “early” zoledronic acid 
infusion (5 mg; 6 months after last denosumab dose)  
OR 
• 
Switch from Denosumab 60 mg administered subcutaneously (SC) to one “late” zoledronic acid 
infusion (5 mg; 9 months after last denosumab dose) 
 
Participants will be advised to maintain adequate calcium and vitamin D intake per United States Department 
of Agriculture (USDA) and Department of Health and Human Services (DHHS) guidelines. All individuals will 
need ≥ 12 months of previous denosumab treatment (minimum of 2 doses) prior to switching to assigned 
randomization arm. The minimum number of doses (n = 2) is based on published data that the rebound in 
BMD might be less pronounced in patients receiving very limited denosumab.1,13 According to a systematic 
review of patients with multiple vertebral fractures following denosumab cessation, those with ≤2 years of 
denosumab treatment had fewer fractures compared with those with >2 years.14 Therefore, the maximum 
number of prior doses (n = 4) is based on higher incidence of rebound loss of BMD, more rapid turnover, and 

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potentially greater vertebral fractures after discontinuation of denosumab in patients who received more 
extensive treatment. Thus, we will limit our trial to a more restricted use of denosumab duration (2-4 doses) to 
maintain greater homogeneity, given the somewhat smaller planned sample size.  Users of denosumab will be 
sorted into two groups: 
• 
Prevalent users: Defined as individuals with a minimum of one previous dose of denosumab, and up to 
4 previous doses of denosumab (maximum). Prevalent users with one previous dose will receive a 
second dose of denosumab before proceeding to assigned randomization arm. Therefore, 
randomization will occur 2 weeks after screening visit if they had already 2-4 denusomab doses.  
 
• 
New denosumab users: Defined as individuals who have not previously received denosumab. New 
users will receive two doses of denosumab before proceeding to assigned randomization arm. 
Among those participants that are denosumab naïve or that require additional denusomab doses, 
randomization will occur 6 months after their second denusomab dose has been provided and thus 12 
months after the first dose. 
 
• 
Because all denosumab users will be screened for enrollment in the study, some subjects screened  
will not be randomized if they do not meet the requirement of denusomab minimum doses.  
Note: If participants have had previous denosumab doses greater than 8 months ago, they are considered new 
users 
 
5.2 
Rationale for Study Design  
• 
Open-label design: The pilot nature of this study does not allow for a double-blind design, but 
given that the primary outcome is a serological measurement (which will be determined by the 
laboratory blinded to exposure category) this open-label design is unlikely to introduce significant 
bias. 
• 
Need for active comparator: The primary aim of this study is to define an effective exit strategy for 
denosumab users with GIOP. It has been shown that a prompt anti-resorptive treatment is needed 
after denosumab discontinuation, thus the use of placebo would not be ethical. 
• 
Study duration: Total study duration is 48 months; participants will be enrolled for a minimum of 12 
months (prevalent users) or 24 months (new denosumab users) to evaluate changes in bone 
turnover after denosumab discontinuation and switching to one of three study arms. The primary 
outcome will be assessed 6 months after switching to assigned study arm.  
• 
Use of zoledronic acid (ZOL) as intervention: A study of 67 post-menopausal women with 
osteoporosis found that treatment with ZOL 5 mg maintained bone turnover markers in the 
premenopausal range and prevented bone loss in women previously treated with ODN. 
6 
Outcomes 
6.1 
Primary Outcome 
The primary outcome is the absolute difference in the log-transformed CTX values between randomization (V4) 
and 6 months after randomization (V6).    
6.2 
Secondary Outcomes 
• 
Change in the log-transformed CTX between 6 months (V6) and 12 months (V7) 
• 
Percentage change in the log-transformed CTX 12 months (V7) post randomization 
• 
P1NP absolute change (μg/mL) 6 months (V6) post randomization 
• 
P1NP percent change (μg/mL) 12 months (V7) post randomization 

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• 
BMD at spine absolute and percent change (g/cm2) 12 months (V7) post randomization 
• 
BMD at total-hip absolute and percent change (g/cm2) 12 months (V7) post randomization 
• 
BMD at femoral neck absolute and percent change (g/cm2) 12 months (V7) post randomization 
 
6.3 
Safety Outcomes 
Adverse events will be reported as safety outcomes.  
 
6.4 
Exploratory Outcomes 
• 
Fracture outcomes (e.g. vertebral and non-vertebral) as adverse event report 
• 
Serial lateral vertebral assessment (LVA) changes 12 months (V7) post randomization 
• 
High-resolution peripheral quantitative computed tomography (HR-pQCT) parameters changes 6 
(V63), 12 months (V74) post randomization 
• 
Micro-indentation parameters changes 6 (V6), 12 months (V7) post randomization 
 
7 
Patient Population  
 
7.1 
Inclusion Criteria 
• 
Women and  men, age 18 years or older and able to provide informed consent (IC) 
• 
≥ 3 months of glucocorticoid use at > 7.5 mg /day (prednisone equivalent dose) and anticipated to 
remain on glucocorticoids for at least six months 
• 
A baseline BMD T-score of ≤ -1.0 at the lumbar spine, total hip, or femoral neck (prior to denosumab 
use if prevalent user) 
• 
Previous doses of densosumab (for prevalent users) must be continuous and not separated by 
interval greater than 8 months. If interval between densoumab doses is greater than 8 months, the 
participant is considered a new user. 
 
7.2 
Exclusion Criteria 
• 
Patients with fewer than three lumbar vertebrae that could be evaluated on dual energy x-ray 
absorptiometry (DXA) 
• 
No past IV bisphosphonates. Oral bisphosphonates must not have been taken in the past 2 months 
and for no more than 2 cumulative months of use in the past year (e.g. 8 total weekly doses of 
alendronate maximum) 
• 
Greater than 24 months (>4 injections) of prior treatment with denosumab 
• 
Women of childbearing potential, who are not currently using birth control, are pregnant, planning to 
become pregnant, or are breastfeeding. For women of childbearing potential: refusal to use 2 highly 
effective forms of contraception and to continue this practice for 7 months after last injection of 
study medication* 
• 
Men planning to conceive in the next 12 months 
• 
Unstable systemic medical condition 
• 
Uncontrolled hyperthyroidism  
• 
Uncontrolled hypothyroidism  
• 
History of Addison disease 
• 
History of osteomalacia 
• 
History of osteonecrosis of the jaw (ONJ) 
• 
History of atypical femur fracture  
• 
History of tooth extraction, jaw surgery, dental implants, or other dental surgery within the prior 6 
months 
• 
History of anorexia nervosa, bulimia (by history or physical) or obvious malnutrition. 
• 
Invasive dental work(implants/surgery) planned in the next 2 years 
• 
History of Paget’s disease of bone 
• 
Other bone diseases which affect bone metabolism 
• 
Vitamin D deficiency [25(OH) vitamin D level < 20 ng/mL (<49.9 nmol/L)]†  

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7.1 Exclusion Criteria Continuted 
• 
Hypercalcemia >10% above upper limit of normal (ULN) 
• 
Elevated transaminases or total bilirubin ≥ 2.0 x ULN 
• 
History of any solid organ or bone marrow transplant 
• 
Malignancy within the last 5 years (except cervical carcinoma in situ or basal cell carcinoma or 
localized squamous cell carcinoma of the skin) 
• 
Hypocalcemia <10% below lower limit of normal (LLN) 
• 
Estimated glomerular filtration rate < 30 mL/minute/1.73 m^2 
• 
Intolerance to calcium supplements, vitamin D supplements 
• 
Contraindication to, or poorly tolerant of denosumab therapy (including hypersensitivity to the drug) 
• 
Contraindication to, or poorly tolerant of zoledronic therapy (including hypersensitivity to the drug) 
• 
Contraindication to, or poorly tolerant of alendronate (including hypersensitivity to the drug and 
sever gastrointestinance intolerance to oral bisphsphonates) 
• 
Recipient of an investigational drug within 4 weeks prior to study drug administration  
• 
Not a good candidate for study participation in opinion of investigator$ 
† Potential participants could be re-screened after a periord of vitamin D supplementation as prescribed by their primary care physician/health care 
provider.  
 
*Denosumab is contraindicated for use in pregnant women because it may cause harm to a fetus. Animal studies at doses 25-fold higher than the 
recommended human dose have shown increased fetal loss during gestation, stillbirths, and postnatal mortality, and absent lymph nodes. There are no 
controlled data in human pregnancy, and insufficient data to inform any drug-associated risks for adverse developmental outcomes. No information is 
available on the clinical use of this drug during breastfeeding. Premenopausal women will have a pregnancy test before the study starts and again 
throughout the study.  
 
$ If at the time of randomization the site PI deems the participant is no longer a suitable candidate for the study they will be discontinued. 
 
8 
Study Procedures and Assessments 
All study visits and procedures will be performed in facilities at the University of Alabama at Birmingham-UAB 
(US), ReumaClinic (Belgium), University of Verona (Italy), and NWZ (Netherlands) 
 
If participants suspect that they may have become pregnant during the study, the study coordinator will contact 
the study principal investigator (PI) immediately and the PI or Study Coordinator will instruct the participant to 
stop taking all study medication. If it is confirmed that the participant is pregnant, they will be withdrawn from 
the study. The study PI will schedule a follow-up visit and may choose to follow the outcome of the pregnancy. 
If it is discovered that participants are breastfeeding, they are not eligible to participate in the study and their 
participation will be discontinued immediately. 
 
8.1 
Screening Visit (V1, 2 weeks prior to the first denosumab dose or to randomization among 
prevalent users who have received 2-4 prior doses of denosumab) 
At the screening visit, the study objectives will be explained to potential participants. Participants will have the 
opportunity to ask questions before any protocol-specified screening procedures are initiated and informed 
consent (IC) is obtained. After consent is obtained, a study ID will be assigned. During the screening visit, the 
following procedures will be performed, and information will be obtained to determine eligibility to continue in 
this research study. A copy of the signed and dated informed consent form (ICF) will be provided to the patient. 
The following procedures will be completed during the screening visit: 
• IC 
• Review inclusion/exclusion criteria 
• Review of current and/or past treatment with denosumab 60 mg – determination whether the 
subject is an new denosumab user (defined above) or a prevalent denosumab user (defined 
above) 
• Medical history  
o Assess osteoporosis history and past fragility fractures history 
o Current medication review  
o Medication history (including use of: prescription medications (e.g. other osteoporosis 
medications)) 

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o Dietary supplement/vitamin use 
• Full physical exam includes, but is not limited to 
o Vital signs/Weight/Height 
o Dermatological 
o Chest and cardiac  
o Abdominal 
o Musculoskeletal and nervous system examinations 
• Screening visit laboratory  
o Complete blood count (CBC) with differential 
o Comprehensive metabolic panel (CMP)  
o Calcium 
o Vitamin D 
o Phosphorus 
o Intact Parathyroid Hormone (PTH) 
o Bone turnover (serum CTX & P1NP) 
o Serum pregnancy test in non-postmenopausal women‡ 
o Serum banking 
• DXA at lumbar spine, total-hip and femoral neck 
At the conclusion of visit, participants should be advised to maintain adequate calcium and vitamin D intake per 
USDA and DHHS guidelines.   
 
‡Postmenopausal defined as a woman:  Age ≥ 55 years, with cessation of menses for 12 or more months;  Age < 55 years, but no spontaneous menses for at least 2 years; 
Age < 55 years and spontaneous menses within the past 1 year, but currently amenorrheic (e.g. spontaneous or secondary to hysterectomy); AND with documented 
postmenopausal gonadotropin levels (luteinizing hormone and follicle-stimulating hormone levels > 40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or according to the 
definition of "postmenopausal range" for the laboratory involved; Underwent a bilateral oophorectomy. 
 
8.2 
Visit 2 (V2) [for new denosumab users] 
New denosumab users will be required to receive 12 months of denosumab before randomization (switching). 
New denosumab users with zero prior denosumab use will report 2 weeks after the screening visit and signing 
of the ICF to: 
• 
Updated medical history and review of concomitant medications 
• 
Obtain and record vital signs, including pulse rate, sitting blood pressure, and body temperature 
• 
Targeted physical exam includes, but is not limited to 
o Dermatological 
o Chest and cardiac  
o Abdominal 
o Musculoskeletal and nervous system examinations 
o Weight/Height 
• 
Laboratory 
o CBC with differential 
o Calcium 
• 
Administer denosumab 60 mg SC 
• 
Assessment of Adverse Events (AEs) (potentially attributable to denosumab but not study strategy) 
At the conclusion of visit, participants should be advised to maintain adequate calcium and vitamin D intake per 
USDA and DHHS guidelines.   
 
8.3 
Visit 3 (V3) [for individuals with one prior dose of denosumab and new denosumab users seen at 
V2] 
Participants with one prior denosumab dose will report within 6 months after the screening visit for a second 
and participants with no prior denosumab use (determined at screening) will report 6 months after Visit 2 to: 

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• 
Updated medical history and review of concomitant medications 
• 
Obtain and record vital signs, including pulse rate, sitting blood pressure, and body temperature 
• 
Targeted Physical exam includes, but is not limited to 
o Dermatological 
o Chest and cardiac  
o Abdominal 
o Musculoskeletal and nervous system examinations 
o Weight/Height 
• 
Laboratory 
o CBC with differential 
o Calcium 
o Urine pregnancy test 
• 
Administer denosumab 60 mg SC 
• 
Assessment of Adverse Events (AEs) (potentially attributable to denosumab but not study strategy) 
At the conclusion of visit, participants should be advised to maintain adequate calcium and vitamin D intake per 
USDA and DHHS guidelines.   
8.4 
Visit 4 (V4) Randomization visit 
The randomization visit will occur within 2 weeks from the screening visit and signing of the ICF for prevalent 
denosumab users. The randomization visit will occur 12 months after screening visit for new denosumab users. 
During the randomization visit patients will be randomized across study arms. During the randomization visit, 
markers for the study primary and secondary outcomes will be assessed, as well as Bone Mineral Density 
(BMD) at the lumbar spine, total hip and femoral neck, Lateral Vertebral Assessment (LVA), HR-pQCT, micro-
indentation (at one study site), and additional data collection needed for safety monitoring. 
• 
Updated medical history and review of concomitant medications 
• 
Obtain and record vital signs, including pulse rate, sitting blood pressure, and body temperature 
• 
Targeted physical exam includes, but is not limited to 
o Dermatological 
o Chest and cardiac  
o Abdominal 
o Musculoskeletal and nervous system examinations 
o Weight/Height 
• 
Laboratory 
o CBC with differential 
o CMP 
o Calcium 
o Vitamin D 
o Bone Turnover (serum CTX and serum P1NP)  
o Serum banking 
o Urine pregnancy 
• 
DXA at lumbar spine, total-hip and femoral neck 
• 
LVA 
• 
HR-pQCT  
• 
Micro-indentation (participants enrolled at UAB) 
• 
Administer “early” zoledronic acid in patients randomized to this treatment arm 
• 
Dispense alendronate to patients randomized to this treatment arm  
• 
Assessment of Adverse Events (AEs) (potentially attributable to denosumab but not study strategy) 
 

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At the conclusion of visit, participants should be advised to maintain adequate calcium and vitamin D intake per 
USDA and DHHS guidelines.   
 
8.5 
Visit 5 (V5) (3 months post-randomization)  
All participants will report 3 months following the randomization visit (V4) to: 
• 
Updated medical history and review of concomitant medications 
• 
Obtain and record vital signs, including pulse rate, sitting blood pressure, and body temperature 
• 
Targeted Physical exam includes, but is not limited to 
o Dermatological 
o Chest and cardiac  
o Abdominal 
o Musculoskeletal and nervous system examinations 
o Weight/Height 
• 
Laboratory 
o CBC with differential 
o CMP 
o Calcium 
o Vitamin D 
o Bone Turnover (serum CTX and serum P1NP)  
o Serum banking 
o Urine pregnancy 
• 
DXA at lumbar spine, total-hip and femoral neck   
• 
LVA  
• 
Dispense alendronate to patients randomized to this treatment arm 
• 
Administer “late” zoledronic acid in patients randomized to this treatment arm 
• 
Assessment of AEs 
Advise participants to maintain adequate calcium and vitamin D intake per USDA and DHHS guidelines.  
8.6 
Visit 6 (V6) (6 months post-randomization)  
Participants will report 3 months following Visit 5 to:  
• 
Updated medical history and review of concomitant medications 
• 
Obtain and record vital signs, including pulse rate, sitting blood pressure, and body temperature 
• 
Targeted Physical exam includes, but is not limited to 
o Dermatological 
o Chest and cardiac  
o Abdominal 
o Musculoskeletal and nervous system examinations 
o Weight/Height 
• 
Laboratory 
o CBC with differential 
o CMP 
o Calcium 
o Vitamin D 
o Bone Turnover (serum CTX and serum P1NP)  
o Serum banking 
o Urine pregnancy 
• 
DXA at lumbar spine, total-hip and femoral neck 
• 
LVA 

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Version 4.3; 260331 
• 
HR-pQCT  
• 
Micro-indentation (participants enrolled at UAB) 
• 
Dispense alendronate to patients randomized to this treatment arm 
• 
Assessment of AEs 
 
Advise participants to maintain adequate calcium and vitamin D intake per USDA and DHHS guidelines. 
8.7 
Visit 7 (V7) (End of Study Visit; 12 months post-randomization) 
Participants will report 6 months following Visit 6:  
• 
Updated medical history and review of concomitant medications 
• 
Obtain and record vital signs, including pulse rate, sitting blood pressure, and body temperature 
• 
Targeted Physical exam includes, but is not limited to 
o Dermatological 
o Chest and cardiac  
o Abdominal 
o Musculoskeletal and nervous system examinations 
o Weight/Height 
• 
Laboratory 
o CBC with differential 
o CMP 
o Calcium 
o Vitamin D 
o Bone Turnover (serum CTX and serum P1NP)  
o Serum banking 
o Urine pregnancy 
• 
DXA at lumbar spine, total-hip and femoral neck 
• 
LVA 
• 
HR-pQCT  
• 
Micro-indentation (participants enrolled at UAB) 
• 
Assessment of AEs 
 
Advise participants to maintain adequate calcium and vitamin D intake per USDA and DHHS guidelines. 
8.8 
Post-study assessment 
All patients will be referred to their primary care physician or rheumatologist/endocrinologist at the completion 
of the study. Based on physician estimation of fracture risk (including, but not limited to, the last visit CTX value 
and ongoing glucocorticoid treatment), individuals will continue an out-of-study an anti-resorptive medication. 
9 
Informed Consent (IC) Procedures 
 
The IC process will be carried out by one of the study investigators in conjunction with the study 
coordinator/research assistant involved at the screening visit. During the screening visit, the study participant 
(at a minimum) will review the ICF and the research study coordinator obtaining consent will explain each 
section. The participant will be given as much time as they need to read and ask questions about the ICF. The 
individual or patient’s legally authorized representative will be informed that he/she is not obligated to 
participate in the study and that participation is strictly voluntary and that he/she may withdraw from the study 
at any time, and withdrawal of consent will not affect his/her subsequent medical treatment or relationship with 
the treating physician. The IC process will ensure that there is no penalty for not participating and that 
treatment will not be compromised if an individual does not participate, or if they cease participation at any 
time. 

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By signing the consent form, the participant authorizes the use of their personal health information (PHI), that 
they understand the study and its benefits and risks, and agree to all other aspects of the study outlined in the 
ICF. It allows the participant the opportunity to decide whether they want to participate in a study. During this 
process, individuals will be informed of all aspects of the study so that they can make an informed decision. 
Participants will then confirm their willingness to participate in the research study by signing the ICF. 
After the participant has signed the consent form, the Principal Investigator (PI), and the research assistant 
conducting the visit will each sign and date the ICF. A signed version of the consent form will be kept in the 
study binder and an additional copy of the consent form will also be given to the participant. 
The ICF contains at a minimum the following: 
• 
Disclosure of relevant information to prospective participants about the research 
• 
The participant’s voluntary agreement to participate in a research study without coercion or undue 
influence 
• 
Complete disclosure of any appropriate alternative procedures and their risks and benefits 
• 
Disclosure of the extent of confidentiality that will be maintained 
• 
Statement of compensation and/or medical treatment available if injury occurs 
• 
Name, address, and telephone number of the PIs 
If there is a change to any of the study procedures that may affect the participant, the ICF will be revised and 
submitted for approval to the Institutional Review Board (IRB). All participants enrolled in the study prior to a 
change in procedures will sign the amended consent form. Signed consent forms will be kept as part of the 
study record for at least 7 years after completion of the study. Based on current EU guidelines the longer 
archive is only required for “trials in which the clinical trial data are used to support a marketing authorization 
(including Paediatric Use Marketing Authorisations under Regulation 1901/2006), Directive 2003/63/EC 
(amending Directive 2001/83/EC)”. This pilot study is not being conducted to support a label change.  
10 Study Medications  
10.1 Denosumab  
Denosumab (Prolia) is a fully human monoclonal antibody with a high affinity (Kd 3 x 10(-12)M) for RANKL that 
can bind and neutralize the activity of human RANKL, similar to the action of endogenous OPG. The 2-year 
data from the randomized, double blind, active controlled, phase III trial demonstrated that denosumab 
treatment was effective in the treatment and prevention of glucocorticoid-induced osteoporosis when compared 
with risedronate.15,16 In the United States and Canada, denosumab has approvals for indications including the 
treatment of glucocorticoid-induced osteoporosis. In the European Union, denosumab has been approved for 
the treatment of glucocorticoid-induced osteoporosis. 
10.1.1 Packaging and Labeling of Clinical Supplies  
Denosumab will be manufactured and provided to the investigational pharmacies at the University of Alabama 
at Birmingham (UAB), ReumaClinic, University of Verona, and NWZ by Amgen Inc. Dispensation of 
denosumab will be handled by the investigational pharmacies at the UAB, ReumaClinic, Vrije University, 
University of Verona and NWZ. Received denosumab will be annotated with the approved IRB protocol 
number(s). 
 
 
 

17 
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Table1. Schedule of visits and evaluations 
Visit description / Study 
procedures 
Screening 
(V1) ** 
 
V2  
New users 
with zero 
prior 
denosumab 
doses 
V31  
Prevalent 
users with 
a single (1) 
prior 
denosumab 
dose and 
“new 
users” 
returning 
for second 
dose 
V4 Baseline/ 
Randomization 
 
V5 
 
V6 
 
V7 
 
 
-12 mo 
-6 mo 
0 
3 mo 
6 mo 
12 mo 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Review of current and/or 
past treatment with 
denosumab 
X 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
Updated medical history 
and concomitant 
medications 
 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Physical examination (PE) 
X 
 
 
 
 
 
 
Targeted PE 
 
X 
X 
X 
X 
X 
X 
Laboratory 
 
 
 
 
 
 
 
CBC with diff  
X 
X 
X 
X 
X 
X 
X 
CMP  
X 
 
 
X 
X 
X 
X 
Calcium 
X 
X 
X 
X 
X 
X 
X 
Vitamin D   
X 
 
 
 
 
 
 
Intact PTH 
X 
 
 
 
 
 
 
Bone 
Turnover 
(serum CTX 
and P1NP) 
X 
 
 
X 
X 
X 
X 
Serum 
banking 
X 
 
 
X 
X 
X 
X 
Pregnancy test § 
X 
 
X 
X 
X 
X 
X 
DXA lumbar spine/total-
hip/femoral neck  
X 
 
 
X 
X  
X 
X 
LVA 
 
 
 
X 
X 
X 
X 
HR-pQCT (ReumaClinic) 
 
 
 
X 
 
X 
X 
Micro-indentation (UAB) 
 
 
 
X 
 
X 
X 
Administer denosumab 
60mg SC 
 
X 
X 
 
 
 
 
Dispense oral alendronate 
 
 
 
X 
X 
X 
 
Administer “early” 
zoledronic acid 
 
 
 
X 
 
 
 
Administer “late” 
zoledronic acid 
 
 
 
 
X 
 
 
Assess AEs 
 
X 
X 
X 
X 
X 
X 
 
CMP = Complete metabolic profile, CBC with diff = Complete blood count with Differentiation, PTH = Parathyroid hormone, *Includes sitting blood 
pressure, heart rate, respiratory rate, and body temperature; § for non-postmenopausal women defined in section 7.   
 
** 2 weeks prior to the first DMAB dose for new users or to randomization among prevalent users who have received 2-4 prior doses of denosumab  

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10.1.2 Storage and Return of Clinical Supplies 
Investigational clinical supplies will be handled and stored safely and properly, and kept in a secured location 
to which only the PI and designated staff members have access. Clinical supplies will be dispensed only in 
accordance with the protocol. Study sites will keep accurate records of the clinical supplies received from 
Amgen, the amount dispensed for each patient, and the amount remaining at the conclusion of the study.  The 
coordinator will mark the label of any vials that are not to be used with a large X, and document the reason for 
rejecting them on the drug accountability log. In accordance with good pharmacy practice, gloves will be worn 
during preparation of the dose. We will maintain an inventory of drug supplies received and dispensed. Upon 
completion or termination of the study, all unused denosumab will be destroyed by participating sites, and 
documentation of destruction will be entered into the study database. All drug supply returns will be made to 
the study drug packaging and shipment vendor specified in the list of external facilities and personnel. 
10.1.3 Denosumab Preparation and Administration 
Denosumab will be presented as a pre-filled syringe (PFS) of 60 mg. All new denosumab users will receive 
denosumab through a SC route of administration. Denosumab will not be administered intravenously, 
intramuscularly, or intradermal. Authorized site personnel will administer all SC injections. Denosumab SC 
injection will be administered as the last procedure after all other study visit procedures have been completed. 
Prior to administration of denosumab, it will be brought to room temperature in original container (allowed to 
stand ~15 to 30 minutes); it will not be warmed by any other method. The denosumab solution may contain 
trace amounts of translucent to white protein particles; however, it will not be used if cloudy, discolored (normal 
solution should be clear and colorless to pale yellow), or contains excessive particles or foreign matter. The 
study staff will avoid vigorous shaking. The study staff will administer via SC injection in the upper arm, upper 
thigh, or abdomen. The injection will not be administered in the same arm from which blood is drawn. 
10.2 Zoledronic acid 
Participants who will be randomized in the “early’’ or ‘’late’’ zoledronic acid arm will receive one infusion of 
Zoledronic acid 5 mg. The data from the randomized, double blind, placebo controlled, phase III trial 
demonstrated that zoledronic acid treatment was effective in the prevention and treatment of glucocorticoid-
induced osteoporosis when compared with risedronate. 17 In the United States, the European Union, and 
Canada, zoledronic acid has approvals for indications including the treatment of glucocorticoid-induced 
osteoporosis.  
10.2.1 Packaging and Labeling of Clinical Supplies  
Zoledronic acid will be purchased and labeled by the investigational pharmacy at University of Alabama at 
Birmingham. Dispensation of study drug will be handled by the investigational pharmacies at the UAB, 
ReumaClinic, University of Verona and NWZ. Study drug labeling will be annotated with the approved IRB 
protocol number(s). 
10.2.2 Storage and Return of Clinical Supplies 
Investigational clinical supplies will be handled and stored safely and properly, and kept in a secured location 
to which only the PI and designated staff members have access. Clinical supplies will be dispensed only in 
accordance with the protocol. Study sites will keep accurate records of the clinical supplies received from 
Amgen and UAB, the amount dispensed for each patient, and the amount remaining at the conclusion of the 
study. The coordinator will mark the label of any vials that are not to be used with a large X, and document the 
reason for rejecting them on the drug accountability log. In accordance with good pharmacy practice, gloves 
will be worn during preparation of the dose. We will maintain an inventory of drug supplies received and 
dispensed. Upon completion or termination of the study, all unused zoledronic acid will be destroyed by 
participating sites, and documentation of destruction will be entered into the study database. All drug supply 

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Version 4.3; 260331 
returns will be made to the study drug packaging and shipment vendor specified in the list of external facilities 
and personnel. 
10.2.3 Zoledronic Acid Preparation and Administration 
Zoledronic acid will be presented as a sterile solution in bottles for intravenous infusion. One bottle with 100 
mL solution contains 5.330 mg of zoledronic acid monohydrate, equivalent to 5 mg zoledronic acid on an 
anhydrous basis. All subjects randomized to “early” or “late” zoledronic acid arms will receive zoledronic acid 
through a IV route of administration. Zoledronic acid will not be administered subcutaneously, intramuscularly, 
or intradermal. Authorized site personnel will administer all IV infusions. Zoledronic acid infusion will be 
administered following the procedures indicated in the drug label. Following administration participants will be 
observed for 1 hour for any AEs.  
10.3 Alendronate 
Participants who are randomized to the alendronate arm will receive oral alendronate (70 mg) for 12 months 
(52 pills total). The data from the randomized, double-blind, placebo-controlled, phase III trial demonstrated 
that alendronate treatment was effective in the prevention and treatment of glucocorticoid-induced 
osteoporosis when compared with placebo.18 In the United States, the European Union, and Canada, 
alendronate has approvals for indications including the treatment of glucocorticoid-induced osteoporosis.   
10.3.1 Packaging and Labeling of Clinical Supplies  
Alendronate will be purchased by the investigational pharmacy at the University of Alabama at Birmingham 
(Chris Chapleau, PHarmD; 205-975-0376). Labeling of study drug will be handled by the investigational 
pharmacy at University of Alabama at Birmingham. Study drug labeling will be annotated with the approved 
IRB protocol number(s). Dispensation of study drug will be handled by the investigational pharmacies at the 
UAB, ReumaClinic,  University of Verona and NWZ. Study drug labeling will be annotated with the approved 
IRB protocol number(s). 
10.3.2 Storage and Return of Clinical Supplies 
Investigational clinical supplies will be handled and stored safely and properly, and kept in a secured location 
to which only the PI and designated staff members have access. Clinical supplies will be dispensed only in 
accordance with the protocol. Study sites will keep accurate records of the clinical supplies received from 
Amgen, the amount dispensed for each patient, and the amount remaining at the conclusion of the study.  The 
coordinator will mark the label of any pill case that are not to be used with a large X, and document the reason 
for rejecting them on the drug accountability log. In accordance with good pharmacy practice, gloves will be 
worn during preparation of the dose. We will maintain an inventory of drug supplies received and dispensed. 
Upon completion or termination of the study, all unused alendronate will be  destroyed by participating sites, 
and documentation of destruction will be entered into the study database. All drug supply returns will be made 
to the study drug packaging and shipment vendor specified in the list of external facilities and personnel. 
10.3.3 Alendronate Preparation and Administration 
Alendronate will be presented as tablets for oral administration contain 91.37 mg of alendronate monosodium 
salt trihydrate, which is the molar equivalent of 70 mg of free acid, and the following inactive ingredients: 
microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate. All subjects 
randomized to alendronate arm will receive oral alendronate. All OS administration will be self-administered by 
patients randomized in the alendronate arm. Individuals will be instructed to assume alendronate orally 
following the procedures indicated in the drug label. 
10.4 Concomitant Medications 
Concomitant medications are defined as drug or biological products other than the study drug(s) taken by a 
participant during the clinical trial. This includes other prescription medications (including preventive vaccines), 

20 
Version 4.3; 260331 
over-the-counter medications, herbal medications, vitamins, and food supplements. A comprehensive list of 
participant’s concomitant medications will be collected at baseline and at each visit. This will include the name 
of the drug/vitamin/supplement, dose, route of administration, start and stop dates, and the reason for which 
the medication was taken. All medications will be listed by participant using the generic name(s) of the 
drug/vitamin/supplement. AE related to the use of a concomitant drug/vitamin/supplement will be documented 
on the adverse event case report form (CRF).  
Medications that will not be allowed during participation in this study include the following: 
 
• 
Risedronate (Actonel, Atelvia) 
• 
Ibandronate (Boniva, Bonviva) 
• 
Pamidronate (Aredia) 
• 
Teriparatide (Forteo, Forsteo) 
• 
Abaloparatide (Tymlos) 
• 
Raloxifene (Evista) 
• 
Estrogen or estroprogestinic treatment (Premarin, Prempro, Prefest, Ativella, Femhrt, Climara, 
Menostar, Vivelle) 
• 
Denosumab 120 mg (Xgeva) 
 
11 Statistical Considerations 
 
We intend to use the results of this pilot study to demonstrate feasibility, preliminary efficacy, and estimate 
potential effect sizes (with its accompanying 95% CI) that will lead to future, larger clinical trials using other 
funding mechanisms. 
 
11.1 Sample Size Justification 
The sample size is based on feasibility needs to estimate the change in bone turnover marker (serum CTX) 
using alendronate, "early" zoledronic acid, and "late" zoledronic acid across the three switching arms at 6 
months post-randomization.  The study is descriptive in nature as a Phase II feasibility study, but based on 
data provided by Amgen Inc. from the Denosumab Adherence Preference and Satisfaction (DAPS) study. As can 
be seen from Table 2 below, the range of percent changes on CTX from the DAPS study ranges from -78.65% 
to 815.38% with the median a positive 11.5%.  We chose the log of the change in serum CTX as the 
comparison because it greatly reduces the skewness and appears to show the most normally distributed 
assessments of change facilitating comparisons of mean or median treatment effects in the simplest and least 
distorted manner and because of the normality will enable the most efficient summary of the results using a 
parametric confidence interval in this small feasibility study.  We will compare the log of the absolute difference 
in CTX calculated as CTX at 6 months post-randomization visit – CTX at  randomization visit, equivalent to 
percent change, at the individual level for estimating the overall mean percent changes amongst individuals in 
each of the 3 switching groups.  Based on data kindly provided by Amgen Inc. from the DAPS study, the mean 
change using the metric above was 0.11 with a standard deviation of 0.80 based on 59 participants in the 
alendronate arm. A sample size of 15 subjects per group produces a two-sided 95% confidence interval with a 
distance from the mean paired difference to the limits that is equal to 0.405 when the estimated standard 
deviation of the paired differences is 0.80 for characterizing the change within any one of the treatment groups.  
Group sample sizes of 15 produce a two-sided 95% confidence interval using a normal-distribution based on 
the pairwise differences between the three groups. The distance from the difference in mean log of the 
changes from randomization to 6 months post randomization is equal 0.573 for any pair of the switching 
groups when the estimated standard deviations are 0.80 in the alendronate arm.  Given this is a feasibility 
study, we have not adjusted the Type I error level in these planned confidence intervals of the differences 
between the switching arms, although it is known that adjusted intervals for the 3 pairwise estimates would be 
at 98.3% confidence level if we used a Bonferonni Correction will be slightly wider, 0.697, but probably will not 
alter the decisions about future studies and thus, were not incorporated. 
 
 

21 
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Table 2. Descriptive statistics for CTX data from the DAPS study used for sample size calculation 
Variable 
N 
Mean 
Std Dev 
Minimum 
Lower 
Quartile 
Median 
Upper 
Quartile 
Maximum 
% Change 
59 
53.79 
146.28 
-78.65 
-35.00 
11.50 
103.31 
815.38 
Diff in 
log(CTX)* 
59 
0.11 
0.80 
-1.54 
-0.43 
0.11 
0.71 
2.21 
Cube root of 
% change 
59 
1.14 
4.02 
-4.28 
-3.27 
2.26 
4.69 
9.34 
AUC 
59 
1.16 
0.56 
0.38 
0.77 
0.96 
1.52 
3.06 
AUC baseline 
adjusted** 
59 
0.10 
0.52 
-1.12 
-0.14 
0.04 
0.36 
1.60 
N: number of subjects with non-missing data 
*: calculated as log(CTX at 18M) – log(CTX at 12M) at individual level. 
**: with rectangle of baseline subtracted. 
 
11.2 Data Management  
 
Dr. Gary Cutter of the UAB School of Public Health will oversee all data management and analysis for the 
proposed study. Dr. Cutter and the study team at UAB will ensure that the data collected and analyzed for this 
study are of the highest quality possible and will be accomplished in part by having thorough edit checks as 
close to collection in time as possible, and updated as needed to guarantee high quality data through quality 
control and quality assurance. Edit checks will be reviewed by the statisticians, program manager, as well as 
other team members on an ongoing basis to evaluate whether any checks need to be added or any existing 
checks need to be modified. All data will be entered into the REDCap electronic Data Entry System (Nashville, 
TN) for seamless data management and auditing across the study sites. All analyses will be conducted using 
Statistical Analysis System (SAS; Cary, NC) Version 9.4 or higher or R-routines for specialty programs as 
needed. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored in the REDCap electronic Data Entry System. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by clinical sites 
and by research staff will be secured and password protected. The study participant’s contact information will 
be securely stored at each clinical site for internal use during the study. At the end of the study, all records will 
continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional 
policies, or sponsor requirements. 
 
11.3 Statistical Analyses 
 
Intervention groups will be compared on baseline characteristics and will include the following.  
• 
Inclusion and Exclusion Criteria 
• 
Demographics (e.g. race, age) and Baseline Characteristics  
• 
Medical History 
• 
Disease History (e.g. duration of disease) 
• 
Medication History (e.g. previous doses of DMAB) 
• 
Laboratory Values (e.g. serum CTX/P1NP) 
Demographics will be summarized using descriptive statistics, by treatment group and site.  
 

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The analysis population will be the intent to treat population for analysis for both primary and secondary 
outcomes will include all randomized participants who received at least one dose of study medication 
(alendronate or zoledronic acid) during treatment period.  While the sample size was evaluated using pairwise 
differences and normal distribution derived confidence intervals, the primary analysis will be conducted using 
all available data at 3 months (visit2) and 6 months (visit 3) post-randomization for the primary endpoint for log 
change in CTX in a repeated measures model that has treatment group as a fixed effect and participants as 
random effects to estimate the confidence intervals. This will assume that any individuals not completing the 
study who have a 3 month observation are missing at random, but will allow the use of the maximum number 
of participants and their observations.  While statistical significance of the differences can be tested using 
these models, we do not propose hypothesis testing, but confidence intervals and effect size comparisons.   
 
Sensitivity analyses will be conducted using imputation of the missing observations from the same treatment 
groups using 5 replicates and averaging the missing results.  These two (ITT and imputed results) will be 
compared to the results of a completers analysis for the descriptive summarization.   
 
Secondary endpoints will be similarly evaluated.  CTX absolute and percent change (ng/mL; log transformed) 6 
(visit 3) and 12 months post-randomization (visit 7) and P1NP absolute and percent change (μg/mL) 6, 12 
months post randomization will utilized the mixed effects models.  BMD at spine absolute and percent change 
(g/cm2) 12 months post randomization; BMD at total-hip absolute and percent change (g/cm2) 12 months post 
randomization; BMD at femoral neck absolute and percent change (g/cm2) 12 months post randomization will 
be examined using the dependent variable as the BMD parameters, adjusted for baseline with comparisons of 
treatment groups.   We will explore subgroup differences in outcomes between new and prevalent denosumab 
users, and descriptive analyses comparing the two sets of changes will be produced. 
 
11.3 Interim Analyses  
 
Not applicable  
 
12 Safety Officer 
 
As the safety of the study participants is the highest priority for this project, we will appoint an independent 
safety officer, without conflict of interest with the study, to be responsible for evaluating the scientific issues 
related to the study. The safety officer will receive data periodically (e.g. every 6 months) including any pre-
specified time points. The outcome of each patient is the top priority and as such, a process for the ongoing 
monitoring of results by independent scientists is important to maintain throughout the duration of the project. 
The safety officer may recommend at any point that the study be stopped if the risk-benefit assessment for 
continuance is deemed unfavorable. 
 
Safety will be summarized by occurrence and per participant over the study descriptively, although no safety 
issues are expected. 
 
12.1 Responsibilities  
 
The Safety Officer responsibilities are to:  
• 
Review the research protocol, ICFs and plans for data safety and monitoring  
• 
Evaluate the progress of the trial, including periodic assessments of data quality and timeliness, 
recruitment, accrual and retention, participant risk versus benefit, and other factors that can affect 
study outcome 
• 
Consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the participants or 
the ethics of the trial 
• 
Review study performance, make recommendations and assist in the resolution of problems 
reported by the PI  
• 
Protect the safety of the study participants 

23 
Version 4.3; 260331 
• 
Report on the safety and progress of the trial  
• 
Make recommendations to the PIs, and, if required, to the FDA concerning continuation, termination 
or other modifications of the trial based on the observed beneficial or AEs of the treatment under 
study 
• 
Ensure the confidentiality of the study data and the results of monitoring  
• 
Assist in the commenting on any problems with study conduct, enrollment, sample size and/or data 
collection 
• 
The Safety Officer will discharge himself/herself from his/her duties when the last participant 
completes the study 
 
12.2 Review Process  
 
At the first meeting, the Safety Officer will discuss the protocol, suggest modifications, and establish study-
monitoring guidelines. The Safety Officer, in consultation with the study team, will prepare the agenda to 
address the review of study materials, modifications to the study protocol and ICF, initiation of the trial, 
reporting of AEs, statistical analysis plan etc. Meetings with the Safety Officer will be held twice a year. The 
study investigators and staff will attend most meetings. The Safety Officer or the PI may call an emergency 
meeting at any time should participant safety questions or other unanticipated problems arise. Meetings are 
closed to the public because discussions may address confidential participant data. Meetings may be 
convened as conference calls as well as in-person.   
 
12.3 Meeting Format 
 
Meetings will consist of open sessions. Discussion held in all sessions will be confidential. The PI and key 
members of the study team attend the open sessions. Discussion will focus on the conduct and progress of the 
study, including participant accrual, protocol compliance, and problems encountered. Each meeting must 
include a recommendation to continue or to terminate the study and whether the Safety Officer has any 
concerns about participant safety. A recommendation to terminate the study may be made by the Safety 
Officer at any time. The Safety Officer will provide such a recommendation to the PI immediately by telephone 
and email. 
 
12.4 Meeting Materials  
 
The study staff, typically the statistician, will prepare report templates to be reviewed by the Safety Officer at 
the first meeting.  Format and content of the reports will be finalized and approved at the initial Safety Officer 
meeting, although changes throughout the trial may be requested. The reports will list and summarize safety 
data and describe the status of the study.  All meeting materials will be sent to PI who will forward the materials 
to the Safety Officer at least 7 to 14 days prior to the meeting.  
 
12.5 Reports  
 
Reports generally include administrative reports by site that describe participants screened, enrolled, 
completed, and discontinued, as well as baseline characteristics of the study population. Other general 
information on study status may also be presented. Listings of AEs and Serious Adverse Event (SAEs) as well 
as any other information requested by the Safety Officer may also be in the open session. The Safety Officer 
may direct additions and other modifications to the reports on a one-time or continuing basis. The reports may 
also contain data on study outcomes, including safety data, and perhaps efficacy data.   
 
The Safety Officer will prepare a formal report containing the recommendations for continuation or 
modifications of the study. It is the responsibility of the PIs to distribute the Safety Officer recommendation to 
all co-investigators and to ensure that copies are submitted to the UAB, ReumaClinic, , University of Verona, 
and NWZ ethics committees. 
 

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Version 4.3; 260331 
12.6 Confidentiality  
All materials, discussions, and proceedings of the Safety Officer are completely confidential. Meetings are 
expected to maintain confidentiality. A summary report of the Safety Officers recommendation will be provided 
to the IRB and Amgen annually.  
 
13 Adverse Events (AE) 
 
Definitions below incorporate guidelines provided by the Office of Human Research Protections (OHRP) of the  
DHHS and describes FDA reporting requirements. 
 
All AEs will be collected. An AE is any untoward event whether or not considered related to the use of 
denosumab or zoledronic acid or alendronate. Any worsening (i.e., any clinically significant adverse change in 
frequency or intensity) of a preexisting condition which is temporally associated with the use of denosumab or 
zoledronic acid or alendronate is also considered an AE. Abnormal laboratory values or test results constitute 
AEs only if they induce clinical signs or symptoms or require therapy, and are recorded on the AE CRF under 
the signs, symptoms or diagnosis associated with them. Screening conditions will not be considered adverse 
events; however, worsening of a preexisting condition may be considered an AE. We will report all AEs 
according to, the IRB, Amgen Inc. (per terms of the Safety Data Exchange Agreement), and the appropriate 
health authority (e.g., Food and Drug Administration [FDA]).  
 
13.1 Serious AE (SAE) 
 
Any AE occurring at any dose that results in any of the following outcomes:  
• 
Death  
• 
Is life-threatening (places the patient, in the view of the Principal Investigator, at immediate risk of 
death from the AE as it occurred) 
• 
Inpatient hospitalization or prolongation of existing hospitalization (hospitalization is defined as an 
inpatient admission, regardless of length of stay, even if hospitalized as a precautionary measure 
for continued observation) 
• 
A permanent, persistent, or significant disability (substantial disruption of the ability to conduct 
normal life functions). A medically significant AE that may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition 
• 
Congenital anomaly/birth defect  
• 
Other medically important serious event  
Other events not considered SAEs:  
• 
Hospitalization for treatment, which was elective or pre-planned, for a pre-existing condition that did 
not worsen 
• 
Treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of 
serious given above and not resulting in hospital admission 
 
13.2 Suspected Unexpected Serious Adverse Reaction (SUSARs). 
 
Any adverse drug experience, the specificity or severity of which is not consistent with the current 
Investigator’s Brochure. Suspected SUSARs will be reported to the IRB within 48 hours of the principal 
investigator becoming aware of the event, and to Amgen at the same time as the regulatory submission (w/in 
15 days).  
 
13.3 AE Severity  
 
The assessment of severity will be determined by the investigator and recorded on the electronic case report 
form (eCRF) for AE and SAE according to the investigator’s best clinical judgment, taking into consideration 
various factors such as the subject’s report, the physician’s observations, and the physician’s prior experience. 

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The investigator will assess the individual AE severity using the following scale as defined by Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03.19 
 
Table 3. Safety Data Reporting Timeline 
Safety Data 
Timeframe for Submission to Amgen 
Suspected Unexpected Serious Adverse Reaction 
(SUSARs) 
At time of regulatory submission (within 15 days) 
Pregnancy/Lactation 
Within 10 calendar days of investigator becoming 
aware 
Annual Safety Report 
At time of submission to any body governing or 
regulating research conduct (e.g., SO, IRB, etc) 
Other Aggregate Analyses 
(any report containing safety data generated during 
the course of a study) 
At time of submission to any body governing or 
regulating research conduct (e.g., IRB, etc) 
End of Study Report* 
At time of submission to any body governing or 
regulating research conduct (eg, RA, IRB, etc) but 
not later than 1 calendar year of study completion 
*Specific requirements are to be outlined in the Research Agreement  
 
13.3.1 Mild AE 
 
Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing no loss of time 
from normal activities. Symptoms do not require therapy or a medical evaluation; signs and symptoms are 
transient 
13.3.2 Moderate AE 
 
Events introduce a low level of inconvenience or concern to the participant and may interfere with daily 
activities, but are usually improved by simple therapeutic measures; moderate experiences may cause some 
interference with functioning. 
13.3.3 Severe AE 
 
Events interrupt the participant’s normal daily activities and generally require systemic drug therapy or other 
treatment; they are usually incapacitating  
 
13.4  Adverse Event (AE) Classifications  
 
13.4.1 Expected AE  
 
The expected adverse effects of denosumab, zoledronic acid or alendronate could be found in the drug 
Investigator’s Brochure. AEs will be collected as described in section 8. 
13.4.2 Unexpected AE 
 
Any AE, the specificity, frequency, or severity of which is not consistent with either: 
The known or foreseeable risk of AEs associated with the procedures involved in the research that are 
described in the protocol-related documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, the current IRB-approved informed consent document, and other relevant sources of 
information, such as product labeling and package inserts; or the expected natural progression of any 
underlying disease or condition of the participant(s) experiencing the AE. 
 

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13.4.3 Related to the research 
 
An event is related to the research if, in the opinion of the investigators, it was more likely than not to be the 
result of the interventions and interactions used in the research or the collection of identifiable private 
information in the research (i.e., there is a reasonable possibility that the event may have been caused by 
participation in the research). 
 
13.4.4 Unrelated to the research 
An AE is unrelated to the research if, in the opinion of the investigators, the AE is not related to the research. 
 
13.4.5 Unanticipated Problems Involving Risks to Participants or Others (Unanticipated Problems)  
Problems that are (1) unexpected (in terms of nature, severity or frequency) given the research procedures 
and the participant population being studied; and (2) suggest that the research places participants or others at 
a greater risk of harm or discomfort related to the research than was previously known or recognized including 
physical, psychological, economic or social harm.  
 
13.5 Relationship to Study Drugs 
The determination of the likelihood that the study drug caused the AE will be provided by the study site 
Investigator. The study site Investigator’s signature and date on the source document and eCRF that supports 
the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. The 
assessment of relationship will be reported to the IRB and to the study sponsor (Amgen Inc. per safety data 
exchange agreement) by the study site Investigator according to his/her best clinical judgment. The following 
scale of criteria may be used as a guidance (not all criteria must be present in order to be indicative of a drug 
relationship). 
 
13.5.1 Probably Related to Study Drug 
• 
There is evidence of exposure to the study drug 
• 
The temporal sequence of the AE onset relative to administration of the study drug is reasonable 
• 
The AE is more likely explained by the study drug than by another cause 
 
13.5.2 Possibly Related to Study Drug 
• 
There is evidence of exposure to study drug 
• 
The temporal sequence of the AE onset relative to administration of the study drug is reasonable 
• 
The AE could have been due to another equally likely cause 
 
13.5.3 Unlikely Related to Study Drug 
• 
There is evidence of exposure to the study drug 
• 
There is another more likely cause of the AE 
• 
There is no temporal relationship to study drug 
 
14 Investigational Study Sites 
• 
University of Alabama at Birmingham; Birmingham, AL, United States  
• 
ReumaClinic; Genk, Belgium 
• 
University of Verona; Verona, Italy 
• 
NoordWest Ziekenhuisgroep (NWZ); Alkmaar, Netherlands 
 
Approximately 15 participants will be enrolled from each study site. 
 
14.1 Site Recruitment  
 
Investigational study sites will be three large academic medical centers. The study site staff will ensure 
participants are consented and randomized in accordance with established good clinical research practices. 

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Additionally, site investigators and their staff will be required to have prerequisite human subjects training, and 
will answer study related questions, as needed. 
 
14.2 Participant Recruitment and Consent 
 
The site study staff will: 
• 
Provide participants with adequate information concerning the study procedures, and scope 
• 
Provide adequate opportunity for the participant to consider all available options 
• 
Respond to the participant’s questions and concerns 
• 
Ensure that each participant understands all information provided 
• 
Confirm that birth control is being used 
• 
Obtain the participant’s written voluntary consent to participate 
• 
Sign the consent form as witnesses 
• 
Provide participants with a copy of the consent form 
• 
Keep the signed form in the participant’s binder 
• 
Attempt to schedule an early end of study assessment in the case of study drug discontinuation 
 
14.3 Site Monitoring  
 
Since this is a three-site study, sites will be monitored by the PIs at each respective site (University of Alabama 
at Birmingham, ReumaClinic,  University of Verona and NWZ) according to established monitoring standard 
operating procedures (SOPs). Study site PIs will oversee the study to assure satisfactory data recording, 
adherence to the study protocol, Good Clinical Practice (GCP), and study medication accounting. University of 
Alabama at Birmingham, ReumaClinic,, University of Verona and NWZ will monitor recruitment utilizing 
automated reports generated from the study database. University of Alabama at Birmingham, ReumaClinic, 
University of Verona and NWZ investigators and staff will have meetings monthly to monitor site recruitment 
and to determine any intervention for poor recruitment. The staff listed in the study roster will be responsible for 
all aspects of the trial. This includes but is not limited to the following: 
• 
Development of the study protocol 
• 
Development of the manual of procedures and its maintenance 
• 
Participant randomization  
• 
Development and implementation of the data flow and data tracking 
• 
Development of procedures for data entry, error identification, and error correction 
• 
AE monitoring and reporting 
• 
Quality control procedures  
• 
Submitting for IRB review and approval 
• 
Creating reports - enrollment, AEs, participant status (e.g. withdrawals) 
• 
Preparing and sending required reports to the Safety Officer and the IRB 
• 
Submitting all required reports to the study appointed Safety Officer. 
• 
Distribution of all changes, updates and policies of above mentioned reports and documents to the 
study appointed Safety Officer.  
• 
Maintaining the study binder (regulatory and clinical documents) 
• 
Preparation of all study materials- data tables, recruitment materials, official reports 
• 
Identifying, recruiting, screening, and enrolling participants 
• 
Obtaining IC from each participant 
• 
Protecting participants' rights 
• 
Collecting study data and following participants through study completion 
• 
Compliance and accountability of administration of study intervention 
• 
Communicating questions, concerns, and/or observations to the PIs 
 
All of the above activities will be carried out by the study’s project coordinators, project managers, and 
research assistants on a weekly basis (or more frequently as needed) and monitored by the principal and co-
investigators. In the event, a problem is identified by either study site PI or staff, a teleconference/webinar will 

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be scheduled to review the issue. These teleconferences/webinars will include discussions of overall 
recruitment status and identified barriers to recruitment experienced by the site with the study team. Detailed 
recruitment issues and suggestions will be discussed, as well as identified barriers.  
 
 
15 Institutional Review Board (IRB)  
 
The study will be conducted under the auspices of the IRBs at University of Alabama at Birmingham, 
ReumaClinic,, University of Verona and NWZ. The respective site investigators will ensure that an 
appropriately constituted IRB that complies with the requirements of the current International Conference on 
Harmonization (ICH)-GCP version or applicable regulations will be responsible for the initial and continuing 
review and approval of the clinical study. Prior to initiation of the study, the investigator will forward copies of 
the protocol, ICF, Investigator's Brochure, Investigator's curriculum vitae (if applicable), study advertisements 
(if applicable), and all other subject-related documents to be used for the study to the IRB for its review and 
approval. Before initiating a study, the site PI will have written and dated full approval from the responsible IRB 
for the protocol. The investigators will also promptly report to the IRB all changes in the study, all unanticipated 
problems involving risks to human subjects or others, and any protocol deviations, to eliminate immediate 
hazards to subjects. 
 
The study site PI and/or staff will not make any changes in the study or study conduct without IRB approval, 
except where necessary to eliminate apparent immediate hazards to the subjects. For minor changes to a 
previously approved protocol during the period covered by the original approval, it may be possible for the 
study site PI to obtain an expedited review by the IRB as allowed. As part of the IRB requirements for 
continuing review of approved studies, the Investigators will be responsible for submitting periodic progress 
reports to the IRB (based on the Committee's requirements), at intervals appropriate to the degree of subject 
risk involved but no less than once per year. The study site PI should provide a final report to the IRB following 
study completion. 
 
16 Administrative Procedures  
 
16.1 Protocol Amendments 
 
Any change that affects the conduct of the study or significantly alters the protocol will be made in the form of 
an amendment. Any change or addition to this protocol requires a written protocol amendment that must be 
approved by the UAB before implementation. Amendments significantly affecting the safety of participants, the 
scope of the investigation, or the scientific quality of the study require additional approval by the IRB. Examples 
of amendments requiring such approval are: 
• 
An increase in drug dosage or duration of participant exposure  
• 
A significant change in the study design (e.g. addition of a new immunosuppressive) 
• 
An increase in the number of study visits and procedures to which participants are exposed 
 
16.2 Compliance with Law, Audit, and Debarment 
 
Study site PIs will conduct the study in an efficient and diligent manner and in conformance with this protocol; 
generally accepted standards of ICH GCP20; and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical study. The study site PIs also agree to allow the Safety 
Officer, IRB/Independent Ethics Committee, and regulatory agencies to inspect and review trial-related 
documents and procedures, and provide for direct access to all study-related source data and documents. The 
study site PIs will not seek reimbursement from patients, their insurance providers, or from government 
programs for procedures included as part of the study.  
 
The study site PIs will prepare and maintain complete and accurate study documentation in compliance with 
GCP standards and applicable federal, state, and local laws, rules and regulations. Study documentation will 
be promptly and fully disclosed by the study site PI upon request for inspection, copying, review, and audit at 

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reasonable times by any regulatory agencies. The study site PI agrees to promptly take any reasonable steps 
that are requested by designated representatives as a result of an audit to cure deficiencies in the study 
documentation and CRFs. 
Persons debarred from conducting or working on clinical studies by any court or regulatory agency will NOT be 
allowed to conduct or work on this studies.  
 
16.3 Compliance with Financial Disclosure Requirements  
 
The study site PIs will provide accurate financial information to allow submission of complete and accurate 
certification and disclosure statements as required by US FDA regulations (21 CFR Part 54). This requirement 
also extends to Sub-Investigators. 
 
16.4 Confidentiality and Privacy 
 
Participant confidentiality and privacy will be strictly held in trust by the participating investigators, their staff, 
and their interventions. This confidentiality is extended to cover testing of biological samples in addition to the 
clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. All research activities will be conducted in as private a 
setting as possible. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as long a period 
as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored in the REDCap electronic Data Entry System. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by clinical sites 
and by research staff will be secured and password protected. At the end of the study, all study databases will 
be archived at UAB. Study participants will be informed that their identifiable information may be reviewed by 
health regulators.  
16.5 Study Reports 
 
Annually, the study team will provide to Amgen copies of all reports related to study safety. These including 
annual safety reports filed with the IRB, FDA reports (if required), reports to/from the Safety Officer. In addition, 
within 1 calendar year of study completion the study team will provide to Amgen an End of Study Report that 
will detail study findings and aggregate analyses.  
 
16.6 Publication of results 
 
It is mandatory that the first publication will be based on data from all three centers that has been analyzed as 
stipulated in the protocol. Participating PIs agree not to present data gathered from one center before the full 
publication, unless formally agreed to by all other PIs. 
 
16.7 Changes in study personnel 
 
If there is a change of any personnel listed on the Form FDA 1572, a new form reflecting the change will be 
completed and forwarded to the IRB along with the new staff member’s signed curriculum vitae, medical 
license (if relevant), and signed financial disclosure statement. 
 
 
 

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