Conditions: IOP Osteoporosis
Keywords: premenopausal women
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
The primary goal of the study is to assess the extent to which bisphosphonate therapy will prevent decreases in bone mass that may occur after cessation of denosumab in premenopausal women with idiopathic osteoporosis (IOP) enrolled in AAAN0161 (FD05114) "Denosumab for the prevention of post-teriparatide bone loss in premenopausal women with idiopathic osteoporosis".

In addition, the investigator will observe participants for a second year off bisphosphonate therapy to assess duration of response.

The hypothesis is that bisphosphonate therapy with alendronate or zoledronic acid, initiated after recovery of bone remodeling activity, will prevent significant bone loss after discontinuing denosumab.

Detailed description:
Osteoporosis in premenopausal women with normal menstrual function and no specific cause is termed idiopathic osteoporosis (IOP). IOP is a rare disease with an estimated prevalence of \<200,000 affected premenopausal women in the United States.

Women with IOP completing at least one year and up to three years of denosumab (Protocol AAAN0161) will be offered participation in this open-label study in which they would choose whether to take oral alendronate 70 mg weekly for 12 months or a single intravenous dose of zoledronic acid 5 mg. Subjects and study personnel will be blinded to BMD outcomes until 12 months.

Discontinuation of denosumab is followed by substantial increases in bone turnover markers to well above baseline, bone resorption reaching twice baseline levels for about 6 months. Over the first 12 months off therapy, all the bone density gained on treatment is lost. Studies done at the institution has demonstrated the occurrence of multiple vertebral fractures in some patients who have stopped denosumab. Based upon these new fracture data, the Prolia label is currently recommending that consideration should be given to transition to another antiresorptive drug in patients stopping denosumab. The main goals of this extension study are to determine rates of bone loss and incidence of radiographic vertebral fractures during one year of bisphosphonate therapy (oral alendronate or intravenous zoledronic acid) initiated after completing denosumab.

Arms:
arm 1: Subjects will receive oral alendronate arm 2: Subjects will receive zoledronic acid

Interventions: intervention 1: Alendronate intervention 2: Zoledronic Acid
Intervention descriptions: intervention 1: oral alendronate 70 mg weekly for 12 months will be given for the prevention of osteoporosis intervention 2: single intravenous dose of zoledronic acid 5 mg will be given for the prevention of osteoporosis

Protocol document:
Prot_SAP_000.pdf: 
AAAR5220 Protocol Version 1.0 
Bisphosphonates for Prevention of Post-Denosumab Bone Loss in Premenopausal Women with 
Idiopathic Osteoporosis 
Amgen Reference Number: 20177429 
NCT03396315
Study Protocol Version 1.0: December 6, 2017 
1. Study Purpose and Rationale
Osteoporosis in premenopausal women with normal menstrual function and no specific cause is termed 
idiopathic osteoporosis (IOP). IOP is a rare disease with an estimated prevalence of <200,000 affected 
premenopausal women in the United States. We recently completed an NIH-funded study of 64 
premenopausal women with IOP, most with major osteoporotic fractures1. High resolution peripheral 
quantitative computed tomography (HR-pQCT), central QCT, and microCT of iliac bone biopsies documented 
that, compared to 40 normal controls, women with IOP have substantial microstructural deficits: thinner more 
porous cortices; fewer, thinner, more widely separated and heterogeneously distributed trabeculae; and 
markedly lower bone stiffness2-4.  To determine whether teriparatide (TPTD), an osteoanabolic drug that 
increases bone formation, improved bone microarchitecture and strength in premenopausal women with IOP, 
we conducted an open-label, 24-month pilot study of TPTD, 20 µg daily, in 21 affected women. This study, 
published in 2013, revealed impressive gains in areal BMD (aBMD) by dual energy x-ray absorptiometry (DXA) 
at the spine (10.8 ± 6.4%), total hip (6.2 ± 5.7%) and femoral neck (7.6 ± 3.4%), and no significant change at 
the forearm5. Paired transiliac bone biopsies before and after TPTD revealed improved trabecular structure 
and a 71% increase in trabecular stiffness. Cortical thickness increased by 22% but cortical porosity also 
increased by 46%5. By HR-pQCT, trabecular structure and whole bone stiffness improved, despite a 17% 
increase in cortical porosity at the radius6. 
Most patients require antiresorptive therapy to maintain TPTD-induced increases in BMD. However, several 
studies have shown that BMD remains stable after TPTD is discontinued in postmenopausal women on 
estrogen7-9 and in premenopausal women who regained normal menses after completing a course of nafarelin 
for endometriosis10. Based on these studies, we had previously hypothesized that the gains in BMD would be 
maintained in the IOP-TPTD pilot study participants because they were menstruating and estrogen replete. 
Therefore, we did not institute sequential antiresorptive therapy. However, contrary to our hypothesis, in 2015, 
we reported that participants in the pilot study sustained average losses of 4.8 ± 4.3% at the spine (p=0.0007), 
-1.1 ± 3.7% at the total hip and 1.5 ± 4.2% at the femoral neck over the 1-2 years after TPTD discontinuation11. 
In 2016, we completed enrollment of 41 premenopausal women with IOP into a randomized, 24-month, FDA 
Orphan Diseases Program-funded trial, “A Phase 2 Study of Teriparatide for the Treatment of Idiopathic 
Osteoporosis in Premenopausal Women” (FD003902; PI, Shane). Based on the follow-up data from our pilot 
study11, we concluded that participants in FD003902 would require antiresorptive treatment to prevent bone 
loss after completing TPTD. To assess this, we are currently enrolling women into AAAN0161, an open-label, 
24-36 month pilot study of denosumab (Prolia®, 60mg SC every 6 months). Denosumab is a potent 
antiresorptive drug that has been shown to increase BMD and reduce fracture incidence in postmenopausal 
women with osteoporosis. The denosumab study is also funded by the FDA Orphan Diseases Program 
(FD05114; PI, Shane). Only women who have completed FD003902 are eligible to participate in FD05114. 
We selected denosumab because it is not retained in the skeleton and may thus be preferred by young women 
who may be contemplating future pregnancies. We hypothesized that denosumab, initiated in women who 
complete two years of TPTD in FD003902, would maintain or further increase central and peripheral areal and 
volumetric BMD, microstructure and stiffness in premenopausal women with IOP. We selected an open-label, 
observational design for FD05114 because FD003902 enrolled 41 women and some may not choose to 
participate; thus, power would be too low for a randomized, placebo-controlled design. The goals of the study 
are to estimate the effects of denosumab on central and peripheral, as well as trabecular and cortical, bone 
mass and microstructure and to obtain preliminary data to inform the design of a future randomized study.  


AAAR5220 Protocol Version 1.0 
 
Discontinuation of denosumab is followed by substantial increases in bone turnover markers to well above 
baseline, bone resorption reaching twice baseline levels for about 6 months12,13. Over the first 12 months off 
therapy, all the bone density gained on treatment is lost12. Since we began enrolling subjects in FD05114 
(AAAN0161), several case reports and series have documented the occurrence of multiple vertebral fractures 
in some patients who have stopped denosumab14-20. Based upon these new fracture data, Amgen recently 
changed the Prolia label recommending that consideration should be given to transition to another 
antiresorptive drug in patients stopping denosumab. Therefore, all participants in AAAN0161 will be invited to 
participate in an extension study after they complete AAAN0161 (FD05114).  
 
The primary goal of the study is to assess the extent to which bisphosphonate therapy will prevent 
decreases in bone mass that may occur after cessation of denosumab in premenopausal women with 
idiopathic osteoporosis (IOP) enrolled in AAAN0161 (FD05114) “Denosumab for the prevention of post-
teriparatide bone loss in premenopausal women with idiopathic osteoporosis”.  
 
For the bisphosphonates, we have selected alendronate 70 mg weekly because bone density remained stable 
in 115 postmenopausal women who transitioned from denosumab to alendronate in the Denosumab 
Adherence Preference Satisfaction (DAPS) study21. However, in the DAPS study, compliance and persistence 
with alendronate was significantly lower than with denosumab 21 and some women have contraindications or 
intolerance to alendronate. Therefore, we have also included intravenous zoledronic acid 5 mg as an option. 
Zoledronic acid did not prevent bone loss in a case series of six women who received a single infusion 6 
months after their last denosumab dose and had BMD measured 18-23 months later 22; this timepoint reflects a 
combination of response to bisphosphonate and duration of response, but does not distinguish between the 
two. However, this may be because bone turnover would still have been very low 6 months after the last 
denosumab injection, and thus uptake of zoledronic acid to bone surfaces would have also been low at the 
time of the zoledronic acid infusion. For this reason, we will delay the initiation of zoledronic acid (and 
alendronate) until 6 months + 4 weeks (no later than 7 months) after the last denosumab injection. We 
selected the 6 month + 4 week time point based on Figure 4 of the paper by Bone et al. that indicated the bone 
resorption marker, C-telopeptide (CTX) exceeded baseline by 9 months after last dose12. 
 
The main goals of the new extension study are to estimate rates of bone loss during one year of 
bisphosphonate therapy (oral alendronate or intravenous zoledronic acid) initiated after completing 
denosumab. In addition, we will observe participants for a second year off bisphosphonate therapy to assess 
duration of response. We hypothesize that bisphosphonate therapy with alendronate or zoledronic acid, 
initiated after recovery of bone remodeling activity, will prevent significant bone loss after discontinuing 
denosumab. However, should there be significant bone loss during the first year of bisphosphonate therapy, 
defined as greater than the Least Significant Change (LSC) at spine or hip, and/or resulting in a T score < -
2.5), we would abrogate the proposed year of observation, and consider additional bisphosphonate therapy or 
reinstitution of denosumab, whichever we deemed most appropriate for the participant. Those who do not meet 
stopping criteria would continue to the second year of observation off bisphosphonates. 
 
 
The rationale for conducting this study is as follows. The study is intended for premenopausal women who 
have completed 2 years of teriparatide and 2 to 3 years of denosumab and have responded well (BMD T or Z 
scores > -1.5 at the spine) and for whom we could now consider a drug holiday because the risk of adverse 
effects of long-term antiresorptive therapy may be slightly higher after 5 years of continuous therapy. As 
stopping Prolia may result in loss of BMD gained on drug, an important goal of the study is to assess whether 
providing consolidation therapy with an oral or intravenous bisphosphonate will prevent that expected bone 
loss. Additional goals are to assess the effects of consolidation therapy on bone turnover markers and on bone 
quality as assessed by HR-pQCT, as well as on safety, specifically incident fractures and other adverse 
events. For those who remain at increased risk for fracture (BMD T or Z scores < -1.5 at the spine and/or hip 
after 2 years of Forteo and 2 to 3 years of Prolia, or fragility fractures during therapy), continuation of 
denosumab would also be an option. 
 
 


AAAR5220 Protocol Version 1.0 
 
2. Study Design and Statistical Procedures 
 
Women with IOP completing at least one year and up to three years of denosumab under AAAN0161 will be 
offered participation in an open-label study in which they would choose whether to take oral alendronate 70 mg 
weekly for 12 months or a single intravenous dose of zoledronic acid 5 mg.  
 
Operationally, we propose to combine the final AAAN0161 visit and the initial Bisphosphonate Extension visit 
as follows. We will delay the final AAAN0161 visit by 4 weeks in order to permit partial recovery of bone 
remodeling activity before initiation of bisphosphonate therapy and to avoid a second visit soon after the final 
AAAN0161, as many of our participants travel long distances. Oral alendronate or intravenous zoledronic acid 
would be initiated 6 months plus 4 weeks after their last dose of denosumab. The transition from denosumab to 
bisphosphonate therapy will occur no later than 7 months after the participants’ last injection of denosumab. 
 
While a randomized controlled trial is the most rigorous design, and balancing the zoledronic acid and alendronate 
group size would be highly desirable, we do not believe that can achieve that without adversely impacting uptake 
of subjects from the parent study. Our experience indicates that many women in this age-group have specific 
concerns that influence their decision to take one or the other of the drugs. Some have relative contraindications to 
one or the other drug. We are concerned that if we require women to be randomized to zoledronic acid or 
alendronate, a substantial proportion may decline to enroll and thus be at risk for rapid bone loss and perhaps 
fractures. We feel that providing young women of childbearing potential with the ability to select the intervention 
that fits best with their particular clinical situation will increase recruitment and retention. In addition, the maximum 
number of women available to enroll in the extension study is 34. With only 17 subjects per group, power will likely 
be too low, even in a 1:1 randomized trial design, to detect between-groups differences, particularly with an active 
comparator design. In summary, we have selected an open-label design for three reasons:  
1. The maximum number of women available to enroll in the extension study is 34. With only 17 subjects per 
group, power will likely be too low in a 1:1 randomized trial design to detect between-groups differences, 
particularly with an active comparator design. 
2. Providing young women of childbearing potential with the abillity to select the intervention that fits best with 
their particular clinical situation will increase recruitment and retention. 
3. This design will enable us to acquire data on the personal factors and beliefs that determine the 
participants’ choice of intervention and will thus inform design of future studies involving young women with 
osteoporosis.  
Statistical Analysis Plan 
The main Specific Aim and main Hypothesis of this study are as follows: 
 
In premenopausal women with IOP who have first completed two years of TPTD in FD003902 followed by 24-
36 months of denosumab (Prolia®, 60mg SC every 6 months) and then complete 12 months of 
bisphosphonate therapy and 12 months of post-bisphosphonate observation, to estimate: 
 
Aim 1: The percent change from baseline (bisphosphonate initiation) in areal BMD of the lumbar spine, total 
hip, femoral neck and one-third radius at 6, 12, 18 and 24 months after bisphosphonate initiation. The primary 
outcome will be percent change in lumbar spine areal BMD by DXA at 12 months. Exploratory outcomes will 
be the percent change in total hip, femoral neck and 1/3 radius areal BMD by DXA at 12 months as well as 
BMD changes at all sites at other timepoints. 
 
Hypothesis 1: The gains in areal BMD by DXA that occurred on denosumab will be maintained at the spine, 
total hip and femoral neck during the 12 months of bisphosphonate therapy.  
 
In the same population of women, we will address three Exploratory Specific Aims and one Safety Aim: 
1. Estimate the percent change from baseline in total, cortical, and trabecular volumetric BMD, trabecular 
plate and rod microarchitecture, cortical porosity and stiffness of the distal radius and tibia by HR-pQCT 
and finite element analysis of HR-pQCT datasets at 12 and 24 months. 


AAAR5220 Protocol Version 1.0 
 
2. Estimate the AUC and percent change in the resorption marker, C-telopeptide from baseline (at 6, 12, and 
18 and 24 months), and associations between C-telopeptide at bisphosphonate initiation and change in C-
telopeptide after bisphosphonate initiation, and changes in areal and volumetric BMD, microarchitecture 
and stiffness. 
3. Estimate the relationship between baseline and teriparatide-stimulated bone formation rate on the 
quadruple-labelled transiliac crest bone biopy obtained during “A Phase 2 Study of Teriparatide for the 
Treatment of Idiopathic Osteoporosis in Premenopausal Women” (FD003902; PI, Shane) and change in 
BMD of the lumbar spine, total hip, femoral neck and one-third radius after 12 months of bisphosphonate 
therapy and 12 months of post-bisphosphonate observation. 
4. Delineate the incidence of adverse events, including vertebral and non-vertebral fractures, and episodes of 
abnormal serum calcium based on safety labs collected at each study visit. 
 
Expected Results: After stopping denosumab, it is well-established that bone remodeling increases and BMD 
by DXA declines12,13. In addition, over the past two years, there have been several publications describing 
vertebral fractures in postmenopausal women stopping denosumab 14-20. More recently, it has been 
appreciated that there is a small but significant imbalance in the incidence of multiple vertebral fractures after 
discontinuation of denosumab in a comparison between those completing denosumab versus those completing 
placebo. One risk factor for this outcome was the presence of vertebral fractures prior to therapy. This is of 
particular concern for women with IOP participating in AAAN0161 because a substantial proportion came to 
medical attention because of multiple vertebral fractures. There are no published data on the effects of 
stopping denosumab on BMD, bone turnover and fractures in premenopausal women stopping denosumab. 
This study will be the first to examine the effect of alendronate or zoledronic acid during the first year of 
withdrawal from denosumab in premenopausal women. Bone density remained stable in 115 postmenopausal 
women who transitioned from denosumab to alendronate in the Denosumab Adherence Preference 
Satisfaction (DAPS) study 21. Zoledronic acid provided only partial protection from bone loss in a case series of 
six women who received a single infusion 6 months after their last denosumab dose and had BMD measured 
18-23 months later 22. However, this may be because bone turnover would still have been very low 6 months 
after the last denosumab injection, and thus uptake of zoledronic acid to bone surfaces would have also been 
low at the time of the single zoledronic acid infusion.  
 
Because we will delay the initiation of zoledronic acid (and alendronate) until 6 month + 4 weeks after the last 
denosumab injection, a time when we expect CTX to be returning toward pre-denosumab concentrations 12, we 
expect that both oral and IV bisphosphonate therapy will prevent clinically significant bone loss (defined as 
greater than the Least Significant Change (LSC; see Section 3.C., 3.C.1) at spine or hip, and/or resulting in a T 
score < -2.5) during the first year after denosumab is stopped. Should there be significant bone loss during the 
first year of bisphosphonate therapy, defined as greater than the Least Significant Change (LSC) at spine or 
hip, and/or resulting in a T score < -2.5), we would discuss the findings with the participant and evaluate 
whether to abrogate the proposed year of observation. We would consider additional bisphosphonate therapy 
or reinstitution of denosumab, whichever we deemed most appropriate for the participant and was consistent 
with their wishes. Those who do not meet these criteria would continue to the second year of observation off 
bisphosphonates. 
  
ANALYSIS PLAN 
Sample Size Considerations 
For this Bisphosphonate Extension Study, given the number of women who have completed FD003902 and 
who have initiated denosumab (n=25) and the number who remain on FD003902 (n=9), we anticipate that a 
maximum of 34 and a minimum of 30 women would enroll in the Bisphosphonate Extension Study. 
 
Primary and Exploratory Outcome Variables 
 
 


AAAR5220 Protocol Version 1.0 
 
Aim 1: In subjects who stop denosumab therapy and complete 12 months of bisphosphonate therapy and 12 
months of post-bisphosphonate observation: 
 
Primary outcome variable: By DXA, the within-group difference (% change) in BMD at the 
 
Lumbar spine (L1-4) between the final Denosumab/Bisphosphonate initiation visit (DB baseline) 
and the 12-month bisphosphonate visit  
 
Exploratory DXA outcome variables:  
The within-group difference (% change) in BMD by DXA at the 
 
Lumbar spine (L1-4) between the final Denosumab/Bisphosphonate initiation visit (DB baseline) 
and the 24-month visit 
 
Lumbar spine (L1-4) between the 12-month bisphosphonate visit and the 24-month visit 
 
Total hip, femoral neck and 1/3rd radius aBMD between the final Denosumab/Bisphosphonate 
initiation visit (DB baseline) and the 12-month bisphosphonate visit  
 
Total hip, femoral neck and 1/3rd radius aBMD between the final Denosumab/Bisphosphonate 
initiation visit (DB baseline) and the 24-month visit  
 
Total hip and femoral neck radius aBMD between the 12-month bisphosphonate visit and the 24-
month visit 
 
Other exploratory outcome variables: 
1. By HRpQCT, the within-group difference (% change) between the final Denosumab/Bisphosphonate 
initiation visit (DB baseline) and the 12- and 24-month bisphosphonate visit in 
a. Trabecular volumetric density of the distal radius and tibia  
b. Total volumetric density and trabecular number of the distal radius and tibia  
c. Trabecular plate and rod number by ITS of HR-pQCT datasets 
d. Cortical density, thickness, and porosity of the distal radius and tibia  
e. Whole bone stiffness of the distal radius and tibia by FEA of HR-pQCT scans 
 
2. The within-group difference (% change) in serum C-telopeptide from the final 
Denosumab/Bisphosphonate initiation visit (DB baseline) and the 12 month bisphosphonate visit as 
well as the 12 month observation off bisphosphonate visit; the within-group difference in the net Area 
Under the Curve (AUC) during the first 12 months of bisphosphonate therapy and the second 12 
months of observation off bisphosphonate therapy  
 
3. The association between baseline and teriparatide-stimulated bone formation rate during FD003902; 
and percent change in aBMD by DXA of the lumbar spine, total hip, femoral neck and one-third radius 
between the Denosumab/Bisphosphonate initiation visit and the 12- and 24-month bisphosphonate visit 
 
Safety outcome variables: 
1. Number of incident vertebral fractures 
2. Number of incident nonvertebral fractures 
3. Number of episodes of abnormal serum calcium 
Analysis: the main analyses will be to assess whether there are within-group differences between baseline 
versus 12 months during the 12 months of bisphosphonate treatment and between 12 months versus 24 
months during the 12 months of observation after bisphosphonate treatment. We will conduct an exploratory 
between-groups analysis comparing rates of bone loss in subjects who choose alendronate versus those who 
choose IV zoldedronic acid. Finally, we will conduct an exploratory analysis to assess whether there are 
between-group differences between subjects who discontinue denosumab and receive bisphosphonate 
treatment for 12 months and 15 IOP subjects (historical controls) who completed 24 months of teriparatide 
without consolidation therapy and sustained average losses of 4.8 ± 4.3% at the spine (p=0.007), -1.1 ± 3.7% 
at the total hip and -1.5 ± 4.4% at the femoral neck by 2 years after TPTD discontinuation11.  
 
 


AAAR5220 Protocol Version 1.0 
 
POWER ANALYSIS 
 
For the Analysis, the primary analysis is the within-group analysis to assess whether there are differences in 
primary and exploratory DXA outcomes in bisphosphonate-treated patients at 12 and 24 months after 
cessation of denosumab (baseline). We expect to have a sample size of 30 subjects who agree to take 
bisphosphonate therapy after completing denosumab therapy. Using a two-tailed one-sample t-test and the 
largest SD (4.30%) for change in spine aBMD that we observed both in our historical cohort and in women with 
IOP who discontinued teriparatide11, and given a sample size of 30 subjects who stop denosumab and take 
bisphosphonate therapy, a 3% margin and a 4.30% SD, we will have 98% power (the bisphosphonate within-
group analysis), to estimate the confidence interval for an absolute change in aBMD at the spine (primary 
outcome), total hip and femoral neck (exploratory outcomes) in women who discontinue denosumab and take 
bisphosphonate therapy. 
 
 
STATISTICAL METHODS 
 
Given the non-randomized nature of this study, the primary objective will be to estimate the change in aBMD 
by DXA at the lumbar spine (primary), total hip and femoral neck (exploratory) after cessation of denosumab 
treatment. The main analysis is the within-group difference analysis: A one-sample two-tailed T-test against 
the null hypothesis of no change will be used to assess whether bisphosphonate treated patients differ on DXA 
outcomes relative to the measurements acquired at the cessation of denosumab.  
 
3. Study Procedures 
 
3.A. Calcium and Vitamin D, Fractures 
All participants under protocol AAAN0161 are currently receiving calcium and multivitamin supplements. 
Supplements will continue to be provided during the new study: a daily multivitamin that contains 400 IU of 
vitamin D and very little or no calcium and a calcium supplement (Citracal +D), which contains 315 mg calcium 
and 250 IU vitamin per caplet. They will be instructed to take 2 Citracal +D daily (630 mg calcium and 500 IU 
vitamin D in total). Thus their total vitamin D intake from supplements will be 900 IU daily. 
 
FRACTURES: We will capture all incident fractures by structured interview at each visit. Incident clinical and 
morphometric vertebral fractures will be ascertained by Spine X-rays at baseline,12 and 24 months. All 
subjects are instructed to notify their study team if they sustain a clinical vertebral fracture or a nonvertebral 
fracture. In addition, subjects will be specifically queried about incident fractures at each visit. All nonvertebral 
fractures will be verified by review of radiographs or radiograph reports.   
 
3.B. STUDY PROTOCOL (Table 2) 
Schedule of Visits 
 
Visit 1 (Month 0): Enrollment Visit /Denosumab Cessation/ Bisphosphonate Initiation: 
a. Oral inspection to assess for osteonecrosis of the jaw (ONJ) 
b. Pregnancy testing 
c. Imaging: DXA, VFA, Spine Radiographs, HR-pQCT  
d. Laboratory assessments - plasma/serum collection 
e. Administration of IV zoledronic acid 5 mg or dispensation of alendronate 70 mg weekly 
 
Visit 2 (Month 6): 
a. Oral inspection to assess for osteonecrosis of the jaw (ONJ) 
b. Pregnancy testing 
c. Imaging: DXA  
d. Laboratory assessments - plasma/serum collection 
e. Dispensation of alendronate 70 mg weekly 
 


AAAR5220 Protocol Version 1.0 
 
Visit 3 (Month 12): 
a. Oral inspection to assess for osteonecrosis of the jaw (ONJ) 
b. Pregnancy testing 
c. Imaging: DXA, Spine Radiographs, HR-pQCT  
d. Laboratory assessments - plasma/serum collection 
 
Visit 4 (Month 18): 
a. Oral inspection to assess for osteonecrosis of the jaw (ONJ) 
b. Pregnancy testing 
c. Imaging: DXA  
d. Laboratory assessments - plasma/serum collection 
 
Visit 5 (Month 24): 
a. Oral inspection to assess for osteonecrosis of the jaw (ONJ) 
b. Pregnancy testing 
c. Imaging: DXA, Spine Radiographs, HR-pQCT  
d. Laboratory assessments - plasma/serum collection 
 
Table 2: Visit Protocol 
 
Protocol 
Review/ 
Informe
d 
Consent 
Safety 
Labs 
Fractures 
and 
 Adverse 
Events 
Pregnancy 
Testing and 
Oral Exam 
 
BP 
Spine 
X-rays,  
HR-
pQCT 
DXA 
Serum 
for  
PTH, 
BTMs 
Visit 1 
X 
X 
X 
X 
ZA or 
ALN 
X 
X 
X 
Visit 2 
 
X 
X 
X 
ALN 
 
X 
X 
Visit 3 
 
X 
X 
X 
 
X 
X 
X 
Visit 4 
 
X 
X 
X 
 
 
X 
X 
Visit 5 
 
X 
X 
X 
 
X 
X 
X 
 
Recruitment:. We will inform subjects of the option to enroll in the Bisphosphonate Extention Study before 
enrolling in AAAN0161 or during AAAN0161, as dictated by the time of their participation. We will discuss study 
protocol, risks and benefits prior to their final visit of the denosumab study. The Bisphosphonate Extension 
study will include only those subjects who have completed FD003902 and at least one year of Denosumab 
treatment. 
 
 
3.C. Study Procedures 
 
3.1. BMD by DXA: BMD (aBMD) of the LS (L1-4), right proximal femur and non-dominant forearm will be 
measured on Hologic QDR Discovery densitometers (Hologic, Inc., Waltham, MA). At CUMC and Creighton, 
dedicated, licensed x-ray technicians with long-term research experience perform all scans. Phantoms are 
scanned daily to check for detector drift and the results are appended to a quality control (QC) database. 
Results are downloaded to specific project databases. QC procedures include circulation of phantoms 
biannually. At CUMC, precision is 0.86% for the LS (LSC 2.4%), 1.36% for the FN (LSC 3.8%), and 0.70% 
(LSC 1.5%) for the 1/3 radius. At Creighton, precision is 0.94% (LSC 2.6%) for the LS, 1.40% for the FN 3.9) 
and 1.62% (LSC 2.6%) for the 1/3 radius.  In terms of absolute BMD changes, the LSCs reported by Hologic 
are 0.022 g/cm2 at the spine, 0.027 g/cm2 at TH, 0.029 g/cm2 at the FN and 0.023 g/cm2 at the 1/3 radius. 
Radiation exposure for DXA of the spine, hip and forearm with the Hologic Discovery machine is 7.45 µSv. 
 
 
3.2. Lateral (only) Spine Radiographs: Lateral spine radiographs at the lumbar and thoracic spine will be 
performed at New York Prebsyterian Hospital and Creighton University Medical Center according to standard 
techniques because VFA can sometimes miss fractures in the upper thoracic spine and because the 


AAAR5220 Protocol Version 1.0 
 
ascertainment of vertebral fracture is of such important in this particular group of patients. Radiation exposure 
for thoracic spine radiographs is 300 µSv and for lumbar spine radiographs is 200 µSv.  
 
3.3. High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT): HR-pQCT is performed 
on the XtremeCT II (Scanco Medical AG, Switzerland). The nondominant distal radius and tibia are 
immobilized in a carbon fiber shell (158-160).  The region of interest (ROI) is defined on a scout film by manual 
placement of a reference line at the endplate of the radius or tibia; the first slice is 9.0 mm and 22.0 mm 
proximal to the reference line at the radius and tibia respectively. A stack of 168 parallel CT slices is acquired 
at the distal end of both sites (68kVp effective energy, 900 µA current, 43 ms integration time) with a nominal 
isotropic resolution of 60.8 µm. This provides a 3D image of 10.2 mm in the axial direction. Attenuation data 
are converted to equivalent hydroxyapatite (HA) densities. The European Forearm Phantom is scanned 
regularly for quality control. Scans are manually scored for motion on a scale of 1 (no motion) to 5 (significant 
blurring of the periosteal surface, discontinuities in the cortical shell, or streaking in the soft tissue). Images 
with motion score of 4-5 are excluded from analyses. We recently acquired the 2nd generation HR-pQCT 
scanner that has a higher resolution and thus permits direct quantification of virtually all microstructural indices 
that previously had to be derived. For HRpQCT of the forearm and leg, the estimated local average skin dose 
is 5 µSv per scan, and the effective whole body dose is below 5 µSv per scan, since only a very small fraction 
of the distal forearm or leg is irradiated. 
 
3.4. Biochemical and Hormonal Assays  
Safety: At each study visit, fasting morning blood samples for basic metabolic panel, including serum calcium, 
will be collected and processed at a commercial laboratory (Quest Diagnostics, Teterboro, NJ). 
Mineral Metabolism and Bone Turnover: Fasting morning plasma/serum will be collected at CUMC, and at 
Creighton. Specimens will be shipped frozen from Creighton University to CUMC, aliquoted and frozen at -80o 
for batch analysis in the Biomarker Core of the Irving Institute for Clinical and Translational Research (CUMC 
CTSA), under the direction of Serge Cremers, PhD., PharmD. All assays are currently in place and inter- and 
intra-assay precision values are given in brackets after each test.  
PTH is measured by a well-established total intact PTH IRMA (Scantibodies Laboratory, Inc., Santee, CA; 
6.8%, 4.8%), serum calcium by colorimetric assay (Cobas Integra 400 Plus, Roche Diagnostics, Indianapolis, 
IN; 3.5%, 0.99%), C-telopeptide (CTX) by CLIA (Immunodiagnostic Systems, Scottsdale AZ; 6.3%, 3.2%), 25-
OHD by RIA (Diasorin RIA, Stillwater, MN; 10.5%, 8.2%). 
 
 
4. STUDY DRUGS OR DEVICES 
 
Alendronate or zoledronic acid will be provided to subjects at no cost. Both medications will be stored and 
dispensed by the research pharmacies at Columbia and Creighton Universities according to standard, IRB-
approved procedures. CUMC will be the primary Research Pharmacy and will ship study drug to Creighton 
University  for subjects enrolled at Creighton. Zoledronic acid (5 mg, open label) will be administered to 
participants once by intravenous injection performed according to standard procedures by licensed providers at 
Columbia University (in the Irving Institute Center for Translational Science or CTSA) and Creighton University.  
  
 
5. STUDY SUBJECTS 
 
INCLUSION/EXCLUSION CRITERIA: 
Inclusion Criteria: All women completing at least 12 months of Forteo treatment under FD003902 and at least 
12 months of denosumab under AAAN0161 who remain without a diagnosis of an excluded medical condition 
and medication exposures as detailed below, will be offered enrollment into this study. Women who 
transitioned into menopause during FD003902 were excluded from participation in AAAN0161 as this could 
affect the results of the study. Women who transition into menopause during the denosumab study will be 
permitted to participate in this Bisphosphonate Extension Study. 
 
Exclusion Criteria:  


AAAR5220 Protocol Version 1.0 
 
1) Known intolerance to calcium supplements 
2) Contraindications to bisphosphonate treatment: 
a. Hypocalcemia 
b. Pregnancy 
c. Known hypersensitivity to bisphosphonates 
3) History of osteomalacia 
4) History of osteonecrosis of the jaw 
5) History of dental extraction or other invasive dental surgery within the prior 4 weeks 
6) Invasive dental work planned in the next 12 months 
7) Any condition or illness (acute, chronic, or history), which in the opinion of the Investigator might 
interfere with the evaluation of efficacy and safety during the study or may otherwise compromise the 
safety of the subject 
8) Self-reported or known alcohol or drug abuse within the previous 12 months 
9) Current or recent (within 1 year of enrollment) inflammatory bowel disease or malabsorption 
10) Abnormal laboratory tests performed during Visit 1 (see below under STUDY PROTOCOL) 
a. Renal insufficiency or liver disease: eGFR < 35 ml/min, AST/ALT >50% above upper limit of 
normal 
b. Hypercalcemia, hypocalcemia 
c. Vitamin D deficiency: 25-OHD < 30 ng/mL 
 
Subjects must be willing to participate voluntarily. Specifically excluded are the following: 1) women less than 
20 (or 35 in the case of those who wish to participate because they have low BMD); 2) protected individuals 
(institutionalized); 3) prisoners; 4) any other prospective participant who, for any reason, might not be able to 
give voluntary informed consent.  
Creighton University is a collaborating site. At Creighton University, Drs. Robert Recker and Joan Lappe will 
recruit subjects and perform the same studies as proposed for Columbia University.  
 
6. RECRUITMENT 
Patients for the study will be recruited from those subjects who have completed FD003902 and at least one 
year of AAAN0161. The Principal Investigators, Dr. Shane and Dr. Cohen, Co-investigators, Dr. Recker, and 
Dr. Lappe, and Research Coordinators, Mrs. Bucovsky, Ms. Kamanda-Kosseh and Mrs. Stubby, will be directly 
responsible for enrolling subjects and obtaining consent for the study. Permission will be first obtained from the 
patients' primary care physician, if appropriate. Written consent will always be obtained according to 
appropriate Informed Consent forms that will be reviewed and approved by the Institutional Review Boards of 
the both institutions. Each patient is counseled at the time of enrollment that all aspects of the study are 
separate from their management as a patient with osteoporosis.  They are assured that participation is entirely 
voluntary and that refusal to participate in the study will not in any way influence their care. Statements to this 
effect will be included in all Informed Consent forms, which will be signed by the investigator obtaining consent 
and by the subject in the presence of a witness. 
 
 
7. INFORMED CONSENT PROCESS 
Written consent will always be obtained according to appropriate Informed Consent forms that will be reviewed 
and approved by the Institutional Review Board of the Columbia University Medical Center. Potential 
participants are assured that participation is voluntary and that refusal to participate will not influence their 
care.  Statements to this effect will be included in all Informed Consent forms, which will be signed by the 
investigator or coordinator obtaining consent and by the subject. All investigators and coordinators have 
completed courses in Good Clinical Practices and HIPAA compliance. Written informed consent will be 
obtained for every subject by the investigators after an explanation of the purpose, risks and benefits of the 
study. Confidentiality will be guarded with the use of computers that are password protected and storing 
questionnaires with sensitive information within a locked file. All subjects will be provided with instructions on 
how to contact the investigative team if any problems or concerns arise. 
 


AAAR5220 Protocol Version 1.0 
 
The informed consent process will be conducted by a study investigator or research coordinator prior to 
initiation of study-related procedures.  Subjects will have an opportunity to asked questions prior to signing the 
form, and all participants will receive a copy of the signed consent form for their records.  
 
8. CONFIDENTIALITY 
 
Dr. Elizabeth Shane is Principal Investigator of this protocol and is also the Sponsor. 
 
Confidentiality of patient data in this project will be ensured. Personal Identifying Health Information (PHI) of 
participants will be kept only in secure files accessible to the PI, investigators and project coordinators. Data 
will be recorded on case report forms on which the only identifier is a research ID code. Only the PI and project 
coordinator have access to the link between the research ID code and PHI. No names or identifying 
information will be included in research reports.  Subjects' names will not appear on questionnaires.  All 
computers housing research data have passwords and timed screen savers requiring a password for access. 
Through these safeguards, the confidentiality of the data will be ensured. 
 
Information obtained in the setting in this study may be made available to the following entities: 
- The Sponsor-Principal Investigator, co-investigators, study staff and other health professionals who may be 
evaluating the study 
- Columbia University 
- New York Presbyterian Hospital 
- Authorized representatives of the Food and Drug Administration ('FDA'), the Office of Human 
Research Protections ('OHRP') or other government regulatory agencies 
- Applicable Institutional Review Boards ('IRBs') that independently review the study to assure 
adequate protection of research participants, as required by federal regulations. 
 
The Sponsor-Principal Investigator, regulatory authorities, and IRB may keep the research records indefinitely. 
If the results of the study are published or presented at a medical or scientific meeting, subjects will not be 
identified. 
 
9. PRIVACY PROTECTIONS 
 
We will take all necessary steps to safeguard each participant’s expectation that the information they offer will 
be held in confidence.  These protections will apply to all research related data collection and procedures, as 
well as to all forums 
 
Only a select group of study personnel will have access to patient study files. We are fully committed to 
safeguarding an individual’s expectation that the information they offer will be held in confidence. All subjects 
will sign a HIPAA form in addition to the informed consent document to prevent inappropriate use or any 
disclosure of individuals' health information and to require any organizations which use health information to 
protect that information and the systems which store, transmit, and process it. The subject has the right to 
revoke the authorization for us to access her health information at any time, as is stated in the HIPAA form that 
each subject will sign prior to participation. 
 
Our safety reporting responsibilities require the investigator to report any adverse events to the IRB, and the 
FDA. These reports will include only a study ID, and will not divulge the participant’s identity.  
 
10. POTENTIAL RISKS 
The risks of this study are related to the venipuncture, radiation exposure and the study medication, 
alendronate/ zolendroic acid. 
 
Venipuncture: The risks of venipuncture for blood drawing include pain, bleeding, bruising, and a remote 
possibility of infection or inflammation at the site. Additionally, there is a possible risk of syncope in individuals 


AAAR5220 Protocol Version 1.0 
 
who are prone to vasovagal responses. To minimize these risks, trained phlebotomists who follow proper 
technique perform all venipunctures.  
 
Radiation: Radiation exposure for DXA of the spine, hip and forearm with the Hologic Discovery machine is 
7.45  µSv. This is about the amount the average person receives from background radiation in 1 day. For 
HRpQCT of the forearm and leg, the estimated local average skin dose is 5 µSv per scan, and the effective 
whole body dose is below 5 µSv per scan, since only a very small fraction of the distal forearm or leg is 
irradiated. Radiation exposure from the lateral thoracic and lumbar spine radiographs is 300 µSv and 200 µSv, 
respectively. Based on these data, we estimate the following radiation exposure for participation in this clinical 
trial, primarily driven by the spine x-rays, is 1550 μSv, approximately half the 2400-3600 μSv of natural 
background radiation received in a year. 
For purposes of comparison, there is 60 μSv radiation associated with a round-trip transcontinental plane flight. 
The amount of radiation from exposure associated with a standard abdominal/pelvic or chest CT scan is 7,000-
10,000 μSv. Expressed as equivalencies to background radiation, a standard mammogram is associated with 
radiation exposure equivalent to approximately 2 to 3 months of natural background radiation. A standard 
abdominal or chest CT scan is associated with radiation exposure equivalent to approximately 15-22 months of 
natural background radiation. We will counsel all study subjects about the total amount of radiation that they 
will receive as a result of participation as part of Informed Consent procedures of that particular study. In 
addition, they will be counseled that radiation exposure is cumulative throughout life and any additional 
exposure should be considered carefully.  
 
Placement of an Intravenous Line for Zoledronic acid infusion: Placing an IV may cause some redness, 
bruising, swelling, bleeding, discomfort or pain at the spot where the needle enters the body. Although rare, 
infection may also occur.  Some people may experience dizziness, lightheadedness and/or fainting. The IV will 
be removed once the infusion has been completed. 
 
Zoledronic acid: Zoledronic acid is contraindicated in individuals with hypocalcemia; creatinine clearance  
less than 35 mL/min and with evidence of acute renal impairment; and hypersensitivity to any component of 
zoledronic acid. Participants with any of these characteristics will not be eligible to receive zoledronic acid. 
There are several potential risks of zoledronic acid.  
Hypocalcemia may worsen during treatment so participants must be adequately supplemented with calcium 
and vitamin Renal impairment may develop, particularly in patients with underlying renal impairment or with 
other risk factors, such as advanced age or dehydration. For this reason the dose will not exceed 5 mg and the 
duration of infusion will be no less than 15 minutes. Creatinine clearance will be measured before the dose, 
which will be withheld if < 35 ml/min   
Osteonecrosis of the Jaw (ONJ) has been reported. All participants will have a routine oral exam by the 
prescriber prior to treatment. 
Atypical Femur Fractures have been reported. Patients with thigh or groin pain will be evaluated to rule out a 
femoral fracture 
If given during pregnancy, Zoledronic acid can cause fetal harm. All participants of childbearing potential will be 
advised to use effective contraception for 12 months after the zoledronic acid infusion. 
Severe bone, joint, and muscle pain may occur and there may be a rise in body temperature (fever) in the 24 
to 72 hours following the first dose of study medication.  These symptoms may last up to three days and 
usually do not come back. All participants will be instructed to drink plenty of fluids and to take acetaminophen 
every 6 hours the day of and the day following the infusion. 
  
The most common adverse reactions to zoledronic acid (greater than 10%) are pyrexia, myalgia, headache, 
arthralgia, pain in extremity flulike illness, nausea, vomiting, diarrhea and eye inflammation.  
 
Alendronate: Alendronate is contraindicated in individuals with abnormalities of the esophagus which delay 
emptying such as stricture or achalasia; inability to stand/sit upright for at least 30 minutes; at increased risk of 
aspiration; hypocalcemia; hypersensitivity to any component. Participants with any of these characteristics will 
not be eligible to receive alendronate. 


AAAR5220 Protocol Version 1.0 
 
Potential risks of alendronate include severe irritation of upper gastrointestinal (GI) mucosa; worsening of 
hypocalcemia; bone, joint, muscle pain; osteonecrosis of the jaw; and atypical femur fractures. The most 
common adverse reactions (≥3%) are abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, 
musculoskeletal pain, and nausea.  
 
 
11. DATA AND SAFETY MONITORING 
 
A Data & Safety Monitoring Board has been established for the parent TPTD study (FD003902) and the 
denosumab study will be invited to continue for the Bisphosphonate Extension Study to ensure continuity. 
The DSMB will monitor subject accrual, ethical conduct of research, as well as oversee adverse events and 
any unforeseen consequences in the study population. The DSMB is chaired by Dr. Mishaela Rubin, an 
endocrinologist and Associate Professor of Medicine at CUMC with expertise in osteoporosis and clinical 
trials, Dr. Judith Korner, an endocrinologist and Professor of Medicine at CUMC outside of the field of 
metabolic bone diseases (obesity and weight control), and a statistician, Dr. Emelia Bagiella, Professor of 
Health Evidence and Policy at Mount Sinai Medical School in New York City. The DSMB is independent of 
all study personnel, and has signed a conflict of interest form to that effect. It meets annually face-to-face 
and by conference call as necessary in case of complications or issues. The DSMB may recommend any 
steps necessary to protect the participants. 
 
Interim Analysis: No efficacy interim analysis is planned. The proposed recruitment of a modest number of 
subjects, with the anticipated recruitment schedule, diminishes the need for an interim efficacy analysis. 
However, this decision will be reviewed at the first meeting of the DSMB. If the DSMB decides that an interim 
efficacy analysis is necessary, we will amend the protocol according to their decision. 
 
Stopping Rules: Stopping rules will be invoked if new information emerges making the questions in this 
proposal moot or new information provides evidence suggesting that the use of bisphosphonates in 
premenopausal women with IOP is contraindicated. Stopping rules will be invoked in individual participants if 
there is significant bone loss during the first year of bisphosphonate therapy, defined as greater than the Least 
Significant Change (LSC) at spine or hip, and/or resulting in a T score < -2.5). If this amount of bone loss is 
documented, we will albrogate the proposed year of observation, and consider additional bisphosphonate 
therapy or reinstitution of denosumab, whichever we deemed most appropriate for the participant. Those who 
do not meet stopping criteria would continue to the second year of observation off bisphosphonates. 
 
Protocol Modifications: The IRB must review and approve any protocol amendment. Modifications will not be 
undertaken without notification of the IRB, the DSMB, Amgen and the FDA. 
 
Reporting:  All adverse events will be reported according to the guidelines set forth by the FDA and applicable 
IRBs. We commit to follow the FDA reporting requirements set forth in the Code of Federal Regulations Title 
21, Section 312.32, which is summarized below. 
 
 The sponsor shall notify FDA, Amgen and all participating investigators in a written IND safety report of 
(A) Any adverse experience associated with the use of the drug that is both serious and unexpected; or 
(B) Any finding from tests in laboratory animals that suggests a significant risk for human subjects including 
reports of mutagenicity, teratogenicity, or carcinogenicity. Each notification shall be made as soon as possible 
and in no event later than 15 calendar days after Dr. Shane, the Sponsor/Principal Investigator, is in receipt of 
the information. Each written notification may be submitted on FDA Form 3500A or in a narrative format and 
shall bear prominent identification of its contents. 
 
Dr. Shane, the Sponsor/Principal Investigator, shall also notify the FDA and Amgen by telephone or by 
facsimile transmission of any unexpected fatal or life-threatening experience associated with the use of the 
drug as soon as possible but in no event later than 7 calendar days after the the Sponsor/Principal 
Investigator's initial receipt of the information. Each telephone call or facsimile transmission to FDA shall be 
transmitted to the FDA new drug review division in the Center for Drug Evaluation and Research or the product 


AAAR5220 Protocol Version 1.0 
 
review division in the Center for Biologics Evaluation and Research that has responsibility for review of the 
IND.                                                                                                                                                                                      
 
The Sponsor/Principal Investigator will ensure that the FDA and Amgen informed of actions, if any, taken by 
the IRB as a result of its continuing review and summary reports will be submitted annually to the FDA.  All 
adverse events that meet the criteria of Columbia University (CU) IRB’s reporting policy are reportable to the 
IRB (link to policy is included below). The CU IRB requires reporting of all unanticipated problems considered 
to be unexpected, related or possibly related to participation in the research, and that suggest that the research 
places subjects or others at a greater risk of harm than was previously known or recognized.  The timeliness of 
this report will depend on whether the event is considered to be serious and whether it occurred at an internal 
or external site. Annual reports will be submitted to the IRB documenting all adverse events and unanticipated 
problems. Individual serious adverse events will be reported to the IRB and DSMB within 1 week. The PI will 
forward the report to the IRB and FDA devoid of patient-specific information.  
 
Dr. Shane, the Sponsor/Principal Investigator will meet all safety reporting obligations as outlined in the 
contract with Amgen.  
 
Columbia University IRB Reporting Policy: 
http://www.cumc.columbia.edu/dept/irb/policies/documents/UnanticipatedProblemsPolicy.FINALVERSION.012
408.pdf) 
 
Creighton University IRB Reporting Policy 
http://www.creighton.edu/fileadmin/user/ResearchCompliance/IRB/Policies_and_Procedures/120_Unanticipate
d_Problems_Involving_Risks_to_Participants_or_Others.pdf 
 
12. POTENTIAL BENEFITS 
The IOP subjects may or may not benefit directly from this study. If patients respond to the medication they 
receive, they will benefit by improving their bone architecture, bone strength, and resistance to fractures. 
 
On a wider scale, the information gained from this research project may apply to all women who have 
idiopathic osteoporosis and may directly impact upon the future treatment of this puzzling disorder. 
 
13. ALTERNATIVES 
The alternative is not to participate in this trial.  If a subject decides to withdraw, she will be counseled about 
other, alternative osteoporosis treatment options. Alternate therapies include, but are not limited to, 
Risendronate (Actonel) and Ibandronate (Boniva). 
 
14. RESEARCH AT EXTERNAL SITES 
Research for this protocol will be conducted at Columbia University Medical Center in NY, NY and at Creighton 
University Medical Center in Omaha, NE. The research team at Creighton University will be responsible for 
securing IRB approval for all research activities conducted at their site related to this protocol.  We will maintain 
current versions of all IRB approvals and approved documents (ie – consent forms, etc) at our site and submit 
any changes promptly to the CUMC IRB.  Our plan for data and safety monitoring will include monitoring 
activities and outcomes at both study sites. 
 
15. COLUMBIA AS LEAD INSTITUTION 
Columbia University will be considered the lead institution in this protocol. There will be one other site, 
Creighton University. As stated in the prior section, we will commit to the following: 1) obtain and maintain IRB 
approval at the Creighton site; 2) ensure that the Creighton site follows consent procedures and utilizes 
consent documents approved by their IRB (if the designated IRB is not the CU IRB, then the IRB-approved 
consent document must be similar to the CU IRB-approved consent document with regards the content and 
style of the document). 
 
Creighton University’s Federal-Wide Assurance # is FWA00001078. 


AAAR5220 Protocol Version 1.0 
 
  
16. Sponsor Responsibilities  
Dr. Elizabeth Shane, the Principal Investigator is the sponsor of and is legally responsible for the legal and 
regulatory compliance of this study. Study compliance and subject safety will be monitored periodically by the 
sponsor-principal investigator, Dr. Elizabeth Shane.  The task of overseeing subject safety will be the 
responsibility of the DSMB, sponsor-principal investigator and study investigators.  Adverse events and/or 
unanticipated problems will be reported to the Columbia IRB in accordance with their policy, to Amgen and to 
the FDA in accordance with their reporting guidelines (see Section 11.0 for more detailed information). Study 
compliance and assurance that the study is conducted in accordance with the protocol will be facilitated by a 
protocol and operations manual developed by the investigator.  Participating research personnel will be 
instructed in proper forms completion and electronic data entry procedures, as it is applicable to their study 
role.  Adherence with the study protocol and recruitment goals will be monitored by the sponsor-principal 
investigator on an ongoing basis, with monthly conference calls made to participating sites (Creighton 
University).  Upon identification of incomplete reports or missing data, this information will be obtained from the 
study site in writing.   
 
It is the responsibility of Dr. Shane, the sponsor-principal investigator, to submit all amendments to the 
protocol, IND safety reports and annual reports to Amgen and to the FDA in compliance with the relevant 
institution’s policies for reporting. Amendments to the protocol must be approved by the IRB prior to the 
implementation of any changes to the protocol or consent forms, including, but not limited to, study 
questionnaires, procedures, and recruitment methods. 
 
Records and documentation pertaining to the protocol will be kept in the protocol regulatory binder and online 
through the Columbia RASCAL system.  Subject specific records will be stored in a password protected 
database or in a locked cabinet to ensure privacy and confidentiality, as is detailed in Sections 8.0 and 9.0. 
Data entry will be ongoing throughout the course of the protocol so that interval reports to the investigators, 
IRB, Amgen and other regulatory bodies are readily accessible.  
 
 
17. Literature Cited. 
1. 
Cohen A, Recker RR, Lappe J, et al. Premenopausal women with idiopathic low-trauma fractures 
and/or low bone mineral density. Osteoporosis international : a journal established as result of cooperation 
between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 
2012;23:171-82. 
2. 
Cohen A, Dempster DW, Recker RR, et al. Abnormal bone microarchitecture and evidence of 
osteoblast dysfunction in premenopausal women with idiopathic osteoporosis. The Journal of clinical 
endocrinology and metabolism 2011;96:3095-105. 
3. 
Cohen A, Lang TF, McMahon DJ, et al. Central QCT reveals lower volumetric BMD and stiffness in 
premenopausal women with idiopathic osteoporosis, regardless of fracture history. The Journal of clinical 
endocrinology and metabolism 2012;97:4244-52. 
4. 
Cohen A, Liu XS, Stein EM, et al. Bone microarchitecture and stiffness in premenopausal women with 
idiopathic osteoporosis. The Journal of clinical endocrinology and metabolism 2009;94:4351-60. 
5. 
Cohen A, Stein EM, Recker RR, et al. Teriparatide for idiopathic osteoporosis in premenopausal 
women: a pilot study. The Journal of clinical endocrinology and metabolism 2013;98:1971-81. 
6. 
Nishiyama K, Wang J, Young P, et al. Teriparatide Is Associated with Improved Microarchitecture and 
Estimated Bone Strength in Premenopausal Women with Idiopathic Osteoporosis: An HR-pQCT Study.  
American Society for Bone and Mineral Research Annual Meeting; 2013; Baltimore, MD: American Society for 
Bone and Mineral Research. 
7. 
Cosman F, Nieves J, Woelfert L, et al. Parathyroid hormone added to established hormone therapy: 
effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. Journal of 
bone and mineral research : the official journal of the American Society for Bone and Mineral Research 
2001;16:925-31. 


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8. 
Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Parathyroid hormone treatment 
can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest 
1998;102:1627-33. 
9. 
Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Bone mass continues to increase 
at the hip after parathyroid hormone treatment is discontinued in glucocorticoid-induced osteoporosis: results 
of a randomized controlled clinical trial. Journal of bone and mineral research : the official journal of the 
American Society for Bone and Mineral Research 2000;15:944-51. 
10. 
Finkelstein JS, Arnold AL. Increases in bone mineral density after discontinuation of daily human 
parathyroid hormone and gonadotropin-releasing hormone analog administration in women with endometriosis. 
The Journal of clinical endocrinology and metabolism 1999;84:1214-9. 
11. 
Cohen A, Kamanda-Kosseh M, Recker RR, et al. Bone Density After Teriparatide Discontinuation in 
Premenopausal Idiopathic Osteoporosis. The Journal of clinical endocrinology and metabolism 2015;100:4208-
14. 
12. 
Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone 
mineral density and bone turnover markers in postmenopausal women with low bone mass. The Journal of 
clinical endocrinology and metabolism 2011;96:972-80. 
13. 
Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density and turnover in 
postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: 
a randomized blinded phase 2 clinical trial. Bone 2008;43:222-9. 
14. 
Anastasilakis AD, Makras P. Multiple clinical vertebral fractures following denosumab discontinuation. 
Osteoporosis international : a journal established as result of cooperation between the European Foundation 
for Osteoporosis and the National Osteoporosis Foundation of the USA 2016;27:1929-30. 
15. 
Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical Features of 24 
Patients With Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review 
and Additional Cases. Journal of bone and mineral research : the official journal of the American Society for 
Bone and Mineral Research 2017;32:1291-6. 
16. 
Anastasilakis AD, Yavropoulou MP, Makras P. Bisphosphonates or denosumab discontinuation and 
risk of fractures. Maturitas 2017;102:75. 
17. 
Anastasilakis AD, Yavropoulou MP, Makras P, et al. Increased osteoclastogenesis in patients with 
vertebral fractures following discontinuation of denosumab treatment. European journal of endocrinology 
2017;176:677-83. 
18. 
Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, Lamy O. Severe spontaneous vertebral fractures after 
denosumab discontinuation: three case reports. Osteoporosis international : a journal established as result of 
cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of 
the USA 2016;27:1923-5. 
19. 
Lamy O, Gonzalez-Rodriguez E, Stoll D, Hans D, Aubry-Rozier B. Severe Rebound-Associated 
Vertebral Fractures After Denosumab Discontinuation: 9 Clinical Cases Report. The Journal of clinical 
endocrinology and metabolism 2017;102:354-8. 
20. 
Popp AW, Zysset PK, Lippuner K. Rebound-associated vertebral fractures after discontinuation of 
denosumab-from clinic and biomechanics. Osteoporosis international : a journal established as result of 
cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of 
the USA 2016;27:1917-21. 
21. 
Freemantle N, Satram-Hoang S, Tang ET, et al. Final results of the DAPS (Denosumab Adherence 
Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in 
postmenopausal women. Osteoporosis international : a journal established as result of cooperation between 
the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 
2012;23:317-26. 
22. 
Reid IR, Horne AM, Mihov B, Gamble GD. Bone Loss After Denosumab: Only Partial Protection with 
Zoledronate. Calcified tissue international 2017.