Clinical trial NCT01440803
Conditions: Adult Idiopathic Generalized Osteoporosis
Keywords: osteoporosis premenopausal forteo idiopathic Idiopathic Osteoporosis in Premenopausal Women
Sponsor: Elizabeth Shane
Start date: 2012-08-02; Completion date: 2019-02-01
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Idiopathic osteoporosis (IOP) is defined as osteoporosis that affects young, otherwise completely healthy individuals with no secondary cause of bone loss. In the course of our prior research with premenopausal women with IOP, the investigators have shown that women with IOP have low areal bone mineral density (aBMD) at the spine, hip and forearm compared to normal women. Additionally, using noninvasive high resolution imaging of the central and peripheral skeleton and detailed analyses of transiliac crest bone biopsies, the investigators identified several features of bone quality in premenopausal women with IOP.

There is currently no FDA-approved therapy for IOP in premenopausal women. However, teriparatide (Forteo) has been shown to improve bone mass and microarchitecture in postmenopausal women and is approved for men with primary or idiopathic osteoporosis, as well as men, premenopausal and postmenopausal women with glucocorticoid-induced osteoporosis. Because IOP in premenopausal women is an orphan disease, with an estimated prevalence of about 113,000 in the United States, pharmaceutical companies are unlikely to support development of therapies for this indication. Therefore, the major objective of this protocol is to establish the safety and efficacy of teriparatide in premenopausal women with IOP in a phase 2 clinical trial. All subjects will receive teriparatide as part of the study, but a randomly selected group of patients (10) will receive one year of placebo injections first before starting their two years of treatment. The remainder of subjects (30) will receive active drug only for two years.

Funding Source - FDA OOPD

Detailed description:
Osteoporosis is a skeletal disorder characterized by reduced bone strength that predisposes to an increased risk of fracture. Osteoporosis affects postmenopausal women and elderly men and is very unusual in healthy individuals under age 50. Moreover, more than 90% of young men and premenopausal women with osteoporosis have a secondary cause of bone lose, such as an underlying disorder (e.g., hypogonadism) or a medication exposure (e.g., glucocorticoids, antiepileptic drugs), that either interfered with acquisition of peak bone mass or caused excessive bone loss thereafter. Idiopathic osteoporosis (IOP) is defined as osteoporosis that affects young, otherwise completely healthy individuals with intact gonadal function and no secondary cause of bone loss. First described by Fuller Albright in 1944, IOP is an uncommon condition with an estimated annual incidence of 0.4 cases per 100,0003. IOP predominantly affects Caucasians, who generally present in their mid-30s with one more low trauma fractures.

In the course of a previously conducted NIH-funded study of premenopausal women, the investigators demonstrated that women with IOP have low areal bone mineral density (aBMD) at the spine, hip and forearm compared to normal women. Additionally, using noninvasive high resolution imaging of the central and peripheral skeleton and detailed analyses of transiliac crest bone biopsies, the investigators identified several distinctive and consistent features of bone quality in premenopausal women with IOP: thin cortices, lower trabecular volumetric bone mineral density (vBMD), fewer trabecular plates, fewer and longer trabecular rods, decreased connectivity between rods and plates, lower mineralization density and lower estimated stiffness of cancellous bone. Bone remodeling and biochemical indices of mineral metabolism did not differ between IOP subjects and controls.

Although not every woman with IOP requires pharmacologic intervention, many have sustained multiple low-trauma fractures or have extremely low bone mineral density (BMD). There is currently no FDA-approved therapy for IOP in premenopausal women, therefore a safe and effective therapy is urgently needed. Bisphosphonates are one therapeutic option but the associated gains in BMD are primarily due to reduction in the remodeling space and increased mineralization of bone rather than improvements in microarchitecture, an important consideration as microarchitectural deficits are a consistent feature of IOP in premenopausal women, while remodeling activity is most commonly normal or low. Furthermore, potential teratogenic effects limit the safety of bisphosphonates in premenopausal women.

However, anabolic therapy with human recombinant parathyroid hormone (hPTH) 1-34 (or teriparatide (TPTD)), has been shown to improve bone mass and microarchitecture in postmenopausal women and is approved for men with primary or idiopathic osteoporosis, as well as men, premenopausal and postmenopausal women with glucocorticoid-induced osteoporosis. TPTD, on the other hand, increases bone formation and BMD, while improving microarchitecture and strength. Moreover, TPTD has been shown to increase BMD in men with IOP, in premenopausal women with glucocorticoid-induced osteoporosis (GIOP) and to prevent bone loss in premenopausal women with nafarelin-induced acute estrogen deficiency. Although there have been no studies evaluating TPTD in estrogen-replete premenopausal women with IOP, data from studies of hPTH(1-34) in postmenopausal women on estrogen are relevant to this proposal. These studies found increased aBMD at the LS and of lesser magnitude at the hip, as well as major reductions in vertebral fracture. Also important, BMD remained stable in postmenopausal women on estrogen followed for two years after TPTD discontinuation. Lane et al. reported similar results in postmenopausal women with GIOP on estrogen. These two studies suggest that in estrogen-replete premenopausal women with IOP, increases in bone mass resulting from TPTD will be sustained after the course of therapy is completed.

The major objective of this protocol is a therapeutic one, namely to establish the safety and efficacy of TPTD in premenopausal women with IOP in a phase 2 clinical trial. The investigators hypothesize that anabolic therapy with teriparatide will improve areal and vBMD in premenopausal women with IOP. The investigators also hypothesize that teriparatide will restore abnormal microarchitecture toward normal and improve other aspects of bone quality in premenopausal women with IOP. The primary aim of this research study will be to establish the efficacy and safety of 6 months of teriparatide versus placebo in premenopausal women with IOP. The secondary aim is to determine the extent to which 12 and 24 months of teriparatide improves areal and volumetric BMD, bone microarchitecture and stiffness compared to baseline measures in premenopausal women with IOP. This study will have high impact on clinical practice as it pertains to the management of premenopausal women with IOP.

Arms: arm 1: Daily injection of Teriparatide for treatment of idiopathic osteoporosis arm 2: Daily injection of saline placebo for 6 months, followed by 24 months of teriparatide treatment for idiopathic osteoporosis.
Interventions: intervention 1: Teriparatide intervention 2: Saline Placebo
Intervention descriptions: intervention 1: Daily injection of 20 mcg teriparatide for the treatment of idiopathic osteoporosis for 24 months. intervention 2: Daily injection of saline placebo for 6 months, followed by teriparatide treatment for 24 months.

Protocol documents:
Prot_SAP_000.pdf: 
Phase 2 Study of Teriparatide for the Treatment of Idiopathic Osteoporosis in Premenopausal 
Women 
IRB AAAF2251 
Protocol Version 3.2 
1. Study Purpose and Rationale
Osteoporosis is a skeletal disorder characterized by reduced bone strength that predisposes to an increased 
risk of fracture1,2. Osteoporosis affects postmenopausal women and elderly men and is very unusual in 
healthy individuals under age 50. Moreover, more than 90% of young men and premenopausal women 
with osteoporosis have a secondary cause of bone loss3, such as an underlying disorder (e.g., 
hypogonadism) or a medication exposure (e.g., glucocorticoids, antiepileptic drugs), that either interfered 
with acquisition of peak bone mass or caused excessive bone loss thereafter3-15. Idiopathic osteoporosis 
(IOP) is defined as osteoporosis that affects young, otherwise completely healthy individuals with intact 
gonadal function and no secondary cause of bone loss. First described by Fuller Albright in 194416, IOP is 
an uncommon condition with an estimated annual incidence of 0.4 cases per 100,0003. IOP predominantly 
affects Caucasians, who generally present in their mid-30s with one more low trauma fractures17.  
In the course of an NIH-funded study of premenopausal women with IOP (R01 AR49896, IRB 
AAAA9245), we have shown that women with IOP have low areal bone mineral density (aBMD) at the 
spine, hip and forearm compared to normal women79. Additionally, using noninvasive high resolution 
imaging of the central and peripheral skeleton and detailed analyses of transiliac crest bone biopsies, we 
identified several distinctive and consistent features of bone quality in premenopausal women with IOP: 
thin cortices, lower trabecular volumetric bone mineral density (vBMD), fewer trabecular plates, fewer 
and longer trabecular rods, decreased connectivity between rods and plates, lower mineralization density 
and lower estimated stiffness of cancellous bone 80, 81, 82, 83. Bone remodeling and biochemical indices of 
mineral metabolism did not differ between IOP subjects and controls 82.  
Although not every woman with IOP requires pharmacologic intervention, many have sustained multiple 
low-trauma fractures or have extremely low bone mineral density (BMD). There is currently no FDA-
approved therapy for IOP in premenopausal women and a safe and effective therapy is urgently needed.  
Bisphosphonates are one therapeutic option, but the associated gains in BMD are primarily due to 
reduction in the remodeling space and increased mineralization of bone rather than improvements in 
microarchitecture. This is an important consideration as microarchitectural deficits are a consistent feature 
of IOP in premenopausal women, while remodeling activity is most commonly normal or low. 
Furthermore, potential teratogenic effects limit the safety of bisphosphonates in premenopausal women.   
Osteo-anabolic therapy with human recombinant parathyroid hormone 1-34, hPTH(1-34) or teriparatide 
(TPTD), terms which will be used interchangeably in this proposal, has been shown to improve bone 
mass and microarchitecture in postmenopausal women and is approved for men with primary or 
idiopathic osteoporosis, as well as men, premenopausal and postmenopausal women with glucocorticoid-
induced osteoporosis. In contrast to bisphosphonates, TPTD increases bone formation and BMD, and 
increases bone strength by improving bone microarchitecture18-35. Moreover, TPTD has been shown to 
increase BMD in men with IOP36, in premenopausal women with glucocorticoid-induced osteoporosis 
(GIOP)37,38 and to prevent bone loss in premenopausal women with nafarelin-induced acute estrogen 
deficiency 84. In addition, we have recently completed a pilot study of TPTD in 21 premenopausal women 
with IOP, in which there were marked improvements in areal BMD by DXA at the lumbar spine, femoral 
neck and total hip and bone microarchitecture and estimated strength at the iliac crest over 18-24 months 
of therapy 72,73,76, 85. Using high resolution CT imaging, we also found that TPTD increased volumetric 
BMD and estimated strength at the distal radius and tibia in the same women.  
NCT01440803 
Version Date: 03/23/2016; IRB Approval Date: 04/06/2016


 
The major objective of this protocol is a therapeutic one, namely to establish the safety and efficacy of 
TPTD in premenopausal women with IOP in a phase 2 clinical trial.  We hypothesize that osteo-anabolic 
therapy with TPTD will improve areal and vBMD in premenopausal women with IOP. We also 
hypothesize that TPTD will restore abnormal microarchitecture toward normal and improve other aspects 
of bone quality in premenopausal women with IOP. The primary aim of this research study will be to 
establish the efficacy and safety of 6 months of TPTD versus placebo in premenopausal women with IOP. 
Secondary aims are to determine the extent to which 12 and 24 months of TPTD improves areal and 
volumetric BMD, bone microarchitecture and stiffness compared to baseline measures in premenopausal 
women with IOP, to assess the effects of TPTD on bone remodeling at the tissue level in women with 
IOP and to determine whether baseline bone turnover, as assessed by quadruple tetracycline labeling 
predicts response to TPTD. This study will have high impact on clinical practice as it pertains to the 
management of premenopausal women with IOP. This study is exploratory and will not support any new 
labeling claims for Forteo in the premenopausal patient population. 
 
For the sub-study: We aim to investigate the pharmacokinetics (pK) and pharmacodynamics (pD) of 
teriparatide (Forteo) to determine if subject weight influences pK or pD. To develop preliminary data 
necessary to plan larger studies on this issue, we aim to study 6 subjects already enrolled in this study 
(AAAF2251) who are already in the open label treatment period. We will enroll 3 normal weight subjects 
(BMI between 18.5 kg/m2 and 24.9 Kg/m2) and 3 overweight or obese subjects (BMI equal to or greater 
than 25 kg/m2). All subjects will be offered participation until enrollment goals for the sub-study will be 
met. 
 
Previous studies have shown that the increases in BMD observed in response to TPTD may dissipate over 
time if patients are not placed on antiresorptive therapy after TPTD is discontinued. However, other 
studies suggest that this dissipation does not occur in women receiving estrogen. Studies in 
postmenopausal women on estrogen found that hPTH(1-34) increased aBMD at the LS and at the hip19,33, 
and resulted in major reductions in vertebral fracture19. Importantly, BMD remained stable in 
postmenopausal women on estrogen followed for two years after TPTD discontinuation19. Lane et al. 
reported similar results in postmenopausal women with GIOP on estrogen26. Although no studies have 
evaluated duration of TPTD effects in menstruating premenopausal women with IOP, an extension study 
of hPTH(1-34) in premenopausal women with endometriosis receiving nafarelin found that the benefits of 
in hPTH(1-34) persisted in women who regained normal menses86. These three studies suggest that in 
estrogen-replete premenopausal women with IOP, increases in bone mass resulting from TPTD would be 
sustained after the course of therapy is completed. However, we recently analyzed new data from our 
open-label pilot study of 21 premenopausal women with IOP who were treated with 18-24 months of 
TPTD, 20 mcg daily85. Specifically, 2-year follow-up data on 15 of the 21 women, has revealed that nine 
(60%) have sustained significant bone loss (7.4 + 3.1%) at the lumbar spine, although they have 
maintained the gains at the hip; six women have maintained their gains. 
 
We believe that these data require an amendment to the study design of R01 FD 009302, Teriparatide for 
Premenopausal Idiopathic Osteoporosis. The current study design includes 12 months of follow-up after 
the study subjects complete 24 months of TPTD. Instead of the current design, in which all subjects 
complete one year of observation after 24 months of TPTD, we would like to offer the subjects three 
choices:  
1. One year of observation 
2. To leave the study and be treated clinically with an antiresorptive drug to maintain gains in bone 
density after treatment with TPTD, which is the current clinical standard of care for 
postmenopausal women and men who have completed two years of TPTD therapy 


3.  Participation in a new study evaluating anti-resorptive therapy for prevention of bone loss after 
stopping TPTD. The new study is currently in the design phase and funding phase and precise 
details are not yet available 
 
All currently enrolled subjects would be re-consented and future participants would sign a new informed 
consent document with the new study design. 
 
On January 26, 2014, the Research Pharmacy informed the Principal Investigator that there was a mistake 
in the randomization table for the study. Subjects (n=40) should have been randomized 28:12, active 
Teriparatide to placebo, for 6 months, followed by a single-switchover design in which all would receive 
active drug. The randomization code in the table provided to the Research Pharmacy by the Study 
Statistician was reversed and the subjects were randomized 12:28, active Teriparatide to placebo. To date, 
18 patients have been enrolled and randomized. Research Pharmacy has informed us that 12 subjects were 
randomized to placebo and 6 to active Teriparatide. As 12 subjects have already been randomized to 
receive placebo first, we will increase enrollment by one subject (total, 41) and generate an adaptive 
randomization table in which one of the 23 subjects yet to be enrolled will be randomly assigned to 
placebo and 22 will be randomly assigned to active Teriparatide. This will maintain the number of 
subjects treated with active drug at 28 and maintain blinding of subjects and study personnel to study 
assignment. 
 
 
2. Study Design and Statistical Procedures 
 
The 
study 
is a 
randomized, double blind, placebo-controlled, single switch-over trial of TPTD in premenopausal women 
with IOP. Forty-one subjects will be assigned to TPTD (Group A; n=28) or placebo (Group B; n=13). At 
the 6 month timepoint, all subjects will receive TPTD, but blinding of original group assignment will be 
maintained for an additional 6 months. At the 12 month visit, the blind will be broken and those initially 
randomized to TPTD (Group A) will continue on study drug for an additional 12 months while those 
initially randomized to placebo (Group B) will continue for an additional 18 months, so that subjects in 
both groups complete 24 months of treatment overall. aBMD by DXA and HRpQCT will be measured at 
baseline and at 6 month intervals. vBMD by cQCT will be performed before randomization and after 24 
months of TPTD (Table 1). A quadruple labeled transiliac crest bone biopsy will be performed at 3 
months for both Group A and B. Eli Lilly & Company will provide TPTD and placebo but will supply no 
other funding. After 24 months of treatment in either Group A or B, all women will be offered three 
choices for follow up: the subjects can A) continue to  to be followed for 12 months off TPTD B) choice 


to leave the study and be treated clinically using an anti-resorptive medication to maintain gains in bone 
density after treatment with TPTD, or C) join a new study to maintain gains in bone density after 
treatment. The new study is currently in the design phase and funding phase and precise details are not yet 
available.  
 
Statistical Analysis Plan 
2.A. Statistical Analysis Plan 
Our aims in this protocol are as follows: 
 
Aim 1: To establish the efficacy and safety of 6 months of TPTD versus placebo in premenopausal 
women with IOP 
 
Aim 2: To determine the effect of 3 months of TPTD on bone remodeling at the tissue level and the 
extent to which baseline and 3 month bone remodeling predicts response to TPTD in 
premenopausal women with IOP. 
 
Aim 3: To determine the extent to which 12 and 24 months of TPTD improves areal and volumetric 
BMD, bone microarchitecture and strength (stiffness) compared to baseline measures in 
premenopausal women with IOP  
 
Prior to statistical analysis, all outcome and covariate data will be summarized with descriptive statistics, 
outliers examined, distributions identified and normalizing transformations applied where indicated. All 
of the above analyses will be based upon the intention-to-treat principle.  The missing data mechanism 
(MCAR, MAR) for all outcomes and covariates will be assessed and, in the event of a non-ignorable 
mechanism, analyses will subjected to the methods of Diggle and Kenward39 for continuous measures or 
Ibrahim and Lipsitz40 for safety outcomes. Bone turnover markers will be log-transformed prior to 
analysis.  Inferential testing will use a 5% two-tailed type I error rate with no adjustment for multiplicity 
taken for primary outcome analyses. Secondary efficacy analyses type I error rates will be adjusted by 
Bonferroni method whereas secondary safety analyses will not.  In keeping with the objective of proposed 
exploratory analyses to generate data patterns consistent or inconsistent with improved bone quality, no 
adjustment for multiplicity will be taken.  No interim efficacy analyses are planned. The statistical 
analysis plan will be modified to account for the adaptive randomization procedure, which is relevant to 
Aim 1 only. 
 
AIM 1: 
Primary efficacy outcome analysis: Analysis of covariance (ANCOVA) comparison of between-group 
(treated vs placebo) differences in mean change in LS aBMD (g/cm2) by DXA from pre-treated baseline 
to 6 months of assigned treatment with adjustment for the following continuous baseline variables LS 
aBMD (g/cm2), age (years) and weight (kg).  
Primary safety outcome analysis: Fisher’s Exact test of between-group difference in the number of people 
in each assigned group reporting at least one hypercalcemia or hypercalciuria event in the first 6 months 
of assigned treatment; followed by Cox proportional hazards model analysis of the between-group 
difference in the time-to-first hypercalcemia or hypercalciuria event; followed by GEE testing of the 
between-group difference in the temporal pattern of the repeatedly sampled hypercalcemia or 
hypercalciuria events in the first 6 months of assigned treatment.  
Secondary efficacy outcome analyses: TH, FN and 1/3 Radius aBMD by DXA will analyzed by 
ANCOVA as described for the primary outcome, above.  
Secondary safety outcome analyses: Fisher’s Exact test will be used to assess treatment group differences 
in numbers of people endorsing each symptom reported on the symptom checklist administered at each 
study visit without adjustment for multiplicity. The GEE test approach proposed for the primary safety 


outcome analysis of longitudinal events will be repeated for any symptom reported by >10% of either 
treatment group.  
 
 
AIM 2:  
Primary analysis:  The between-group mean difference in the quad-labeled histomorphometric measured 
change in Mineralizing Surface (MdPm) and Bone Formation Rate (BFR/BS) at 3 months will be 
analyzed with ANCOVA with adjustment for the baseline continuous variables of age (years) and weight 
(kg.).  Outcomes will be analyzed separately without adjustment for multiplicity. 
Secondary analyses:  In the teriparatide-treated group the relationship between baseline MdPm and 
BFR/BS, and change in MdPm and BFR/BS in the first three months of treatment, and 12 and 24 month 
change in aBMD of the spine and hip by DXA and vBMD of the spine by cQCT will be assessed with 
multiple regression analysis.  Per annum change in DXA and cQCT outcomes will be separately modeled 
as a function of baseline MdPm and BFR/BS, baseline level of the DXA or cQCT outcome, age, weight, 
bone microstructure by microCT of biopsy specimens, and change from baseline in MdPm and BFR/BS 
during the first three months.   Other potential baseline predictors of DXA and cQCT response to 
teriparatide treatment will be explored with multiple regression to determine whether any clinical or 
constitutional measures supercede change in MdPm or BFR/BS in predicting bone change. 
 
AIM 3:  
Primary efficacy outcome analysis: Analysis by linear mixed models for repeated measures (LMMR) of 
the within-group (TPTD) change in LS aBMD (g/cm2) by DXA from pre-treatment baseline with repeated 
measures at 12- and 24-months. (This is a growth curve model testing the hypothesis that the temporal 
trajectory of within-subject change in outcome differs from a random process.) The model estimates the 
fixed effect of time, random effects for subject, error and the quadratic and cubic values of time entered as 
random effects, continuous covariates for age and weight at baseline and with an AR(1) covariance 
structure. The random effects for higher-order factors for time model monotonic and U-shaped 
components of the growth curve. Model estimated within-subject differences between specific timepoints 
will be assessed when the fixed effect of time is statistically significant. The LMMR model will be 
repeated for LS trabecular vBMD by cQCT after 24 months of teriparatide.   
Secondary efficacy outcome analysis: The same LMMR analysis proposed for Aim 2 primary outcomes 
will be used for secondary efficacy outcomes of TH, FN and 1/3rd RD aBMD by DXA and HRpQCT after 
12 and 24 months, and cQCT after 24 months of TPTD. These analyses will also be used  to explore the 
pattern of change in serum BTMs (P1NP and CTx), between baseline and 24 months. 
Exploratory analyses will also be conducted to determine whether clinical factors such as age, BMI, body 
composition, and aspects of the growth hormone axis may predict BMD response to TPTD. 
 
2.B. Power and Sample Size 
We have based our power calculations upon the preliminary data generated from our recent pilot study of 
22 women with IOP who were treated with teriparatide for 24 months. Our power estimates are based 
upon 40 women randomized to TPTD or placebo (28:12) with data for analysis, assuming a 10% drop-out 
and an alpha level of 5%.   
 
AIM 1: 
Primary efficacy outcome:  For the primary endpoint of between-group difference in LS BMD at 6 
months, power calculation assuming the proposed two-group ANCOVA and outcome correlation with 
baseline covariates of 0.3, we will have >90% power to detect a difference of 3.7 + 3.3% in the TPTD-
treated vs. 0.8 + 2.9% in the placebo-treated group (placebo estimate based on interpolation from our 
preliminary data at 12 months).  The estimated effect size is consistent with an annual TPTD-induced 
increases of 7.0-13.5% in studies by Arlot et al. in postmenopausal women, Langdahl et al. in 
premenopausal women with GIOP, and Kurland et al. in male IOP36.  


Primary safety outcome:  For our primary safety outcome, the between-group difference in the number of 
people in each assigned group reporting at least one hypercalcemia or hypercalciuria event, we do not 
expect to have sufficient power to detect group differences in event rate because of the rarity of TPTD-
related safety events observed in our pilot study and reported by others in the literature. 
Secondary efficacy outcome:  For our secondary efficacy endpoints of between-group differences in TH, 
FN and 1/3R, our preliminary data suggest that we will not have sufficient power to detect between 
groups differences in these measures at 6 months, as the increases are less pronounced than at the LS. 
Secondary safety outcome:  While we will closely examine the safety data, our small sample size 
provides minimal power to detect any but the most dramatic differences in safety profile between groups.  
 
AIM 2:  
Primary efficacy outcomes: For MdPm and BFR/BS after 3 months of TPTD, we base our effect size 
assumptions on the Lindsay et al28 estimates of changes from baseline to 1-month of cyclic TPTD 
treatment (assuming these measures are virtually unchanged over 3 months in the placebo treated group). 
Lindsay reports cancellous BFR/BS increased from 0.008 + 0.006 to 0.027 + 0.018 (a standardized effect 
size of 1.42) and cancellous MdPm from 1.33 + 0.95 to 3.78 + 2.53 after 1 month (a standardized effect 
size of 1.28). With the proposed sample size, we will have over 90% power to detect difference 
comparable or larger than the increase in bone formation detected by Lindsay after 1-month of treatment.  
Secondary analyses to assess the predictability of DXA and cQCT changes from baseline and 3-month 
changes in BFR/BS and MdPm:  The proposed sample size enables us to detect between 40% to 55% of 
the variance accounted for in the 12- or 24-month DXA or cQCT change and the baseline to 3-month 
change in BFR/BS or MdPm (assuming 80% power, 5% alpha and a multiple regression model with up to 
3 covariates partialled from both the bone density outcome and the histomorphometric predictor).  
 
AIM 3: 
Primary efficacy outcomes:  For LS aBMD by DXA after 12 and 24 months of TPTD, we will have 
>86% power to detect changes from baseline.  We based our estimate of LS aBMD at 12 months on our 
preliminary data, and at 24 months on the data of Graeff et al.41 who detected a 10.2% increase in aBMD 
over 24 months. We anticipate that the increase between baseline and 12 months will far exceed the 
increase from 12 to 24 months, which may not be statistically significant.  For trabecular vBMD at the 
spine by cQCT after 24 months of TPTD, the work of Rehman et al.32, who detected an increase of 35% 
in vBMD, suggests that we will have power of >99% to detect within-group changes. 
Secondary efficacy outcomes:  We will have 99% power to detect within group increases from baseline in 
TH BMD at 12 and 24 months.  This estimate is based upon our preliminary data.  We do not have 24 
month data; however, published work by Saag et al.42 and Keaveny et al.43 suggests that we may not have 
sufficient power to determine whether TH BMD increases significantly between 12 and 24 months.  In 
addition, we may not have sufficient power to detect significant changes in FN or 1/3R BMD.  For HR-
pQCT measures, the Bogado study44 indicates we will have 99% power to detect within group changes in 
Ct.Th, Tb.N and Tb.Sp.   
 
 
 
 
3. Study Procedures 
 
3.A. Schedule of Visits 
Visit 1 (Screening): Women with IOP fulfilling preliminary eligibility requirements (Telephone 
Questionnaire) will be invited to attend a Screening Visit at CUMC or Creighton. Prior to initiation of any 
screening procedures, an informed consent discussion will take place. Only after the informed consent 
(Screening Consent Form) is signed will screening procedures commence.. The visit will be scheduled 
during days 1-5 of the menstrual cycle to identify women in early menopause (FSH>20 mIU/ml). After a 


negative pregnancy test, all will have BMD, VFA and body composition by DXA. Women who fulfill 
BMD or fracture eligibility criteria will complete a Historical Questionnaire (Appendix 1) on medical and 
reproductive history (menstrual history, menarchal age, parity, OCP use), risk factors for osteoporosis 
(eating disorders, alcohol, tobacco, caffeine intake), personal and family history of fractures, current and 
past medications.  The Eating Disorder Examination - Questionnaire (EDE-Q; Appendix 2) will be given 
to identify women with subclinical eating disorders45,46. All will have a standardized physical (weight, 
height by Harpenden stadiometer) by a physician co-investigator and a Secondary Osteoporosis 
Evaluations (SOPEval). The following must be normal: blood count, Westergren ESR, C-reactive protein, 
electrolytes, creatinine, thyroid and liver function tests, uric acid, calcium, phosphate, 25-OHD (>20 
ng/dl; those with levels between 21-29 ng/ml will be offered supplementation to achieve levels >30), 
intact PTH (<65 pg/ml), tissue transglutaminase IgA antibody (tTG; 99% specific and 95% sensitive for 
celiac disease) and immunoglobulin A (IgA) to exclude celiac disease, 24-h urine for creatinine, calcium 
(<300mg/gCr) (100-250 mg), free cortisol. Other tests may be performed if less common etiologies are 
suspected. In some cases, arrangements may be made for some portions of the screening visit procedures 
(eg laboratory studies) to take place outside of this medical center. In all cases, eligibility will be verified 
by study physicians.  
 
Visit 2 (Imaging): If the SOPEval is normal, candidates will be invited to proceed with Visit 2. Prior to 
initiation of any additional study procedures, an informed consent discussion will take place. Only after 
the informed consent (Study Consent Form) is signed will further research related procedures commence. 
The study will be described, including the bone biopsy procedure. Participants with fractures will be 
asked to bring verification (x-rays or radiology reports). They will complete standardized questionnaires 
to assess current diet and physical activity. We use the validated Block food frequency questionnaire 
(FFQ; Appendix 3)47,48 to assess calcium intake. Physical activity is assessed by the modified Baecke 
questionnaire (Appendix 4)49-51. Equivocal VFA results will be evaluated with spine x-rays. Central QCT 
of the spine (L1 and L2) with additional single slice at L4, and HR-pQCT of the distal radius and tibia 
will be performed to measure volumetric BMD, body composition (subcutaneous and visceral adiposity), 
and cortical and Tb microstructure. Serum will be archived at -80o.At this visit, subjects will also receive 
tetracycline for their first round of antibiotic labeling and instructions with a scheduled dosing according 
to protocol. Subjects will complete labeling before the randomization visit, where they will receive Forteo 
and begin treatment. 
 
52,53 
Visit 3 (Randomization): During this visit, imaging results will be reviewed with the subjects. Eligible 
subjects who agree to participate will be randomized to TPTD or placebo (ratio  28:13) through block 
randomization with randomly varying block sizes of 2, 4 or 6, stratified by whether they are included on 
the basis of history of fractures or low BMD.  Serum/urine will be archived at -80oC for batch analyses of 
specialized biochemistries. DNA will be obtained from peripheral blood lymphocytes for archival 
purposes. We will collect blood for the measurement of osteoblasts, or bone building stem cells, in the 
bloodstream.  
 
Subjects will be provided with calcium (citrate) caplets (Citracal + D; each 315 mg + 250 IU D) and a 
multivitamin (Centrum) that provides 500 IU of vitamin D daily. Most subjects will be instructed to take 
2 Citracal caplets and a multivitamin; the total daily dose of calcium from supplements will be 
approximately 630 mg and of vitamin D 1000 IU. Subjects with very low dietary calcium intake (<500 
mg/d estimated by interview and the FFQ), will be asked to take 3 Citracal caplets, while those with high 
dietary calcium intakes (>1,000 mg/day) will be asked to take 1 Citracal caplet. 
 
Visits 4-5, 8-13 (Study Evaluations): At each study visit, study coordinators will assess any adverse 
events that transpired since the last study visit. Patients will be instructed to bring their Forteo journal and 
pens with them to every visit, which documents their compliance with the study medication. The purpose 


of the 1-week and 1-month visits (Visits 4 & 5) is to monitor for compliance and adverse effects. At the 
1-week and 1-month visit, we will also obtain fasting serum for serum calcium (safety) and at the 1-
Month we will also collect serum for BTMs. These visits may be conducted on site for women who reside 
close to the study sites or may be a telephone contact and local blood draw for those who live at a 
distance. The remainder of the study visits to perform imaging studies and/or blood draws and dispense 
study drug are shown in Tables 1-3. We will perform a single follow-up cQCT scan after 24 months of 
TPTD treatment to minimize radiation exposure in these women who are of child-bearing age. At Visit 
12, subjects will be presented with three options for post-TPTD follow up as described in the study 
design. 
 
 
Visit 6 (Pre-Biopsy Clearance and Labeling): Subjects will have a pre-biopsy clearance visit with the 
surgeon and have safety bloods drawn and processed as per hospital regulations. Subjects will receive 
their second antibiotic labeling agent, demeclocycline, and accompanying labeling schedule.    
 
Visit 7 (Transiliac Bone Biopsy): Transiliac crest bone biopsy is used to investigate 3-dimensional bone 
structure and static indices of bone remodeling. Dynamic remodeling indices (e.g., mineralizing surface 
and bone formation rate) are also assessed with tetracycline labeling techniques. The traditional double 
label biopsy protocol involves administration of two 3-day courses of tetracycline separated by 12 days. 
Tetracycline localizes on bone surfaces undergoing active bone formation and permits precise 
quantification of the rate of bone formation and remodeling. In the quadruple labeling protocol, 2 sets of 
double tetracycline labels are administered: one set before drug treatment, and a second set after 1-3 
months of treatment/placebo; a single biopsy is then performed after the second set of labels (74). 
Because two different tetracyclines are used that fluoresce in different colors, a single biopsy can be used 
to assess dynamic indices of bone remodeling before and during drug treatment. This labeling protocol 
has been previously used by our group to study the osteoanabolic effects of TPTD in postmenopausal 
women (74) and the effects of hPTH(1-84) in subjects with hypoparathyroidism (75).     
 
Transiliac crest bone biopsy will be performed according to procedures established at CUMC and 
Creighton. We will be performing the quadruple labeled bone biopsy at the 3 month visit. We have a long 
track record of performing research quality, bone biopsies and have been successful in obtaining bone 
biopsy specimens in both normal and abnormal cohorts of subjects, including women with IOP.  
 
 
 
 
Table 1: Study 
Visits 
 
1 
Screen 
2 
Imagin
g 
3 
Randomiz
e 
4 
1W 
5 
1M  
6  
2M 
Labelin
g 
7 
3M 
Biops
y 
8 
6M 
Consent 
 
x 
x  
 
 
 
 
 
 
MD Visit 
 
x 
x  
 
 
 
xa  
 
x   
Dispense TPTD 
 
 
 
x 
 
 
 
x 
x 
Telephone Contact#  
 
 
 
 
x 
x 
x  
x 
x 
Pregnancy Test 
 
x 
X 
x 
 
 
 
 
x 
BMD by DXA 
 
x 
 
 
 
 
 
 
x 
History & Physical 
 
x 
 
 
 
 
 
 
 
Questionnaire A & B 
 
x 
 
 
 
 
 
 
 
Questionnaire C & D 
 
 
X 
 
 
 
 
 
 
Adverse Events 
 
 
 
 
x 
x 
 
x 
x 


Serum FSH 
 
x 
 
 
 
 
 
 
 
SOPEval % 
 
x 
 
 
 
 
 
 
 
HR-pQCT 
 
 
X 
 
 
 
 
 
x 
Central QCT 
 
 
X 
 
 
 
 
 
 
VFA by DXA 
 
x 
 
 
 
 
 
 
 
Body Composition by 
DXA 
 
x 
 
 
 
 
 
 
 
Blood/Serum Archive 
 
 
xβ 
xβ 
 
x 
 
x 
x 
24H urine 
calcium/creatinine 
 
x  
 
 
 
x 
 
 
x^ 
Calciotropic 
Hormones 
 
 
 
x 
 
 
 
 
 
Bone Turnover 
Markers 
 
 
 
x 
 
x 
 
x 
x 
Pre-Biopsy Labs 
 
 
 
 
 
 
x  
 
 
Antibiotic Labeling  
 
 
X 
 
 
 
x  
 
 
Bone Biopsy 
 
 
 
 
 
 
 
x 
 
 
 
a Includes pre-biopsy clearance and consent 
β Baseline laboratory collection to be split between the 2 collection 
timepoints 
# Will occur before the scheduled visit 
% Includes baseline 24 hour urine 
^ Will be collected 1M after 6M treatment with TPTD for safety labs  
 
 
 
Table 2: Study Visits –  
Group A* 
9 
9M 
10 
12M 
11 
18M 
12 
24M 
13 
36M 
MD Visit  
 
x 
 
x 
x 
Dispense TPTD 
 
x 
X 
x 
 
Telephone Contact#  
  x 
x 
X 
x 
x 
Pregnancy Test 
 
x 
X 
x 
x 
BMD by DXA 
 
x 
X 
x 
x 
History & Physical 
 
x 
 
x 
x  
Adverse Events 
  x 
x 
X 
x 
x 
Serum FSH 
 
 
 
x 
 
HR-pQCT 
 
x 
 
x 
x 
Central QCT 
 
 
 
x 
 
VFA by DXA 
 
x 
 
x 
x 
Blood/Serum Archive 
  x 
x 
X 
x 
x 
Calciotropic Hormones 
 
x 
 
x 
x 
Bone Turnover Markers 
 
x 
X 
x 
x 
 
* Only for treatment group assigned immediately to active 
treatment (Group A) 
# Will occur before the scheduled visit 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For the sub-study: This sub-study involves only one visit that can be done at the same time as a visit 
completed for the main study. Four blood draws will be performed. These bloods will be collected while 
subject is fasting.  The first blood draw will be collected right before the subject completes the Forteo 
injection. These will be considered the baseline bloods. The remainder 3 blood draws will be collected 30 
minutes after injection of Forteo, 60 minutes after Forteo injection and 4 hours after Forteo injection. 
Samples will be stored for measurement of drug (Forteo: PTH1-34) and drug effects (calcium). 
 
3.B Study Procedures 
1. BMD by DXA: Areal BMD (aBMD) of the LS (L1-4), proximal femur and non-dominant forearm will 
be measured at CUMC on Hologic QDR 4500 densitometers (Hologic, Inc., Waltham, MA). Dedicated 
technologists, certified by the International Society of Clinical Densitometry, with long-term research 
experience perform all scans. Phantoms are scanned daily to check for detector drift; the results are 
appended to a quality control (QC) database. Results are downloaded to specific project databases. The 
effective dose for BMD by DXA is7.45 µSv. 
2. Body Composition by DXA: Total fat mass, lean mass, and percent fat mass will be measured by 
DXA. The effective dose for whole body DXA is 5.2 mrem.  Our precision is 1%. 
3. Vertebral Fracture Assessment (VFA) by DXA: Visual semiquantitative identification of vertebral 
fractures is obtained from images acquired by fan-bean DXA scanners. VFA demonstrates good 
agreement with conventional radiographs (96.3%, k=0.79) in classifying vertebrae as normal or 
deformed. With its low radiation and good precision, VFA is useful to identify subjects with and without 
vertebral fractures. The total effective radiation dose associated with each VFA 5.2µSv. 
4. High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT): HR-pQCT is 
performed on the XtremeCT (Scanco Medical AG, Switzerland). The nondominant distal radius and tibia 
are immobilized in a carbon fiber shell (158-160). The region of interest 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 9.5 mm and 
22.5 mm proximal to the reference line at the radius and tibia respectively. A stack of 110 parallel CT 
slices is acquired at the distal end of both sites using an effective energy of 40 keV, slice thickness of 82 
Table 3: Study Visits 
– Group B** 
9 
9M 
9 
12M 
10 
18
M 
11 
24
M 
12 
30
M 
13 
42
M 
MD Visit  
 
x 
 
x 
 
X 
Dispense TPTD 
 
x 
x 
x 
 
 
Telephone Contact#  
  X 
x 
x 
x 
X 
X 
Pregnancy Test 
 
x 
x 
x 
X 
X 
BMD by DXA 
 
x 
x 
x 
X 
X 
History & Physical 
 
x 
 
x 
 
X 
Adverse Events 
  x 
x 
x 
x 
X 
X 
Serum FSH 
 
 
 
 
X 
 
HR-pQCT 
 
 
x 
 
X 
X 
Central QCT 
 
 
 
 
X 
 
VFA by DXA 
 
x 
 
x 
 
X 
Blood/Serum Archive 
  x 
x 
x 
x 
X 
X 
Calciotropic Hormones 
 
x 
 
x 
 
X 
Bone Turnover 
Markers 
 
x 
x 
x 
X 
X 
 
** Only for treatment group that started with 6 months of 
placebo injections (Group B) 
# Will occur before the scheduled visit 


µm, image matrix size 1024x1024, nominal voxel size of 82 µm. This machine provides a 3D image of 9 
mm in the axial direction. HR-pQCT provides microstructural information (cortical and trabecular 
density, cortical thickness, trabecular number, thickness and separation) previously obtainable only by an 
invasive bone biopsy. We are one of only 5 US medical centers with this new technology. For HRpQCT 
of the forearm and leg, the estimated effective whole body dose is below 5 µSv per scan, since only a 
very small fraction of the distal forearm or leg is irradiated. 
 
5. Volumetric BMD by Central QCT: Volumetric QCT acquisitions of the L1-L2 vertebrae (80 kVp, 
140 mAs, 2.5 mm slice thickness, pitch=1.2, standard reconstruction algorithm, 3-Bar Image Analysis 
QCT Calibration Phantom (Image Analysis, Columbia, KY) will be carried out on a Siemens Biograph 40 
Slice CT Scanner (Siemens Medical Solutions, Malvern, PA), located within CUMC’s Kreitchman 
PET/CT Center.  Scan data are archived to CD and forwarded to a central analysis site (UC San 
Francisco, Dept. of Radiology) for scan quality assurance and analysis.  Spine CT images are analyzed 
with image analysis software developed by our collaborator and consultant, Thomas Lang, Ph.D. L1-L2 
measures analyzed by this software include vBMD of an integral compartment containing the vertebral 
body and posterior elements (viBMD), the areal BMD of this region obtained by computing its bone 
mineral content and dividing by the projected area in the AP plane (QCTaBMD), and the vBMD of a 
region containing almost all of the trabecular bone in the vertebral centrum (vtBMD). BMD data obtained 
on each scanner are converted to the calibration-phantom equivalent BMD. To ensure comparability of 
data obtained on different CT scanners used at CUMC, CT data are cross-calibrated using the Image 
Analysis Torso Quality Control phantom (Image Analysis, Columbia, KY) which is scanned multiple 
times on each system. Total effective radiation dose from a central QCT scan of the spine is estimated at  
470 µSv which is equivalent to approximately 2-3 months of background radiation (assumed to be 3 
mSv/year). 
 
6. Body composition by CT: At the time that L1-L2 cQCT measures are acquired, as above, one 
additional axial image slice (10mm thick) will be obtained at the mid L4 vertebra level77. Based upon this 
image, the cross-sectional areas of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) 
in cm2 will be calculated by the method of Zhao et al 54. The additional radiation exposure from the single 
slice is estimated to be 10% of the exposure for the L1-L2 scan above (approximately 5µSv). 
 
7. Spine Radiographs: Lateral thoracic and lumbar spine radiographs for diagnosis of prevalent or 
incident vertebral fractures, performed using the protocol used in the Study of Osteoporotic Fractures 
(SOF) 55, will be used in subjects for whom VFA diagnosis of fractures is ambiguous. Total critical organ 
absorbed dose from a lateral thoracic and lumbar spine radiograph is equivalent to about 350 mrem. Our 
skeletal radiologist, Ronald Staron, M.D., evaluates and reads these x-rays. 
 
8. Biochemical Assays: All blood samples will be collected fasting in the morning. General tests (CBC, 
serum calcium, phosphate, albumin, renal and liver function tests, urine calcium and creatinine) will be 
run when collected by standard methods. Serum for PTH, 25-OHD, 1,25(OH)2D, osteocalcin, BAP, 
P1NP, CTx, IGF-I, IGFBPs, leptin, adiponectin, insulin, glucose, IL-6, homocysteine, c-reactive protein 
(CRP), lipid studies, E2, testosterone, SHBG, OPG, RANKL will be aliquoted, frozen immediately and 
stored at -80o. Specimens will be shipped frozen from the CORC to Columbia. Additional serum/urine 
will be archived for measurement of BTMs and mineral metabolites that may become available in future. 
Blood for DNA will be obtained from peripheral blood lymphocytes for archival purposes. We intend to 
isolate and store these samples for future genetic studies that may identify a polymorphism linked to one 
of our phenotypes, or identify a new candidate gene polymorphism in our study population. Blood for 
osteoblasts, which are bone-building stem cells, found in the bloodstream, will be collected. These will be 
processed and stored frozen at -80°C. All assays are currently in place either in the CUMC Bone Marker 
Laboratory within the Division of Endocrinology, under the direction of Serge Cremers, PhD., PharmD or 


the Core Laboratory of the Irving Institute for Clinical and Translational Research (CUMC CTSA). Lipid 
particle size analysis will be conducted at Liposcience, Inc. 
 
9. Bone Biopsy of Iliac Crest: Transiliac crest bone biopsy will be performed according to procedures 
established at CPMC and CORC. Participants will receive instructions and medications for tetracycline 
and demeclocycline "quadruple labeling" at the beginning of the study and one month prior to second 
label. Transiliac crest bone biopsy will be performed according to standard procedures established here at 
CUMC and Creighton University under the direction of Drs. Shane and Recker, who both have long track 
records of performing successful research quality bone biopsies. Bone biopsies will be performed by Dr. 
Shane, Dr. Stein or Dr. Nickolas in the Milstein Operating Rooms at CUMC. The biopsy sample will be 
placed in a 30 ml liquid scintillation vial containing 70% ethanol and shipped to Dr. Ralph Müller's 
laboratory for microCT and FEA. Next, the specimens will be shipped to Dr. David Dempster's laboratory 
(Helen Hayes Hospital, West Haverstraw, NY) for embedding and analysis. 
 
4. Study Drugs or Devices 
Teriparatide has been FDA approved for the treatment of osteoporosis since November 2002. The pen 
delivery device will be fully coded and ready for distribution by our research pharmacy. Two identical 
sets of pens will contain placebo (vehicle alone) or 20 mcg of teriparatide. Drug will be stored in a 
refrigerator in the research pharmacy until it is dispensed. Subjects will be instructed to refrigerate the 
medication at home during their pen training. 
 
The study drug will be packaged in a pre-filled pen delivery device (20 mcg or placebo in 3 ml) in such a 
manner as to make active and placebo TPTD indistinguishable.  Each pen will be labeled with the subject 
identifier and the 24-hr telephone number of the research pharmacist who will retain information of 
treatment allocation in the event that unblinding becomes necessary. All other study related items and 
documents are only identified with the subject identifier. All subjects will be trained to self-administer 
agent (drug or placebo) by our research nurse.  All medication will be dispensed by the research 
pharmacy of the Office of Clinical Trials at Columbia University. 
 
5. Study Instruments 
Subjects will complete the following standardized questionnaires as part of this protocol. 
1. Historical Questionnaire on medical and reproductive history (menstrual history, menarchal age, 
parity, OCP use), risk factors for osteoporosis (eating disorders, alcohol, tobacco, caffeine 
intake), personal and family history of fractures, current and past medications.   
2. Dietary Rapid Calcium Assessment to assess calcium intake 
3. The Eating Disorder Examination Questionnaire (EDE-Q) to screen out subjects with a current 
eating disorder 
4. Block Food Frequency Questionnaire (FFQ) to assess dietary habits 
5. Modified Baecke Questionnaire to assess physical activity 
6. Phone Screening Questionnaire 
 
Questionnaires 2-4 are all validated, standardized instruments.  These questionnaires are all attached in 
the RASCAL system. 
 
6. STUDY SUBJECTS 
Inclusion Criteria:  
 
Premenopausal women, aged 20-48, with regular menses and no historical or biochemical secondary 
cause of osteoporosis; the lower age limit is to ensure epiphyses are fused, the upper to make it less 
likely that women will enter menopause during the study. All subjects under age 25 will be screened 
prior to drug administration to rule out open epiphyseal plates. 


 
Documented adult fractures judged to be low-trauma (trauma equivalent to a fall from a standing 
height or less) and/or T < -2.5 or Z score <-2.0 at the LS, FN or TH. Inclusion criteria vary slightly 
based on age category: 
o Premenopausal women ages 20-35 years must have at least one major osteoporotic fracture 
(excluding fractures of fingers, toes and face) AND low BMD defined as a T-score or Z-score 
≤ -1.5. 
o Premenopausal women above the age of 35 years should have a history of fracture AND/OR 
low BMD defined as Z-score < -2.0. Women above age 35 may also be enrolled on the basis 
on low BMD alone, without presence of prior low trauma fracture. 
 
Must be willing to use effective contraception throughout the period of study drug administration 
 
Exclusion Criteria: 
 
History of any condition that increases the risk of osteosarcoma (Paget’s disease, skeletal irradiation) 
 
Early follicular phase serum FSH>20 mIU/ml (to exclude perimenopausal women) 
 
Disorders of mineral metabolism: 1o/2 o hyperparathyroidism, osteomalacia, osteogenesis imperfecta 
(OI) or Ehlers Danlos (ED). Subjects will not routinely undergo genetic testing for OI or ED as part 
of their screening evaluation. However, each subject will have a detailed medical and family history 
and a complete physical examination by one of the physician investigators. Women with historical 
features or physical examination findings suggestive of OI or ED will be referred for genetic 
evaluation. If the genetic evaluation is positive for OI or ED, the subject will be excluded from 
participation. 
 
Suspicion of osteomalacia (elevated alk phos, worsening bone pain with weight bearing, or bone 
tenderness)  
 
Vitamin D deficiency (serum 25-OHD<20 ng/ml). Women with levels of 10-20 ng/ml will be eligible 
after treatment with vitamin D has resulted in levels ≥20 ng/ml. 
 
 Pregnancy within the last 3 months if there was no lactation or lactation within past 6 months 
 
Prolonged amenorrhea (> 6 months) during reproductive years (except pregnancy or lactation) 
 
Prior eating disorder (hypothalamic or exercise induced amenorrhea now resolved may be acceptable 
if symptoms occurred at age >20 years, for <1year, >5 years ago)  
 
Malignancy, except cured basal or squamous cell skin carcinoma 
 
Endocrinopathy: new onset untreated hyperthyroidism, hypothyroidism, Cushing’s syndrome, 
prolactinoma  
 
Renal insufficiency (serum creatinine above upper limit of female normal range) 
 
Liver disease (AST, ALT, bilirubin, total alkaline phosphatase activity above upper normal limit) 
 
Intestinal disorders (celiac disease, pancreatic insufficiency, inflammatory bowel disease)  
IBD: only Crohn’s Disease or Ulcerative Colitis are exclusions 
 
 
 
 
History/current GCs, anticonvulsants, anticoagulants, methotrexate, depot progesterone, GnRH 
agonists 
 
Oral glucocorticoid use (subject will not be excluded if used dose equivalent to less than prednisone 5 
mg for <3 months). Inhaled steroid exposure will require assessment of dose used.  
 
Current anticoagulant  use (past use of warfarin (Coumadin) or low molecular weight heparin is not 
an exclusion) 
 
Depo Provera use (subjects will not be excluded if used at age>20, >5 years ago) 
 
Drugs for osteoporosis (raloxifene, bisphosphonates, denosumab, calcitonin, TPTD). Subjects who 
discontinue these medications will be eligible 3 months after stopping raloxifene or calcitonin, 12 
months after stopping alendronate, risedronate, ibandronate, or pamidronate and 18 months after 
stopping denosumab.  Subjects with prior use of zoledronate may be eligible if received only one dose 
>4 years ago. Total bisphosphonate exposure must be < 1 year. Subjects who have taken TPTD in the 
past will not be eligible unless used for <3 months, > 2 years ago. 


 
7. RECRUITMENT 
Subjects from CUMC will be recruited from previously enrolled and newly recruited subjects. 
Recruitment to studies of uncommon diseases is always challenging. Although recruitment of cases to the 
original R01 grant (AAAA9245) was slow for the first 2 years, we ultimately enrolled 64 subjects with 
IOP. In addition, we were able to recruit 22 women to the pilot study of TPTD in Premenopausal Women 
with IOP in 12 months. Our study teams have developed ongoing relationships with these patients that 
will be useful in recruitment. We anticipate that some of the subjects in protocol AAAF2251 will come 
directly from protocol AAAA9245, as, in our experience, many women with IOP are anxious to pursue 
treatment options for their condition.  
 
We recruit subjects locally, nationally and internationally. Locally, we recruit patients referred to the 
Metabolic Bone Disease Unit at CUMC in New York. We post flyers and speak at inter-departmental and 
inter-institutional conferences, particularly to Orthopedics and Obstetrics & Gynecology departments. We 
speak at national and international conferences (ISCD, NOF, ECTS, ASBMR, TES). Dr. Shane recently 
conducted the first ASBMR Webinar on premenopausal osteoporosis, which was attended by >200 
individuals. We send biannual email reminders to physicians from surrounding states of both centers who 
care for patients with osteoporosis and also to our clinical colleagues in ASBMR. The study will be 
posted on CUMC, NOF, NIH, and clinicaltrials.gov. A large source of referrals is patients themselves.  
 
When a patient is referred to our center, we will conduct a brief phone screening to ascertain whether the 
subject may be appropriate for the study. Prior to enrollment, a study investigator or research coordinator 
will review the study at length with the subject during the informed consent process.  
 
8. 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. 
 
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.  
 
9. CONFIDENTIALITY 
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 investigator, 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 investigator, regulatory authorities, IRB and study sponsor 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. 
 
10. 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, the 
FDA and Eli Lilly, who is providing us with the study drug. These reports will include only a study ID, 
and will not divulge the participant’s identity.  
 
11. POTENTIAL RISKS 
The risks of this study are related to the venipuncture, radiation exposure and the study medication, 
teriparatide. 
 
1) Teriparatide 
a. Teratogenicity: In contrast to bisphosphonates, TPTD does not accumulate in the skeleton. Therefore, 
teratogenic effects, if any, would essentially be limited to the period of administration. Thus, it is a more 
attractive choice for treating osteoporosis in women of childbearing age, as there would be no potential 
for subsequent pregnancies to be affected by residual drug. All participants will be required to use 
effective contraception during the study. 
b. Osteosarcoma: Rats exposed to TPTD, in amounts 3-58 fold higher than the human dose for the 
equivalent of 75 human years (18-24 rat months), develop osteosarcoma in a dose related manner. 
Therefore, the FDA approved TPTD for therapy of osteoporosis with a “black box” warning and 
recommended a 2-year limit on duration of treatment. It is highly likely that this toxicity as particular to 
the rat. There are marked differences in skeletal physiology between rodents and primates. The rat 
skeleton grows throughout most of their lives56 and shows very little evidence for remodeling. In contrast, 
humans typically cease longitudinal growth by 15-20 years of age57 and the adult human skeleton is 
characterized by remodeling rather than growth. Perhaps because of these differences, the anabolic 
response of the rat skeleton to daily PTH treatment is far greater in rats58 than in humans59. Most recently, 
in a second toxicity study in rats, a “no effect” dose was defined that was larger than any human being 
will experience60. Finally, there was no evidence of any carcinogenic toxicity when the non-human 


primate macaque was treated with the same toxicity protocol61. To date, two cases of osteosarcoma have 
been reported in among almost 430,000 patients treated with TPTD62-64; this is approximately the same 
incidence as the 1.7 patients expected to develop osteosarcoma by chance alone, given an expected 
incidence of 4-5 per million. An additional case recently reported in abstract form, had osteosarcoma 
before TPTD was initiated65. Moreover, the pathology of the first case was controversial and the second 
case developed in a man who had received pelvic radiation for prostate cancer and the cancer developed 
within the field of radiation, rather than in the long bones, as is typical of sporadic osteosarcoma64. 
Among the millions of individuals with hyperparathyroidism who are exposed to chronically elevated 
levels of PTH, there are only rare reports of osteosarcoma, most of which have not been well-
documented66.  There were no reports of osteogenic sarcoma among the participants in any of the clinical 
trials with PTH, amounting to over 2500 patients.  In the largest clinical trial with 1637 subjects, there 
was no increase in cancer incidence between subjects receiving TPTD and placebo and no woman 
developed an osteosarcoma28. Given all these considerations, it appears that, in general, PTH is safe in 
humans and that TPTD will be a safe treatment for premenopausal women with IOP.  Nevertheless, it is 
important that subjects in this study are informed of the rat toxicity data and the case reports. Consistent 
with FDA guidelines, no patient will receive active drug for more than 2 years. In addition, the dynamic 
histomorphometry measurements we will have will offer an extra measure of safety parameters. We plan 
to minimize the already small risk by excluding adolescents who may not have fused epiphyses and 
women with a history of skeletal radiation. 
c. Hypercalcemia, Hyperuricemia and Hypercalciuria: Hypercalcemia and mild increases in serum uric 
acid are known side effects of PTH, although not very common at the FDA-approved 20 mcg/day dose 
that we will use. A post-hoc analysis of two prospective randomized clinical trials involving 1,637 
postmenopausal women and 2,437 men found that urinary calcium excretion increases by an average of 
32 mg/d on the 20 mcg dose of TPTD67. Dr. Shonni Silverberg, the Study Monitor, will monitor pre-dose 
serum calcium and uric acid and urinary calcium excretion at 1 to 6-month intervals to determine the 
incidence of these abnormalities in our study participants. We will exclude subjects with hypercalcemia 
(fasting serum calcium >10.2 mg/dl) and hypercalciuria (>300 mg/g creatinine) at baseline.  
 
For subjects in the placebo group during months 0-6, there may be a risk of bone loss. However, Peris et 
al. reported a retrospective analysis of 16 women with IOP, managed with calcium, vitamin D and 
increased physical activity68 They documented small increases in BMD and no fractures over an average 
3 years of observation, supporting the safety of a placebo-controlled design. We have longitudinal BMD 
data in 18 women with IOP followed on calcium (1000-1500 mg/day) and vitamin D (800-1000 IU/day) 
for an average of 4 years. LS BMD increased by 0.8 + 2.9%, while there were slight decreases at the FN 
(-1.2 + 5.3%), TH (-0.5 + 3.4%) and 1/3 Radius (-2.4 + 2.8%). None of the decreases were statistically 
significant. Thus, we do not expect major declines in BMD in the women randomized to placebo for the 
first 6 months and in any case, all subjects will receive teriparatide after the first 6 months.  
 
2) Radiation 
Radiation exposure (effective dose) for DXA of the spine, hip and forearm with the Hologic QDR4500 is 
7.45 µSv, for VFA 5.2 µSvand for Body Composition is 5.2µSv. This is about the amount the average 
person receives from background radiation in 19 days. For HRpQCT of the forearm and leg, the estimated 
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 a central QCT scan of the spine and additional slice for body 
composition is about475 µSv, which is equivalent to approximately 3 months of background radiation. In 
subjects where VFA diagnosis of fractures is ambiguous, subjects will be asked to have lateral thoracic 
and lumbar spine radiographs to assess presence of a vertebral compression fracture. This amounts to the 
equivalent of an extra 12 months of background radiation. We anticipate that the need for this additional 
procedure will be necessary in less than 10% of subjects. 
 


For purposes of comparison, this amount of radiation exposure is similar to that associated with many 
other x-ray procedures: 45 mrem for a mammogram, 1300-1800 mrem for a standard abdominal/pelvic or 
chest CT scan, 6 mrem for a round-trip transcontinental plane flight and 240-360 mrem natural 
background radiation in a year. Expressed as equivalencies to background radiation, a standard 
mammogram, often obtained annually, 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 24 to 60 months of natural background radiation. Thus, 
the maximum amount of radiation that would be received by participation in this study (<600 mrem) is 
less than that from a standard CT scan of the chest or abdomen. 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.   
 
Incidental findings: Upon finding of an incidental finding (IF), the clinical readers have been instructed to 
inform the research team of the study regarding the subject. The subject will be informed of the IF in 
accordance with timing related to the Class A or Class B severity by the PI of the study. Imaging results 
will be sent to subject's primary care provider as requested. 
 
 
3) 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 who 
are prone to vasovagal responses. To minimize these risks, trained phlebotomists who follow proper 
technique perform all venipunctures.  
 
12. DATA AND SAFETY MONITORING 
 
A Data and Safety Monitoring Board will be established. 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 that will be convened will include three members who will be independent of 
Columbia University College of Physicians & Surgeons and Creighton University. Among them will be 
an endocrinologist with expertise in osteoporosis, a physician outside of the field of metabolic bone 
diseases, and a statistician. The DSMB will be independent of all study personnel, and will sign a conflict 
of interest form to that effect. It will meet semi-annually by conference call and 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 in each group, 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. Performance 
data will be evaluated. The first interim look at performance will occur when the initial 20 participants 
have completed the 6-month follow-up visit; thereafter interim reviews will occur at 6-month intervals. 
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 TPTD in premenopausal 
women with IOP is contraindicated.  
Protocol Modifications: Modifications will not be undertaken without notification of the IRB, the 
DSMB and the FDA Program Officer for the grant. 
Registry: All subjects enrolled on our protocol will be counseled on enrollment in the FORTEO Patient 
Registry (http://www.forteoregistry.rti.org/). We are supportive of this program as a way to learn more 
about the long-term safety of using this medication.  
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 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 the sponsor's initial 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 
 
The sponsor shall also notify FDA 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 sponsor'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 review division in the Center for Biologics Evaluation and 
Research that has responsibility for review of the IND.                                                                                                             
 
The Principal Investigator will ensure that the FDA is 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.  
 
Columbia University IRB Reporting Policy: 
http://www.cumc.columbia.edu/dept/irb/policies/documents/UnanticipatedProblemsPolicy.FINALVERSI
ON.012408.pdf) 
 
Creighton University IRB Reporting Policy 
http://www.creighton.edu/fileadmin/user/ResearchCompliance/IRB/Policies_and_Procedures/120_Unanti
cipated_Problems_Involving_Risks_to_Participants_or_Others.pdf 
 
13. 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. 
 
14. 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, 
Alendronate (Fosamax), Risendronate (Actonel), Ibandronate (Boniva), Zometa (Reclast), Denosumab 
(Prolia).  
 
15. 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. 
 
16. 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. 
  
17. Sponsor Responsibilities  
Study compliance and subject safety will be monitored periodically by the sponsor-investigator, Dr. 
Elizabeth Shane.  The task of overseeing subject safety will be the joint responsibility of both the DSMB 
as well as the task of the study investigators.  Adverse events and/or unanticipated problems will be 
reported to the Columbia IRB in accordance with their policy and to the FDA in accordance with their 
reporting guidelines (see Section 12.0 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 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 the sponsor-investigator to submit all amendments, IND safety reports and 
annual reports 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 
9.0 and 10.0. Data entry will be ongoing throughout the course of the protocol so that interval reports to 
the investigator, IRB and other regulatory bodies are readily accessible.  
 
18. Timeline:  
9/16/11 – 1/31/12 
Define and refine study operations prior to funding 
2/1/12 – 2/29/12 
Begin recruitment 
1/31/14  
 
Complete recruitment 
7/31/14  
 
Last subject completes randomized phase and bone biopsy 
8/1/14 - 9/1/14 
Data checking, analysis and manuscript preparation for Aim 1 and Aim 2 
(primary analysis) outcomes 
 
 
 
3/15/15  
 
Apply for no cost extension 
7/31/16  
 
Last subject completes drug treatment phase 


8/1/16 – 9/1/16 
Data checking, analysis and manuscript preparation for Aim 2 (secondary 
analyses) and Aim 3 
 
 
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