Clinical trial NCT02972424
Conditions: Osteoporotic Fractures
Keywords: pelvic fracture healing teriparatide
Sponsor: Hospital for Special Surgery, New York
Start date: 2017-05-01; Completion date: 2021-07-08
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In the proposed trial the investigators will recruit women and men \>65 years of age with acute osteoporosis-related pelvic fractures and address 3 specific aims over 3 months of treatment in a placebo controlled double blind study to determine if standard care and teriparatide 20 mcg/day versus placebo for pelvic fractures:

1. Results in earlier evidence of cortical bridging on routine radiographs followed by confirmatory Focus CT, a novel method to reduce radiation exposure from CT scans (primary outcome).
2. Leads to a faster reduction in pain as assessed by both the Numeric Rating Scale and a reduction in the use of narcotics (secondary outcome).
3. Leads more rapidly to improved functional outcome using a short physical performance battery to assess lower extremity function (secondary outcome).

Detailed description:
The incidence rate of pelvic fractures increases dramatically with age, from 5.4 and 3.8 per 10,000 person-years in women and men aged 65 to 69 years to 93.5 and 44.5 per 10,000 person-years in women and men aged 90 years and older, respectively. Pelvic fractures are accompanied by severe pain, chronic immobility and loss of function and independence in the elderly. Pelvic fractures consume substantial healthcare resources, and based on administrative claims data, they are one of the most costly osteoporosis related fractures. Un-healed fractures, occurring in one-third of pelvic fracture patients at 3 months, can cause continued pain and impact mobility. With aging of the population, and expected concomitant increase in the incidence of pelvic fractures, there is a pressing need to find effective treatments that will accelerate healing. Fracture of the pubic ramus is most relevant and practical for randomized double-blinded placebo controlled study as this fracture is accompanied by severe pain and immobility in elderly, is associated with delayed fracture healing, and is almost always treated non-operatively. The current standard of care for pelvic fractures includes pain management, patient mobilization, and the prevention of complications associated with comorbid conditions. The investigators hypothesize that development of a successful adjunctive therapy to accelerate fracture healing would lead to improved care and reduce both direct and indirect costs from pelvic fractures. In the proposed trial the investigators will recruit women and men \>65 years of age with acute osteoporosis-related pelvic fractures and address 3 specific aims over 3 months of treatment in a placebo controlled double blind study to determine if standard care and teriparatide 20 mcg/day versus placebo for pelvic fractures:

1. Results in earlier evidence of cortical bridging on routine radiographs followed by confirmatory Focus CT, a novel method to reduce radiation exposure from CT scans (primary outcome).
2. Leads to a faster reduction in pain as assessed by both the Numeric Rating Scale and a reduction in the use of narcotics (secondary outcome).
3. Leads more rapidly to improved functional outcome using a short physical performance battery to assess lower extremity function (secondary outcome).

The investigators will extend this study with 9 months of open label TPTD to determine if any potential differences between the placebo and TPTD groups during the 3 months of treatment are evident and persist over time, even in patients who use TPTD after the three month placebo controlled intervention. If TPTD can improve fracture healing, this study will have an impact on the treatment of persons with pelvic fracture who are not surgical candidates and often face severe pain, chronic immobility, and loss of function in the elderly. A positive finding of accelerated healing of pelvic fractures would also encourage study of TPTD for treatment of other osteoporotic fractures.

Arms: arm 1: TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4. arm 2: Placebo is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Interventions: intervention 1: Teriparatide Prefilled Syringe intervention 2: Placebo
Intervention descriptions: intervention 1: TPTD 20 mcg intervention 2: Matching placebo as a prefilled syringe with all inactive ingredients

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
   
Protocol 
PTH(1-34) and Pelvic Fracture Healing - a Randomized Controlled Trial-  
Version 6-  June 21, 2019 
Identifiers: 
NCT02972424   Unique Protocol ID: 2015-330 
IND 126129 
 
1. General Information 
 
Sponsor 
 
Jeri W. Nieves, PhD 
 
 
 
Senior Research Scientist 
 
 
 
Hospital for Special Surgery 
 
 
 
535 E 70th St,  
 
 
 
New York, NY 10021 
email: nievesje@hss.edu 
 
Monitor:  
 
Joseph Lane, MD 
 
 
 
Hospital for Special Surgery 
535 E 70th St,  
New York, NY 10021 
(212) 606-1172 
 
Other Investigators: Michael Loftus, MD, NYP/Weill Cornell Medical Center 
 
 
 
Roger Bartolotta MD, NYP/Weill Cornell Medical Center 
 
 
 
Dr. Mont at Lenox Hill Hospital- Northwell  
 
 
 
Dr. Galmer and Dr. Goldwyn at New York Presbyterian-Queens.   
 
Trial Sites: 
Helen Hayes Hospital 
55 Route 9W 
West Haverstraw NY 10993 
845-784-4833 
 
Hospital for Special Surgery 
535 E 70th St,  
New York, NY 10021 
(212) 606-1172 
 
NYP/Weill Cornell Medical Center 
525 East 68th Street 
New York, NY 10065 
(212) 606-1172 
 
Lenox Hill Hospital- Northwell Health 
100 E 77th St, New York, NY 10075 
Phone: (212) 434-2000 
 
New York Presbyterian Queens 
Orthopedics & Rehabilitation  
Street1: 56-45 Main Street (4th Floor South) 
Flushing, NY 11355-5045 
Phone Number:718-670-2558 
 
 


2 
 
 
 
Protocol Summary: 
 
This is a prospective randomized, double-blinded, placebo-controlled, phase 2, three-month study of the 
efficacy of TPTD in postmenopausal women and men ≥ 65 years of age with acute fractures of the pelvis. We 
will extend this study with 9 months of open label TPTD to determine if any potential differences between the 
placebo and TPTD groups during the 3 months of treatment are evident and persist over time, even in patients 
who use TPTD after the three month placebo controlled intervention.   
 
We will include men or women with single or multiple rami fractures and a presence of absence of sacral 
fracture. We will randomize 100 patients 1:1 in a blinded fashion to receive either 20mcg of TPTD 
subcutaneously (SC) every day or identically appearing placebo SC for 12 weeks. All patients will have ideal 
medical care for comorbidities, pain management and progressive mobilization. A routine clinical protocol will 
be followed to quickly normalize 25-hydroxyvitamin D (goal >20 ng per milliliter; the current IOM guideline 
201035) before starting treatment. All patients will receive a loading dose of vitamin D2 (at a dose of 50,000 IU 
given orally). After the loading dose, daily supplementation with 1000 IU vitamin D will be used for the duration 
of the study. This will allow for patients to be recruited and to begin the trial of TPTD or placebo within 2 weeks 
of the fracture with improved 25(OH)D levels. Calcium intake will be assessed and dietary suggestions or 
supplementation will be used to bring total intake to approximately 1000 mg a day, slightly lower than the 
recommended calcium intake for women over age 50 (in order to prevent hypercalcemia). 
 
Our primary outcome is radiographic evidence of fracture healing at the 12-week endpoint.  At 4, 8 and 12 
weeks after initiating TPTD or TPTD placebo, all patients will get follow-up pelvic radiographs, although these 
radiographs will stop when healing occurs. If the radiologist notes cortical bridging on the monthly x-ray, or at 3 
months a confirmatory limited low dose Focus CT at the fracture site(s) will be performed to assess the degree 
of bridging. Cortical bridging will be quantified with bridging of 3 or 4 cortices as "healing", 1 or 2 cortices as 
"partial healing", and 0 cortices as "minimal/no healing” by two independent radiologists and adjudication by a 
third. If there are multifocal fractures, cortical bridging at each site will be evaluated and an adjudicated score 
representing the state of healing (0 to 4) will be recorded. Secondary analysis will examine treatment group 
differences in the change in follow-up pelvic fracture healing scores over the repeated monthly assessments 
during the 3 month placebo-controlled phase. 
 
A secondary outcome is pain and narcotic use. The numeric rating scale (NRS) will be administered by 
research staff that is blinded to treatment group. We will also quantify use of narcotics and other adjunct 
medications for pain by recording their reported use and also asking for narcotic bottles to be brought in at 
each visit and performing a pill count.  The NRS and recording of pain medications will be done at baseline, 4, 
8 and 12 week visits and at the 6, 9 and 12 month visits.   
 
Another secondary outcome is lower extremity physical function at 3 months and again from 3-12 months.  
Physical performance tests will be administered by research staff that is blinded to treatment group. The lower 
extremity physical function tests, tests include normal walking speed over 4 meters (with or without an assistive 
device), repeated chair stands (stand up from a chair with their arms folded across their chest), and balance 
(ability to maintain balance for 10 seconds in each of 3 positions: side-by-side, semi-tandem, and tandem foot 
positions).  In addition, the Timed Up and Go test will be completed by each subject.  Each subject will also 
complete the survey of ADLs and the SF-36.  
 
The primary outcome analysis is an ITT analysis of the categorization of the level of cortical bridging see on 
focus CT at 3-months. The operational definition of cortical bridging is a five-level ordinal scale from “not 
healed” to “healed” (cf. protocol) adjudicated by the radiologists and clinicians, with two qualifications: 1) if 
endpoint assessment is missing because of a drop-out or loss-to-follow subsequent to an AE or SAE, the 
endpoint will be coded as “not healed”; 2) if the endpoint is missing for any other reason, the endpoint will be 
coded as the last available coding of the focus CT assessment. The treatment difference in cortical bridging 
will be evaluated by a 2x5 chi-square (group x score) with a trend test (Jonckheere-Terpstra) for the ordinal 


3 
 
level of bridging to see whether the TPTD treated participants “trend” to have a greater proportion of higher 
bridging scores than the placebo group. 
 
Secondary analysis of the treatment group differences in the change in fracture healing scores across the 3-
months of the placebo-controlled phase will use a generalized estimating equation for longitudinal repeated 
measures assuming a Poisson distribution with observation-level weighting from a logistic regression analysis 
of the missingness pattern following the approach used by Fitzmaurice, Lair and Ware (2011). The outcome 
will be coded as described for the primary outcome ITT analysis. Missing covariate values will be filled using 
the fully conditional specification multiple imputation method to impute a monotonically missing data pattern: 
outcomes will not be imputed. Continuous covariates will use the predictive mean matching method while 
classification covariates will use a logistic regression method. 
 
For the secondary outcome of pain, we will use a between-groups linear mixed model for repeated measures 
(LMMrm) to estimate the between-group difference in the mean within-subject change from baseline to the end 
of the placebo controlled trial (0-3 months) and again to explore change from 3 to 12 months in the open label 
extension. Narcotic and non-narcotic pain medication use will enter the model as time-dependent covariates. 
Separately, treatment group differences in the cumulative narcotic and non-narcotic drug exposure in the 3-
month placebo-controlled phase will also be estimated with linear mixed model for repeated measures. This 
analysis addresses the two questions, “Do patients treated with TPTD show more rapid reduction in reported 
pain level than those not so treated? If so, when?” 
 
For the secondary outcome of lower limb physical function, we will use a between-groups linear mixed model 
for repeated measures (LMMrm) model for the analysis to estimate the difference in within-subject change 
from 0 to 3 months in the CSPP score in the two groups. A secondary analysis for this aim will explore the 
changes in physical function from 3 to 12 months in the two groups. 
 
If TPTD can improve fracture healing, this study will have an impact on the treatment of persons with pelvic 
fracture who are not surgical candidates and often face severe pain, chronic immobility, and loss of function in 
the elderly.  A positive finding of accelerated healing of pelvic fractures would also encourage study of TPTD 
for treatment of other osteoporotic fractures. 
 
 
2. Trial Objectives and Purpose:   
By 2030 over 25% of the entire US population will be older than 65 years of age. Pelvic fracture rates are 
higher in women1 Over 90% of pelvic fractures in patients >60 years are defined as osteoporosis related 
fractures.2  In a recent study in Germany, the rate of all first pelvic fractures in persons over 60 was 22.4 [95% 
CI 22.0–22.9] per 10,000 person-years.3 The incidence rate increases dramatically with age, from 5.4 and 3.8 
per 10,000 person-years in women and men aged 65 to 69 years to 93.5 and 44.5 per 10,000 person-years in 
women and men aged 90 years and older, respectively.4 This is in agreement with studies in the US and 
Finland, also showing an increase in incidence of pelvic fractures with age.2,5 Pelvic fractures are most often a 
result of low-energy trauma, such as a fall from standing height. Pelvic fractures are the most relevant for this 
proposed randomized placebo controlled study. This fracture is accompanied by severe pain, chronic 
immobility and loss of function and independence in the elderly.6 The current treatment strategy of pelvic 
fractures includes pain management, patient mobilization, and the prevention of complications associated with 
comorbid conditions. In a review of six studies with over 500 patients,7 the mean length of hospital stay was 
13.4 days and the average 1-year mortality was 16.3%. Mortality rates in 1300 pelvic fracture patients were still 
elevated at 3 years.1 Pelvic fractures are associated with slow healing and a delayed return to full function and 
normal activity.8 Pelvic fractures consume substantial healthcare resources, and based on administrative 
claims data, they are one of the most costly osteoporosis related fractures.9 Un-healed fractures, occurring in 
one-third of pelvic fracture patients at 3 months,8 can cause continued pain and impact mobility. With aging of 
the population, and expected concomitant increase in the incidence of pelvic fractures, there is a pressing 
need to find effective treatments that will accelerate healing. There are strong preclinical data10-13 as well as 
clinical evidence that administration of parathyroid hormone (PTH) peptides may improve bone union, hasten 
fracture healing and improve physical function.8,11,13-15 In one nonrandomized, un-blinded study, 100% of pelvic 


4 
 
fracture patients given 1-84PTH were healed within 12 weeks compared to 68% of the controls.8 However, 
there is not sufficient evidence at this time to recommend routine use of PTH peptides for fracture healing. 
Pelvic fractures are ideal to study for the impact of Teriparatide (TPTD) on rate of fracture healing because 
there are no surgical repairs for the vast majority of the fractures.  Prior studies of TPTD on wrist fracture 
healing were limited and confounded by the increased prevalence of surgical fixation to treat these fractures.14 
Strong evidence of pelvic fracture healing that may result from this study may not only have an impact on 
pelvic fractures but perhaps may indicate a potential use for other fractures as well.   
 
In our proposed randomized, double blind, placebo controlled clinical trial in patients >65 years of age with 
acute pelvic fracture, we plan to evaluate whether treatment with daily subcutaneous TPTD 20 mcg/day 
compared with placebo, in addition to standard treatment (pain management, bed rest and prevention of 
complications from comorbid conditions), is effective in accelerating fracture healing in women and men 
compared to standard treatment alone. We hypothesize that development of a successful adjunctive therapy 
(TPTD) will accelerate radiographic evidence of fracture healing and speed functional recovery.  If this 
hypothesis holds true, it would lead to a change in clinical practice and an improved quality of care for pelvic 
fracture patients. Evidence of an impact on the healing of pelvic fractures may also extend to a potential to 
improve healing of other osteoporosis-related fractures. In the planned trial we will recruit women and men with 
acute pelvic fractures and address 3 specific aims over 3 months of treatment in a placebo controlled double 
blind study to determine if TPTD in addition to standard care versus placebo and standard care:   
1. Results in earlier evidence of cortical bridging on routine radiographs followed by confirmatory Focus CT, 
a novel method to reduce radiation exposure from CT scans (primary outcome). 
2. Leads to a faster reduction in pain as assessed by both the Numeric Rating Scale and a reduction in the 
use of narcotics (secondary outcome).   
3. Leads more to a more rapidly improved functional outcome using a short physical performance battery to 
assess lower extremity function (secondary outcome). 
Although our primary analysis will be based on data from 0 to 3 months, whether the benefit of TPTD on 
fracture healing wanes over time is unclear,16 making a longer follow-up important to extend our knowledge on 
the persistence of early TPTD effect on these outcomes. Therefore, we will extend this study with 9 months of 
open label TPTD to determine if any potential differences between the placebo and TPTD groups during the 3 
months of treatment are evident and persist over time, even in patients who use TPTD after the three month 
placebo controlled intervention.   
If TPTD can improve fracture healing, this study will have an impact on the treatment of persons with pelvic 
fracture who are not surgical candidates and often face severe pain, chronic immobility, and loss of function in 
the elderly.  A positive finding of accelerated healing of pelvic fractures would also encourage study of TPTD 
for treatment of other osteoporotic fractures. 
 
3. Background:  
The economic and clinical toll of osteoporosis related fractures is well known.17 Most fractures among the 
aging population are at least in part related to osteoporosis and the costs for acute health care alone top $15 
billion annually. Pelvic fractures are among the most costly osteoporosis related fractures due to loss of 
function, long hospitalizations and rehabilitation and the difficulty in managing these fractures.18,19  Pelvic 
fractures can serve as a model of fracture healing for other osteoporosis related fractures. Success in this trial 
may also help encourage patients and doctors to initiate treatment soon after a fracture. This is important 
because subsequent fractures occur with greatest frequency shortly after the first fracture.20 The drug, 
rhPTH(1-34), referred to in this application as Teriparatide (TPTD), is currently marketed as a treatment for 
osteoporosis in men and women at high risk of fracture. Elderly patients with non-traumatic pelvic fracture have 
osteoporosis and are at high risk for future fracture, thus are eligible for treatment with TPTD. TPTD stimulates 
bone formation and remodeling with formation of new bone tissue, improved skeletal architecture, increased 
bone mass (i.e. a true increase in the amount of bone tissue), and potentially by periosteal bone formation, an 
increase in the diameter of some bones in the skeleton.21-24 A large body of evidence in preclinical models 
supports the concept that TPTD can improve fracture healing.10-13 In addition, daily subcutaneous injection of 
TPTD for bone union using local bone grafting after instrumented lumbar posterolateral fusion in women with 
postmenopausal osteoporosis was more effective than oral administration of bisphosphonate in an 
observational study.15 Recently, an acceleration of fracture healing with TPTD (20 mcg per day) was reported 


5 
 
in a randomized controlled trial of 102 postmenopausal women who had sustained a distal radial fracture.14 
The authors concluded that their result should be interpreted with caution and noted that there was no further 
improvement with the 40 mcg dose. This provides rationale for our using a dose of 20 mcg TPTD per day.  A 
recent study8 reported the successful use of PTH 1-84 to enhance the healing of fractures of the pubic ramus 
in 65 patients, based on x-ray and CT images. This study was not randomized or blinded and is therefore 
subject to bias, particularly since patients in the PTH 1-84 treatment group were treated at a single center, and 
patients from both this center and another center served as controls (no PTH 1-84 treatment). In that study, 
100 mcg of PTH 1-84 (equivalent to about 40 mg TPTD) resulted in fracture healing at a mean of 7.8 weeks, 
and 100% of the treated group had healed at 8 weeks following PTH1-84 administration, significantly faster  
than the control group (9% healed at 8 weeks and 68% at 12 weeks). Results of that study need to be 
confirmed for several reasons. First, a randomized, controlled, blinded study is required. Second, there may be 
some difference between 1-84PTH and 1-34PTH, as illustrated in a small study comparing the effects of these 
two peptides on cortical porosity assessed by high resolution pQCT.25 However, it does add to the growing 
clinical evidence that PTH peptides may improve fracture healing and also may improve physical function 
(using the Timed Up and Go test).8 Recent reviews and case series of TPTD and fracture healing state that 
there is a potential benefit of TPTD  but all conclude that further randomized, placebo controlled, clinical trials 
are warranted.26-30 An important additional question is whether the benefit of TPTD on fracture healing wanes 
over time. In a recent study, improved mobility was seen at 3 and 6 months but not 12 months in TPTD treated 
patients with unstable pertrochanteric fractures,16 making a longer follow-up important in the proposed trial.   
  In summary, pelvic fractures are costly for both the individual and society due to the lack of surgical 
intervention and the long time to heal, making this an ideal fracture to use in a study of fracture healing. In 
addition, the lack of surgical repair means that the effects of TPTD on fracture healing cannot be confounded 
by a surgical procedure. Although both TPTD and (1-84PTH) have been shown to lead to some improvements 
in fracture healing, a randomized double-blinded placebo controlled clinical trial is now needed to confirm and 
extend any beneficial effects of TPTD on the acceleration of fracture healing. Additionally, since the pelvic 
bone has a higher proportion of cancellous bone and thinner cortical walls than long bones31,32 and TPTD 
increases bone mass most effectively in cancellous bone,22,33 pelvic fracture might be particularly amenable to 
accelerated fracture healing with TPTD. The TPTD or placebo would be administered in addition to current 
standard of care for pelvic fractures, which includes pain management, patient mobilization, and the prevention 
of complications associated with comorbid conditions.7 Given that pelvic fractures are an osteoporosis related 
complication and represent severe osteoporosis, we recommend treating all pelvic fracture patients for the 
underlying disease of osteoporosis. Therefore, after the 3 month trial, we will offer all study participants a year 
of open label TPTD. Since the optimal time to initiate osteoporosis treatment is when the patient has a fragility 
fracture, clinicians need to know if the drug is neutral or accelerates fracture healing. If the current study clearly 
demonstrates enhancement of fracture healing, the fracture team will be more motivated to start osteoporosis 
care (currently < 20% of patients get treated).34 Therefore, any evidence that fracture healing is improved with 
TPTD would markedly change the clinical care of this fracture. Furthermore, any benefit of TPTD to healing of 
pelvic fractures, may serve as a model for the study of other osteoporosis fractures.  
 
At this time, there are no currently approved drugs for fracture healing. Therefore the premises for this trial 
include: (1) the need for a treatment for pelvic fractures that cannot be surgically repaired, (2) the need to study 
fracture healing in a well-designed placebo controlled, double blind, randomized trial to determine whether the 
findings of Peichel et al8 can be confirmed (3) to determine if 1-34hPTH can improve fracture healing similarly 
to findings with 1-84PTH (4) to corroborate pre-clinical data, findings from case series, and trials which suggest 
that TPTD may accelerate fracture healing. If the results of this trial are positive with more rapid fracture 
healing and potentially quicker return to normal physical function; we anticipate that more pelvic fracture 
patients would be appropriately treated for their osteoporosis post-fracture. In addition, a positive finding may 
have a dramatic impact on clinical care of patients with other osteoporosis related fractures.  
Preliminary and published data strongly recommend TPTD as a bone anabolic therapy to treat the 
underlying osteoporosis, the ultimate cause of the fracture. The patients enrolled in this trial would all be 
eligible for an osteoporosis treatment with TPTD being an excellent choice. We believe there will be an added 
benefit of TPTD beyond the treatment of osteoporosis, including radiographic evidence of accelerated fracture 
healing, a quicker improvement in physical function, and a faster reduction in pain. The risks associated with 
the study include the potential side effects of TPTD and the radiation dose from plain x-rays and CT scans.  


6 
 
However, during our prior NIH planning grant (U34), we developed a technique to lower the radiation exposure 
in this study to be lower than that typically associated with standard care. 
 
4. Study Design:    
Overview:  In the proposed phase 2 study, we plan to evaluate if treatment with TPTD 20 mcg daily compared 
with identical appearing placebo, both with the standard management of non-surgical pelvic fractures (pain 
management, bed rest and prevention of complications from comorbid conditions), is effective in accelerating 
fracture healing. This is a prospective randomized, double-blinded, placebo-controlled 3 month study of the 
efficacy of TPTD in postmenopausal women and men ≥ 65 years of age with acute fractures of the pelvis. Our 
primary outcome is radiographic evidence of fracture healing using low dose Focus CT  at 3 months. 
Secondary outcomes include assessment of pain and narcotic use, and assessment of lower extremity 
physical function at 3 months and again from 3-12 months.  We will randomize 100 patients 1:1 in a blinded 
fashion to receive either 20mcg of TPTD subcutaneously (SC) every day or identically appearing placebo SC 
for 12 weeks. All patients will have ideal medical care for comorbidities, pain management and progressive 
mobilization. A routine clinical protocol will be followed to quickly normalize 25-hydroxyvitamin D (goal >20 ng 
per milliliter; the current IOM guideline 201035) before starting treatment. All patients will receive a loading dose 
of vitamin D2 (at a dose of 50,000 IU given orally36) following the protocol used by Lyles et al to normalize 
vitamin D in a clinical trial of similar patients with acute hip fracture.36  After the loading dose, daily 
supplementation with 1000 IU vitamin D will be used for the duration of the study. This will allow for patients to 
be recruited and to begin the trial of TPTD or placebo within 1 month of the fracture with improved 25(OH)D 
levels. Calcium intake will be assessed and dietary suggestions or supplementation will be used to bring total 
intake to approximately 1000 mg a day, slightly lower than the recommended calcium intake for women over 
age 50 (in order to prevent hypercalcemia). 
Subjects 
Inclusion criteria:  Postmenopausal women and men >65 years of age with acute pelvic fractures, occurring 
with minimal trauma, presenting to Helen Hayes Hospital, Lenox Hill Hospital, New York Presbyterian-Queens, 
Hospital for Special Surgery, or New York Hospital (Cornell Medical) within one month of the onset of 
symptoms. Since 25% of pelvic fractures occur in men, it is important to include men in this trial. The inclusion 
of males will also extend the results of the Aspenberg14 and Peichel8 trials). Given that 53% of fractures have 
an associated injury in the posterior pelvic ring,37 it is important to include these multiple rami fractures.  
Patients that have either one or multiple pelvic fractures or sacral and pelvic fractures will be included in the 
study.   
Exclusion Criteria: 
1) Persons unable to complete the NRS and other surveys based on their mini-mental status score (≤18; 
consistent with moderate and severe cognitive impairment) 
2) Previously (prior to fracture) non-ambulatory subjects 
3) Exclusion criteria related to contraindication or intolerance to TPTD: 
a) Hypersensitivity to TPTD  
b) Patients with increased risk of osteosarcoma: Paget’s disease, history of radiation exposure 
c) Patients with active hypercalcemia  
d) Current hyperparathyroidism and other metabolic bone disease including osteogenesis imperfecta 
e) History of multiple renal calculi or renal calculus within the last 2 years 
f) Normal alkaline phosphatase levels will not be used as an entrance criterion because most fracture    
patients will have elevations due to the acute fracture.  However, we will attempt to obtain lab tests from 
the period prior to fracture to determine if they were normal.  If unexplained elevations in alkaline 
phosphatase are found in labs prior to the fracture we will exclude that subject. 
g) Evidence of metastatic cancer or history of bone cancer or any active cancer other than basal or 
 
squamous cell carcinoma. 
 
Protocol: 
Recruitment:  
Subjects will be recruited, during their initial hospitalization (median length of stay is 9 days1) or from the 
emergency room or physician office from Hospital for Special Surgery/New York Hospital, Lenox Hill Hospital, 
New York Presbyterian Queens, or Helen Hayes Hospital. The goal will be to start treatment within one month 


7 
 
of fracture.  Since not all pelvic fractures are hospitalized,1 radiologists at each institution have agreed to 
contact us regarding patients with pelvic fractures who are not admitted. We will recruit approximately 100 
subjects (female and male) > 65 years of age over a total of 4 years (30 in years 1, 2 and 3 and 10 in year 4) to 
complete 80 subjects with 3 months of treatment, to accommodate a drop-out rate of 20% in the 3 month 
treatment portion of the study.   
 
Screening and Baseline visit: Subjects will have their screening and baseline visit during their initial 
hospitalization or by coming into one of the participating hospitals for a follow-up orthopedic or outpatient visit 
for those with documented pelvic fractures who were not hospitalized. 
 
Screening visit: At the screening visit, a Mini Mental Status Exam (MMSE) will be given to be sure that the 
patient is capable of providing informed consent and of completing the trial. Any persons with moderate or 
severe cognitive impairment will be excluded (score ≤18 of 30 points). The consent form will be reviewed and 
signed.  A comprehensive assessment of medical history and a brief physical exam will be performed. Blood 
samples will be obtained and levels of creatinine, alkaline phosphatase, calcium, intact-parathyroid hormone, 
and 25(OH)D will be measured. Pelvic radiographs and a full CT scan will be reviewed or obtained to 
determine if fractures are: single rami, multiple rami fractures or sacral and pelvic fractures (healing of sacral 
fractures will not be assessed, although the existence of a sacral fracture with a pubic rami fracture will not 
exclude an individual). In addition, the fracture will be classified by amount of displacement/overriding with 3 
categories: Minimal/No displacement, Mild displacement, Moderate displacement.38 A loading dose of vitamin 
D (50,000 IU) will be given36 in order to normalize vitamin D in this population with high prevalence of vitamin D 
deficiency before initiating treatment (goal within 2 weeks of the fracture).  Serum calcium must be below or 
equal to normal for the lab. Calcium supplements or dietary modifications will be recommended as needed to 
bring total calcium intake to approximately 1000 mg daily. Subjects who meet all inclusion and exclusion 
criteria based on labs and history will be scheduled for a baseline visit. Concomitant medications and existing 
baseline conditions will be collected by interview.  Information about the use of prior osteoporosis treatment will 
be obtained and recent BP use will be categorized for randomization.  
 
Baseline Visit:  Baseline visits will be scheduled when all results are in and within one month of fracture.  
Subjects will be seen in the morning after an overnight fast. Blood will be drawn and subjects will be allowed 
breakfast. Vitamin D supplements (1000 IU daily) will be provided to help to maintain adequate 25OHD serum 
levels and calcium intake will be reviewed.  A blood sample will be collected at baseline and at every visit to 
assess calcium level for safety.  Blood samples for biochemical indices of bone turnover (serum PINP for bone 
formation and serum CTX for bone resorption) and 25(OH)D will be obtained at baseline and every month and 
analyzed by batch at the Helen Hayes Hospital Regional Bone Center. Subjects will complete the lower 
extremity physical function tests, an Activities of Daily Living (ADLs) and SF-36 physical function survey, NRS 
for pain and a survey with pill count to determine narcotic use. Subjects will be randomly assigned (with 
separate schemes for males and females and prior BP use) to receive either TPTD 20 mcg or identically 
appearing placebo. Only the statistician will be aware of subject assignment and the pharmacist will distribute 
the appropriate TPTD or placebo medication. Subjects will be taught by the research nurse the method of daily 
self-administered subcutaneous injection techniques using TPTD or placebo pens, and provided written 
instructions for drug administration with a diary to track injections. We have extensive experience teaching 
subjects to administer TPTD with >90% compliance in elderly populations21,33,39,40 and subjects in the modelling 
recruitment phase were willing to take TPTD. Treatment will continue for the 3 months of the proposed study. 
Even if the fracture heals sooner, these subjects all have osteoporosis and should maintain their osteoporosis 
treatment for the duration of the double blind trial while other outcomes are evaluated (0 to 3 months).   
 
Retention: Subjects will be called weekly during the 3 month blinded trial to monitor side effects and adverse 
events, and to ensure compliance with the protocol, including medication adherence.   
 
Follow-up visits:  All visits will occur at the center where the subject was recruited and would normally be 
seen, following the schedule of procedures listed in Table 2.  Visits will occur every month for 3 months. At 
every visit a pelvic radiograph will be taken. If the radiologist notes cortical bridging on pelvic x-ray, then a 
confirmatory low dose Focus CT at the fracture site(s) will be performed to assess the degree of bridging at the 


8 
 
fracture site(s).  If full union is noted at the superior and/or inferior pubic fracture site(s) by focus CT, as 
evaluated by both radiologists, then no further radiographs or CT scans are needed, although all other 
assessments will continue. The CT will be done at either Ramapo Radiology in Suffern or MRI in New City, NY. 
At 3 months the remaining patients who still have not healed will undergo a focused limited low dose CT to 
quantify the degree of cortical bridging at the end of the 3 months of placebo-controlled treatment. In addition, 
radiographic follow-up will continue during the open label extension for those patients who have not healed 
during the 3 month active treatment phase. 
    Blood samples to assess bone turnover and calcium levels will be collected as indicated.  Subjects will be 
encouraged at each visit to consume enough calcium and vitamin D (1000 IU vitamin D and dietary calcium 
with supplements as needed) and TPTD/placebo compliance will be assessed.  
    At each monthly visit (0 to 3), subjects will complete the lower extremity physical function test, ADLs, SF-36, 
NRS for pain and a narcotic use survey and pill count (details below). This information will be recorded by a 
research nurse blinded to treatment status since TPTD and placebo will be identical in appearance.  Lower 
extremity physical function test, ADLs, SF-36, NRS for pain and a narcotic use survey and pill count will be 
repeated at 6, 9 and 12 months visits to determine if starting TPTD immediately after fracture results in better 
long term changes in function and pain, although the extension will be open label with all offered TPTD and 
analyzed as a separate secondary outcome (3 to 12 month; see below).  
 
Withdrawals:  Any subject who wishes to withdraw from the study will be asked to return any study drug and, 
if willing, to complete the lower extremity physical function test, ADLs, SF-36, NRS for pain and a survey and 
pill count of narcotic use.  They will also be asked to get a final x-ray and focus CT if they consent and there 
has not been one within a month. 
 
Randomization and Medication:  This study is being performed under IND 126129 with Jeri W. Nieves, PhD 
as the sponsor. Within one month of the onset of symptoms, all subjects will be given either (1) TPTD or (2) 
TPTD- placebo for 3 months.  Eli Lilly has agreed to provide TPTD and matching placebo in order to mask 
treatment for the double blind study. TPTD is supplied as a sterile, colorless, clear, isotonic solution in a glass 
cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each 
prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide 
(corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate 
(anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 
10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4. The placebo 
pen contains the same solution without the TPTD.  Medication pens must be refrigerated after each daily use.  
Compliance will be assessed by review of subject injection diaries and by weighing returned TPTD/placebo 
pens.   
 
Randomization will be by gender and bisphosphonate (BP) use creating 4 randomly permuted block 
randomization lists.  We will not exclude prior BP use, however, since the recent use of BP may impact TPTD 
effect, BP use will be used to create the following strata for randomization within males and females: (1) 
Recent BP use (greater than one year use within 2 years)/female or (2) Recent BP use (greater than one year 
use within 2 years)/male (3) distant or never (> 3 years since last BP or never users)/female (4) distant or 
never (> 3 years since last BP or never users)/male. We hypothesize that acceleration of pelvic fracture 
healing by TPTD will not be significantly affected by prior BP use because this skeletal site is largely 
cancellous bone and we believe that TPTD response is less affected by prior BP use in primarily cancellous 
sites (vs cortical sites).41 In addition, initial fracture healing is dependent on callus formation which is not 
diminished by BP.42 Furthermore, there was no significant difference in delayed union of the fractured bone 
between placebo and zoledronic acid after hip fracture.36  However, given the potential for recent BP use to 
alter BMD and turnover response to TPTD,39,43,44 we will stratify by BP use to ensure that any effect of BP on 
TPTD is equally distributed between the placebo and TPTD groups. In addition, we will record length and type 
of bisphosphonate use as a potential covariate in the analysis to evaluate effect modification by prior BP use. 
 
Open Label Extension: After 3 months of placebo versus TPTD, when the data for the primary analysis of all 
aims has been collected, all persons will be offered to continue TPTD (open label) for 9 months while pain and 
physical performance are assessed and surveys completed every 3 months. The open label protocol will allow 


9 
 
for an evaluation of the persistence of any potential benefit of TPTD on fracture healing (assuming that one is 
evident after the first 3 months) on functional outcomes. We believe offering open label TPTD after the 3 
months placebo controlled blinded trial will also help aid in the recruitment of patients since they will all 
eventually be treated and the extension follows guidelines to treat patients with pelvic fracture (consistent with 
severe osteoporosis). During the open label extension, the ~32% of the control group that may not have 
healed at 3 months will be followed with radiographs to enable us to determine the time to heal in this group. 
Treatment with open label TPTD may accelerate their healing and mitigate the difference in the secondary aim 
of functional outcomes between groups during the latter part of the year (3-12 months). However, we believe 
most of the effect on the secondary outcomes of physical function and pain would have occurred in the first 3 
months for most people and modest changes will only occur in a few patients. We hypothesize that differences 
seen between PBO and TPTD groups at 3 months will persist when evaluated up to 12 months. This will be 
assessed as a group by time interaction. This extension will add to the data on pain and physical function 
collected at the end of the double blind trial (0 to 3 months).  If the natural history cohort is large enough we 
would also be able to see if the TPTD over 3 months, with continued treatment for the subsequent 9 months 
improves physical function more than no treatment over the year. The open label extension will allow us to 
determine whether our hypothesis of faster healing by TPTD (at the end of 3 months) produces a long term 
benefit of improved function between 3 and 12 months, or if the effect wanes within that group. Evidence of a 
better result if TPTD is started immediately may enhance treatment rates post fracture. 
 
5. Safety:  
Total serum calcium will be assessed at baseline for study eligibility and then at every visit via standard 
automated chemistry.  Avoiding excessive calcium supplements will help prevent hypercalcemia, therefore we 
will assess diet and use supplementation only to obtain a total intake of 1000 mg daily. Serum calcium will be 
reviewed by our safety officer (Dr. Emily Stein at HSS). A preplanned algorithm for hypercalcemia (defined as 
>10.1 mg/dl, the upper limit for our laboratory) requires stopping calcium supplements or reducing dietary 
intake and repeating the measurement within 2 weeks.    If hypercalcemia persists, TPTD/placebo will be 
withheld.  At each monthly visit and during the weekly phone calls while on TPTD/Placebo, adverse events 
(AEs) or serious adverse events (SAEs),comorbidities and concomitant medication use will be recorded by the 
nurse and reviewed with the site MD (RN and MD are blinded to treatment).  Follow-up for any SAE will occur 
until it is resolved.  All SAEs will be reported to the internal safety officer (Dr. Stein) and to the DSMB safety 
officer and NIAMS (through KAI) within 48 hours of the investigator becoming aware of the SAE.  The IRB and 
FDA (IND 126129; Dr. Nieves) will be notified of SAEs as per their guidelines.  The radiographic evaluations 
will expose subjects to radiation, however this will not exceed normal clinical care and in fact we worked to 
reduce exposure using our protocol for focus CT imaging. Dr. Emily Stein will serve as the internal safety 
officer for this study and will review all AE, SAEs and serum calcium for safety.  In addition, there is a 3 person 
DSMB for this study that was appointed by NIAMS.  The DSMB will receive reports from the study team every 
six months for additional safety review.  Annual reports will also be filed with the FDA, IRB and NIH.  
 
6.  Data and Safety Monitoring Responsibilities:  
Data and safety monitoring will be the primary responsibility of all persons with patient contact, the research 
nurse and other staff, Dr. Lane and Dr. Nieves.  In addition, Dr. Stein will review the serum calcium safety labs 
for any evidence of hypercalcemia and will review all AEs and SAEs.   Dr. Nieves in cooperation with the 
research nurse and site investigator will be responsible for reporting these events to the internal safety officer 
and to KAI who will distribute to the DSMB safety officer and NIAMS.  They will also be sure that each IRB and 
the FDA are notified.   
 
For any unanticipated problems or serious adverse events, including hospitalizations, cancers or deaths, the 
internal safety officer and KAI who will distribute to the DSMB safety officer and NIAMS within 48 hours of 
learning of the complication.  The IRB and FDA (IND 126129; Dr. Nieves) will be notified of unanticipated 
problems and SAEs as per their guidelines.   
 
Teriparatide: We will initially minimize risks of teriparatide treatment by excluding subjects who might be at 
higher risk for adverse events. The risks of subcutaneously administered teriparatide injections include local 
skin irritation, dizziness, leg cramps, nausea, arthralgias, myalgias, hypercalcemia and hypercalciuria.  


10 
 
Although no increase in risk of renal stones has been seen in clinical trials with teriparatide, potential subjects 
with recent kidney stones (within 2 years) or a history of multiple stones will be excluded from the protocol to 
minimize this risk.  Because teriparatide treatment has a boxed warning regarding risk of osteosarcoma, 
potential subjects who have an increased risk of osteosarcoma, such as those with Paget’s disease, prior 
history of bone tumor, or history radiation therapy will be excluded from participation in the trial.  Also, to 
minimize risk of hypercalcemia or hypercalciuria, potential volunteers with evidence of hyperparathyroidism will 
be excluded from participating in the trial. To monitor any occurrence of adverse events, side effects, or 
difficulty with medication administration with TPTD, subjects will be called weekly by the Research Nurse 
during TPTD treatment.  In cases where side effects are significant and interfering with quality of life (e.g. 
musculoskeletal pain or nausea), volunteers will be told to reduce TPTD administration to every other day until 
the symptoms abate.   
 
Monitoring of Hypercalcemia: The major safety evaluation of this study is a check for hypercalcemia which 
will first be assessed at 4 weeks after starting TPTD when calcium levels are found to peak.  The development 
of hypercalcemia may be dependent on an individual’s baseline serum calcium level and calcium supplement 
exposure.  Therefore, volunteers will be counseled by the Research Nurse about optimizing dietary calcium 
intake, and avoiding calcium supplement use in order to prevent the development of hypercalcemia.  Calcium 
supplements will be used only as needed to bring daily calcium intake to 1000 mg a day. Serum calcium levels 
will be checked at every visit, which occur monthly for the first 3 months after TPTD or placebo initiation and 
then, during the open label with teriparatide treatment, levels will be checked every three months.  Subjects will 
be advised not to take the TPTD or placebo prior to the blood sample being collected (levels will be obtained at 
least 16 hours after the last TPTD dose).  Serum samples will be analyzed within 24 hours of sample 
procurement and will be reviewed by the Safety officer (ES) within 24 hours of receipt of result.  
 
If the serum calcium is above 11.5 mg/dl, calcium supplements or dietary calcium will be reduced and the level 
will be checked again within 3 days. If the level remains >11.5 mg/dl; TPTD will be given on alternate days.   
 
If the serum calcium is between 10.5 and 11.5 mg/dl, calcium supplements or dietary calcium will be reduced 
and the level will be checked again within 10 days.  If serum calcium levels are persistently above 10.5 mg/dl, 
volunteers will be advised to take TPTD every other day.   
 
In multiple prior trials involving TPTD treatment in hundreds of patients, we have never been required to 
reduce the dose of TPTD due to hypercalcemia.   
 
7. Protocol Details: 
 
Case-Report Forms: Case report forms will be used to record screening information, medical history, 
medication list and lifestyle information (including calcium intake) and the physical exam.  The nurses will 
complete forms for AEs, SAEs and concomitant medications.  All AEs and SAEs will be reviewed with the 
study MD at each site. Standardized forms will also be used for the outcomes: radiologic evaluation of fracture 
healing, NRS for pain and narcotic use, lower extremity physical function.  
Table 2:  Schedule of Procedures 
Procedure 
SCR 
D1 
4 wk 
8 wk 
12 wk 
6 mo 
9 mo 
12 mo 
MMSE, Informed consent 
X 
 
 
 
 
 
 
 
Medical history, medication list and other lifestyle 
X 
 
 
 
 
 
 
 
Physical examination, including height and weight 
X 
 
 
 
 
 
 
 
Screening labs (25(OH)D, PTH, Cr, Ca, prior  alkaline 
phosphatase) 
X 
 
 
 
 
 
 
 
Pelvic radiographs (^until healing occurs-standard care) 
X 
 
X^ 
X^ 
X^ 
 
 
 
Pelvic limited focus CT scan (* as indicated based on 
cortical bridging and until healing occurs) 
X full 
 
X* 
X* 
X* 
 
 
 
Bone turnover  
 
X 
X 
X 
X 
 
 
 


11 
 
Calcium for safety 
 
X 
X 
X 
X 
X 
X 
X 
Loading dose vitamin D (50,000 IU) 
X 
 
 
 
 
 
 
 
Calcium (total intake 1000 mg) /1000 IU vitamin D 
 
X 
X 
X 
X 
X 
X 
X 
Dispense TPTD 20 mcg/day or placebo (blinded for 3 
months, then open label TPTD) 
 
X 
X 
X 
X 
X 
X 
X 
Adverse event and concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
Numeric Rating scale (NRS) for pain and narcotic use 
survey and pill count 
 
X 
X 
X 
X 
X 
X 
X 
Lower extremity physical function (CSPPS and TUG) 
 
X 
X 
X 
X 
X 
X 
X 
Self-reported questionnaires (ADL and SF-36) 
 
X 
X 
X 
X 
X 
X 
X 
Telephone calls will occur weekly 
 
 
X 
X 
X 
 
 
 
 
Specific Methodology: 
CT imaging: The first CT image that identifies the fracture will be a standard pelvic CT.  For follow-up CT 
imaging, we will utilize a novel method to assess fracture healing (Focus CT).  Presently, plain radiographs and 
serial computed tomography are completed every month, a with a radiation dose of 7.5 mSv per exam. 70-73 
Focus CT, which will reduce radiation exposure, could be used in place of standard serial CT to assess the 
healing process.  A low dose technique74,75 using an automatic tube current modulation (ATCM) technique was 
developed for the pelvis, making it possible to achieve a reduction in radiation dose to the patient.76,77 It is 
important to reduce medical radiation exposure as much as possible, the “as low as reasonably achievable” 
(ALARA) concept, which could be achieved by utilizing Focus CT scanning to the area of specific interest e.g. 
limiting radiation exposure to the fracture site alone.78 Focus CT is accomplished by decisions regarding the 
collimation, pitch, tube voltage, current, and rotation and by reducing the scan field of view. Scanning a smaller 
Field of View (FOV) alone resulted in an estimated reduction of radiation exposure of between 40-68% relative 
to a standard full FOV CT of the pelvis. Additionally, there was no difference in the diagnostic quality of the 
Focus CT relative to the baseline full FOV CT for tracking fracture healing, with both musculoskeletal 
radiologists noting a 100% intra-observer concordance in their findings between the full FOV and Focus CT 
images for each case.      
Initial CT Scan: After obtaining frontal and lateral topograms of the pelvis (120 kV; 10 mA), helical CT of the 
pelvis will be obtained from the L5 vertebral body through the ischia without intravenous contrast (GE Light 
Speed Pro 32 CT). Scans at both sites will be obtained following the same protocol with slice thickness of 2.5 
mm, interval of 1.25 mm, keV of 120, and Auto mA with range of 100-500 and noise index of 15.17.  Sagittal 
and coronal reformats will also be created and reviewed.  The initial CT scan will define all pelvic fractures 
including pubic rami and sacrum. The fracture will be classified as: single or multiple rami fractures; presence 
of sacral fracture and amount of displacement with 3 categories: Minimal/No displacement, Mild displacement, 
Moderate displacement.38 
Focus CT Scan (Follow-up): After obtaining frontal and lateral topograms of the pelvis (120 kV; 10 mA), 
focused helical CT will be obtained from 1 cm above the superior pubic ramus to 1 cm below the inferior 
ischiopubic ramus without intravenous contrast (GE LightSpeed VCT).  Scans will be obtained with a slice 
thickness of 2.5 mm with interval of 1.25 mm, keV of 120, and Auto mA with range of 100-500 and noise index 
of 15.17.  Sagittal and coronal reformats will also be created and reviewed. The focus CT will only evaluate 
superior and inferior pubic fractures, since CT determination of sacral fracture healing is difficult.   
At any visit where some cortical bridging is noted on the x-rays, a CT is performed and cortical bridging will be 
quantified with bridging of 3 or 4 cortices as "healing", 1 or 2 cortices with "partial healing", and 0 cortices with 
"minimal/no healing”.45  If there are multifocal fractures, cortical bridging at each site will be evaluated and an 
average of cortical bridging score (0 to 4) will be recorded.  If full union is noted by focus CT (evaluated by both 
radiologists), then no further radiographs or CT scans are needed, although all other assessments will 
continue. At 3 months the remaining patients who still haven’t healed will undergo a focused limited low dose 
CT to quantify the degree of cortical bridging after 3 months of treatment. Radiographs and CT scans will 
continue during the open extension in those who have not yet healed. CT scans will be evaluated 
independently by Drs. Loftus and Bartolotta, who will be blinded to treatment group.  If there is a discrepancy 
between the score for cortical bridging (1 score difference in the reading) between them, a third reader as part 


12 
 
of the Contract Imaging Coordinating Center role at Weill Cornell Radiology will be brought in to blindly 
adjudicate the discrepancy. All CT images will be de-identified and archived using IDEAL (Imaging Data 
Evaluation and Analytics Lab) that houses the research PACS system with individual data devoid of any PHI 
and only having a subject ID.  
The research nurse will record the pain assessment, administer physical performance tests using standard 
methodology and administer all surveys as detailed below. Pain assessment: The research nurse will 
administer the NRS for pain.  Using a scale from 0 (no pain) to 10 (worst pain imaginable), the subject will 
report how intense their pain is now and how intense it was on average last week. They will also report how 
much relief from pain they have achieved using treatment for pain. For this they will use a scale of 0% (no 
relief) to 100% (complete relief). They will also be asked about all of the pain medications they are currently 
taking.  In addition, the nurse will ask the subject to bring any pain medications being used to each visit so that 
a pill count of use can be made.  Physical Performance Measures49-64: The walk is a timed walk at normal 
walking speed with a meter run-in before starting the timed portion and another meter at the end of the course 
in order to measure each subject walking at normal speed over 4 meters. Devices such as canes and walkers 
are allowed and their use will be recorded. The research nurse will record the use of aids and the time required 
to walk on the case report form.  A straight backed chair will be placed against a wall and subjects will be 
asked to stand with their arms folded across their chest.  If they can perform this task they will be asked to 
repeat it five times.  The research nurse will record the amount of time for 5 chair stands to be completed on 
the case report form.  The balance test measures the ability of subjects to maintain balance for 10 seconds in 
each of 3 positions: side-by-side, semi-tandem, and tandem foot positions. The test will be stopped if the 
subject cannot maintain any position for 10 seconds. The final measure for balance is the sum of the time from 
the three positions (range 0-30 seconds).  Subjects unable to perform any of the above three tests will be 
assigned a 0 score. During the course of the balance test there will be two trained individuals standing in an 
appropriate manner to protect a patient against any falls.  The research nurse will complete the case report 
form and follow written instructions in the detailed clinical protocol. Scores will be calculated for the CSPPS 
based on these tests.66-68 Timed Up and Go Test (TUG)69: Patients will be asked to wear their regular 
footwear and told that they can use a walking aid if needed (this will be recorded). The test begins by having    
the subject Stand up from the chair, walk to the line on the floor at a normal pace, turn, walk back to the chair 
at a normal pace  and Sit down again. The person administering the test will time the subject using a 
stopwatch and record the time on case report forms. 
Surveys:  All performance tests and surveys will be administered by the research nurse, who is blinded to 
treatment status during the study visit.  Study participants will complete several questionnaires, including 
assessments of ability to perform activities of daily living (ADLs)79 and the physical component of SF-36.80,81 
The Barthel activity of daily living (ADL)79 survey is a patient self-reporting survey to assess mobility and self-
care. Subjects are asked a series of questions and asked to respond with a multiple choice answer about 
difficulty the level of difficulty with which they are able to complete each task, the baseline ADL will evaluate 
pre-fracture and current ADLs. For the assessments of ADLs, subjects will report 1 of 3 responses, similar to 
those used in WHAS82: 1) no difficulty, 2) little of some difficulty, 3) a lot of difficulty or unable to do without help 
from a person or special equipment. For the SF-36, only the physical sub-scales will be used: Physical 
Function (PF), Role-Physical (RP), Bodily Pain (BP), and General Health (GH).80,81 Subjects will be asked 
questions about general health and physical limitations over the previous 4 weeks (before the fracture during 
screening and then since the fracture will be asked at baseline). All responses are recorded CRF and scored.  
Biochemistry: After blood samples are obtained, all processing and aliquoting procedures are performed in 
the Biochemistry Unit of the Regional Bone Center of Helen Hayes Hospital.  Biochemical evaluations will 
include those used for exclusion criteria, efficacy (bone turnover) and safety (serum calcium).  All efforts are 
made to prepare aliquots according to the assays planned to avoid repeated thawing and refreezing.  For this 
project, serum samples for bone turnover (PINP and CTX) and serum 25(OH)D will be stored in separate 1 ml 
aliquots in a -80 degree freezer.  All biochemical efficacy assays from an individual patient will be performed in 
the same assay to avoid inter-assay variability in individual patients. All assays planned in this proposal have 
been performed for a number of years in the RBC Laboratory.  Specific methods and quality control data for 
each assay have been previously reported.21,33,39,40 
Data Management: Subjects will be enrolled at each Hospital with each site having a dedicated research 
coordinator. All identifying information will be kept on one form in a locked file cabinet at each site along with 
the consent form.  A study ID number will be given to each person and completed CRF’s will be sent to the 


13 
 
data manager on paper. We will enter these into a Microsoft Access database with built-in logical checks. Site 
monitoring of the type that is done for multi-site pharmaceutical studies will be completed. Data collection 
forms have been centrally designed and will be distributed. A case report book for each subject will be 
prepared to contain each case report form required to be completed according to the protocol. Each case 
report form has standard header information identifying the study subject by research identifier, when the data 
is collected, the location where data is collected and a unique identifier signifying the identity of the research 
staff member responsible for the validity of the data recorded on the form. Forms recording the results of 
clinical and/or laboratory evaluations will have countersignature by a study physician to attest to the medical 
review of the data for safety. Data that is de-identified will be entered into the database. While field ranges and 
valid value codes will be checked in the data entry screen application, central data monitoring programs will 
monthly summarize data quality: a) recruitment, enrollment and retention; b) visit attendance and missed visits; 
c) missing forms; d) within form edit checks on item ranges and valid values, skip jumps, and across-item 
logical consistency checks; e) between form within visit logical consistency checks; f) within form between visit 
logical consistency checks. A routine suite of reports summarizing the results of the above data quality reviews 
will be sent back to the research study coordinator at each site and progress at correction or documentation of 
suspicious values will be monitored through edit review and the next month’s reports. The PI and Co-PI will be 
kept appraised of data quality and targets for data timeliness, accuracy and documentation quality will be 
presented and periodically reviewed with research staff. Error checking programs written in SAS, will be run 
periodically. All data will be imported into SAS for analysis. The database and randomization list will be 
password protected, and backed up daily. 
 
Statistical Plan:  There will be no interim analysis and missing outcome data will not be imputed.  Statistical 
analysis will be performed using SAS software (Cary NC).  Between group differences at baseline will be 
compared with t-tests or Wilcoxon rank sum tests and chi-square tests as appropriate (p-value <0.05 for 
significance).  Randomization by the method of randomly permuted blocks will be created for gender and BP 
use groups.  Our primary analysis is ITT analysis and our primary outcome (SA#1) is the categorization of the 
level of bridging seen on focus CT into the scores from 0 to 4, described above between 0 and 3 months. The 
difference in cortical bridging will be evaluated by a 2x5 chi-square (group x score) with a trend test 
(Jonckheere-Terpstra)83 to see whether TPTD treated “trend” to have more higher bridging scores than the 
placebo group. We expect 30% - 50% superiority with TPTD at 3 months. This categorical outcome will be 
further analyzed with generalized estimating equations (GEE) for longitudinal repeated measures assuming a 
Poisson distribution with weighting from logistic regression analysis of the missingness pattern. Secondary 
analyses of covariates, sensitivity analyses and the “per protocol” analysis will incorporate the aforementioned 
approach into this aim’s GEE analysis.  This analysis addresses the question “Do patients treated with TPTD 
show more rapid fracture healing than those given placebo? For SA #2, we anticipate that the difference in 
pain score between the TPTD and placebo groups in the proposed study will be > 30% at each monthly time 
point (0-3 months). We will use a between-groups linear mixed model for repeated measures (LMMrm) to 
estimate the primary outcome of the difference in the mean within-subject change from baseline in the two 
groups at the end of the placebo controlled trial (0-3 months) and again to explore change from 3 to 12 months 
in the open label extension. In addition, narcotic and non-narcotic pain medication use will enter the model as 
time-dependent covariates. This analysis addresses the two questions, “Do patients treated with TPTD show 
more rapid reduction in reported pain level than those not so treated? If so, when?” For SA#3, the CSPPS is 
the outcome. A linear mixed model for repeated measures (LMMrm) will be used with fixed effects of treatment 
group (TPTD vs. placebo), time (D1, 4-, 8- and 12-wk) and their interaction, the baseline level of the CSPPS 
and days from injury to randomization entered as covariates, and a within-subject covariance structure 
selected by empirical methods prior to hypothesis testing. This plan will be repeated for the “per protocol” 
analysis in which subjects are limited to those showing 80% or greater compliance over the 12-week trial. This 
statistical plan addresses the two clinical questions, “Do patients treated with TPTD recover lower limb function 
faster than those not so treated? If so, when?”  LMMrm will be used to analyze data from 3-12 months and 
assess group by time interaction. We will group on prior BP exposure strata to account for possible 
heterogeneity in the R-side covariance structure.  
 
Imbalances in group characteristics at baseline (p-values < 0.20) will be assessed as covariates in secondary 
analyses and findings of significant effect modification will be followed-up with sensitivity analyses. Cumulative 


14 
 
exposure to treatment will be entered as time dependent random effect to incorporate compliance and non-
completer data. Other outcomes will be similarly analyzed in secondary analyses. The following variables will 
be considered and tested as potential covariates in these models using p<0.2 correlation with outcome as 
criterion: gender, age, baseline 25(OH)D, pre-fracture SF36 physical function score, Charlson Comorbidity 
scale, concomitant medications, recent BP use, fracture severity (displacement) and fracture category (single 
or multiple fractures or sacral and pubic).   
 
Sample Size Justification:  We will recruit 100 female and male subjects over 4 years (30, 30, 30, 10) to yield  
80 analyzable subjects completing 3 months of treatment after assuming a 20% overall drop-out rate. Power 
and sample size were calculated for SA#1 fracture healing by radiographic studies: if 100% of TPTD and 60% 
of placebo have completed fracture healing by three months, 40 subjects per group provides > 95% power with 
1% alpha to detect this difference based on an analysis of proportions. For the Timed Up and Go Test 
assuming Peichel’s results (at week 12 TPTD = 22.9 + 7.7 vs Placebo = 54.3 + 19.9), a SD of 18 and a week 4 
to 12 pattern of rapid fracture healing in the TPTD group (at week 8 100% vs 9% in Placebo). A repeated 
measures ANOVA with a Hotelling-Lawly F-test, the same as the Wald test in the LMMrm model with 
unstructured covariance matrix, shows 90% power at 1% alpha is achieved for the fixed treatment effect with 
33 subjects per group and time-by-treatment interaction with 36 subjects per group (SAS 9.4 GLMPOWER).