Clinical trial NCT02176382
Conditions: Postmenopausal Osteoporosis
Sponsor: Massachusetts General Hospital
Start date: 2014-08-01; Completion date: 2020-02-01
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of the study is to assess the effect of an antiresorptive medication in combination with standard dose or alternate dose teriparatide. The study extension will evaluate the effect of one-dose of zoledronic acid after the teriparatide/denosumab combination.

Detailed description:

Arms: arm 1: teriparatide daily subcutaneous injection (months 0-9) plus denosumab subcutaneous injection every 6 months (months 3-15) followed by zoledronic acid at month 15 arm 2: teriparatide alternate dose daily subcutaneous injection (months 0-9) plus denosumab subcutaneous injection every 6 months (months 3-15) followed by zoledronic acid at month 15
Interventions: intervention 1: denosumab intervention 2: teriparatide intervention 3: Zoledronic acid
Intervention descriptions: intervention 1: denosumab subcutaneous injection intervention 2: teriparatide daily subcutaneous injection intervention 3: zoledronic acid infusion

Protocol documents:
Prot_SAP_000.pdf: 
 
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Detailed Protocol: Denosumab and High-dose Teriparatide Administration Study (DATA 2) 
 
I. Background and Significance 
 
As our population ages, osteoporotic fractures are expected to have an increasing impact on the 
health of our population. Today, osteoporosis is estimated to affect over 20 million Americans with 1.5 
million osteoporotic fractures occurring in the United States every year 1. In women, the lifetime risk of 
experiencing a minimal trauma hip fracture, the most devastating consequence of osteoporosis, is 
estimated to be 17% 2. In most patients with osteoporosis, the occurrence of a hip fracture is a 
devastating consequence, conveying 24% excess mortality within 12-months of the fracture and a 
continued increased risk of death for up to 10-years after the event 3. In patients with the most 
advanced osteoporosis, currently available medications can, at best, decrease hip and non-spine 
fracture rates by 50% and 30%, respectively 4,5. At present, the mainstay of osteoporosis treatment is 
the use of oral and intravenous bisphosphonates (BPs).  These drugs act by suppressing bone 
resorption (as well as formation) and have been shown to increase bone mineral density (BMD) and 
reduce fracture rates in certain populations 6. Teriparatide (TPTD- hPTH 1-34) has also been shown 
to increase BMD and reduce fractures, but acts by a different mechanism that involves stimulating 
new bone formation (along with resorption), and reconstituting internal bone microarchitecture 7-14. 
The effects of TPTD are dose dependant both with regard to increases in bone mass and stimulation 
of osteoblast activity 13. Specifically, biochemical markers of bone formation increase more in women 
treated with 40-μg of TPTD daily compared to women treated with 20-μg (the FDA approved dose) 
and this greater stimulation of bone formation is associated with greater BMD increases, particularly in 
trabecular bone 14,15.   Despite stimulating greater increases in bone mass, TPTD 40 mcg/day reduces 
spine and non-spine fractures no more than TPTD 20 mcg/day in humans. We hypothesize that this 
paradox arises because 40-mcg/day increases bone resorption more than 20-mcg/day, a difference 
revealed by biochemical markers of bone resorption 14,16. Unique among osteoporosis medications, 
TPTD has also been shown to stimulate periosteal expansion in animal models though a similar 
property in human studies has yet to be unequivocally shown 8,17-19. 
 
While both TPTD and BPs increase BMD and reduce fracture risk, their beneficial effects are limited 
and neither drug is able to completely normalize BMD or restore skeletal integrity in most patients. 
Initially thought to be a promising approach, trials of combination therapy with anabolic agents and 
BPs have demonstrated minimal or no advantage over monotherapy 20-26. In these combination 
studies, the antiresorptive agent inhibited TPTD or PTH-stimulated increases in bone formation and 
resorption but did not suppress turnover to the degree observed with the antiresorptive agent alone 22-
26. Together, these studies suggest that co-administration of BPs with TPTD blunts the TPTD-
associated stimulation of bone formation in a dose-dependent fashion, particularly in predominately 
trabecular sites such as the spine. The reasons that the combination of BPs and TPTD do not 
stimulate greater gains in BMD are unclear.  BPs presumably interfere with one or more of the 
mechanisms via which TPTD exerts its anabolic effect on bone: increased secretion of IGF-I, bFGF, 
or other paracrine growth factors by osteoblasts, decreased production of sclerostin by osteocytes, 
and/or increased osteoclastic resorption of bone with resultant release of these and other pre-formed 
growth factors 23,27,28.  
 
Rodent models have suggested that TPTD in combination with OPG (a molecule aimed at the same 
molecular target as denosumab– see below) has superior skeletal effects compared to TPTD alone 
29,30. Denosumab (DMAB) is an FDA-approved fully human monoclonal antibody that specifically binds 
to receptor activator of nuclear factor-κB ligand (RANKL)31. It inhibits bone resorption by interfering 
with the binding of RANKL to its receptor on pre-osteoclasts and osteoclasts, the final common 
pathway leading to osteoclast activation and bone resorption 32,33. DMAB suppresses bone turnover 
more than intravenous and oral BPs 34,35. DMAB’s potent antiresorptive properties are best 
demonstrated in iliac crest biopsy specimens from postmenopausal osteoporotic women who had 
been taking the drug for 24-36 months. These biopsies revealed an 80% reduction in eroded surface 


 
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and the complete absence of osteoclasts in more than 50% of the specimens. Furthermore, 
histomorphometric indices of bone turnover were significantly lower in the patients taking DMAB than 
those taking alendronate 36. Despite this dramatic suppression of osteoclast activity, however, bone 
turnover rapidly normalizes after the drug is discontinued 31. Like other antiresorptive agents, DMAB 
increases BMD at the lumbar spine and hip, but unlike most of these agents also increases BMD at 
diaphyseal sites such as the wrist 37-42. Furthermore, DMAB reduces the risk of vertebral and hip 
fractures in postmenopausal women with osteoporosis, and increases indices of bone strength when 
measured by HR-pQCT 43,44. Taken together, the unique mechanism of action of DMAB and the 
suggestive animal studies led us to hypothesize that the combination of DMAB and TPTD would 
increase BMD, bone quality, and estimated bone strength more than either drug alone.  
 
This hypothesis was tested and confirmed in The DATA Study (ClinicalTrials.gov Identifier 
NCT00926380) 45,46 that compared teriparatide and denosumab monotherapy to the combination of 
both drugs in postmenopausal osteoporotic women. As shown below, the results not only showed that 
the combination increased hip and spine BMD more than either drug alone, but also that in the 
presence of DMAB, the pro-resorptive effects of TPTD are completely blocked (unlike combinations of 
TPTD and BPs).  
 
 
The combination group is statistically different from both other groups at all sites (P<0.02). TPTD group is 
statistically different from DMAB at total hip only 
 
 
For clarity, changes are shown for combination and DMAB groups only (*P=0.05 for between-group 
comparison). In the TPTD alone group, typical increases in OC, P1NP (bone formation markers), and CTX 
(bone resorption marker) were observed. 
 
 
These results suggest that even greater gains in BMD, bone quality, and bone strength could be 
achieved if DMAB could be combined with a more potent stimulant of osteoblast function and bone 
formation. Thus, we plan to conduct 15-month study that compares TPTD 40-μg plus DMAB (60-mg 
every six months) to TPTD 20-μg plus DMAB in a design that also takes advantage of recent work 
that suggests that starting TPTD before the antiresorptive has some clinical advantages 47,48. 
 


 
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In performing this clinical trial, we will be able to better understand the mechanisms by which 
antiresorptive agents influence the efficacy of anabolic agents. Furthermore, if our hypothesis is 
confirmed, the findings of this study could define a novel approach to the treatment of high-risk 
osteoporosis patients. 
 
A known limitation of both teriparatide and denosumab therapy is the rapid loss of bone that occurs 
when these drugs are discontinued.49,50 Moreover, both teriparatide and denosumab are expensive 
and administered by subcutaneous injection (daily and every 6-months, respectively). If combination 
teriparatide/denosumab therapy is to become part of a widely used treatment approach, we must 
develop strategies to maintain and expand the unprecedented improvement in bone density and 
microarchitrecture observed, and do so with acceptable risk of serious adverse effects. Zoledronic 
acid is a highly potent bisphosphonate that has been shown to reduce the risk of both vertebral and 
non-vertebral fractures when given as a yearly 5-mg infusion over 3 years.51 Despite the FDA-
approved yearly dosing schedule, it has also been reported that the effects of a single 5-mg 
zoledronic acid infusion are much more prolonged. Specifically, a single administration of zoledronic 
acid continues to reduce bone resorption and increase BMD for an additional 2-5 years.52-55 Moreover, 
it has also been demonstrated that a single dose of zoledronic acid continues to reduce fracture rates 
for at least 3-years and to the same degree as do yearly infusions.56 
 
As the optimal treatment for patients who have previously received combination denosumab and 
teriparatide is not defined, we believe that is useful and important to look at how our study subjects’ 
bone mineral densities have changed a year or more after completion of their participation in our 
study. 
 
II. Specific Aims 
The Specific Aim of this protocol is to test the following hypothesis:  
In postmenopausal women with osteoporosis, the combination of DMAB and high-dose TPTD (which 
will be started 3-months prior to denosumab) will increase BMD, improve bone microarchitecture, and 
increase estimated bone strength more than the combination of DMAB and standard dose TPTD. 
 
The Specific Aim of the Extension trial (DATA-2-EX): 
The extension trial described (DATA-2-EX) will test the hypothesis that the large increases in cortical 
and trabecular BMD, bone quality, and estimated bone strength achieved with combined DMAB and 
high-dose TPTD therapy can be extended for up to 27-months by a single 5-mg dose of zoledronic 
acid. If this hypothesis is confirmed, it will represent a significant advance in the rational development 
of comprehensive treatment strategies, especially for those with severe disease in whom single-agent 
therapy does not adequately reduce fracture risk. Additionally, positive results from DATA-2-EX would 
support the initiation of a larger trial assessing the anti-fracture efficacy of this approach. 
 
The Specific Aim of the Observational visit: 
This optional observational visit is specific to subjects who completed the month-15 trial but did not 
enroll in DATA-2-EX. We wish to test the hypothesis that further transitioning to intravenous 
bisphosphonate from the two treatment groups will prevent the bone loss associated with 
discontinuing these therapies and will further increase bone density. 
 
III. Subject Selection 
350 female volunteers will be screened and 70 female volunteers will be recruited  by advertisement 
in accord with institutional guidelines for clinical studies. Recruitment flyers will be posted in approved 
locations throughout the MGH (including the MGH Bone Mineral Density Center) and email 
announcements will be sent through the Partners Clinical Research Program Network.  Letters will be 
sent to subjects identified through RSVP for Health. Additionally, advertisements will be published in 
local newspapers and a mailing will be sent to targeted populations, including subjects who have 
expressed an interest in one of our research group’s previous studies.  


 
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Subjects will be paid $50 after each completed visit (other than the screening visit) for a total of $300. 
 
Parking vouchers will be provided to subjects at each visit, including the screening visit. 
 
Inclusion Criteria: 
Must satisfy A and B and C and D below: 
A. women aged > 45 
 
B. postmenopausal by either of the following criteria: 
 
> 36 months since last spontaneous menses; 
 
or 
 
> 36 months since hysterectomy, plus serum FSH > 40 units / liter. 
  
C. osteoporosis with high risk of fracture' by one or more of the following criteria: 
DXA spine or hip T-score ≤ - 2.5; 
or 
 
DXA spine or hip T-score ≤ - 2.0 plus > 1 of the following BMD-independent risk factors for 
fracture: fracture after age 50, parental hip fracture after age 50, prior hyperthyroidism, inability 
to rise from a chair with one's arms elevated, current tobacco smoker. 
or 
DXA spine, hip, or forearm T-score ≤ - 1.0 plus > 1 adult low-trauma fracture (low-trauma 
fracture = fracture after no trauma; or fracture after falling < 6 inches when stationary or 
moving slower than a run. 
 
Exclusion Criteria: 
• 
confirmed serum alkaline phosphatase above upper normal limit with no explanation 
• 
liver disease (AST or ALT  > 2 x upper normal limit).  
• 
renal disease  (serum creatinine > 2.0 mg/dl). 
• 
Hypocalcemia or hypercalcemia (Ca <8.5 mg/dL or >10.5 mg/dL) 
• 
Abnormal blood PTH (intact PTH < 10 pg/mL or > 65 pg/mL) 
• 
serum 25-OH vitamin D < 20 ng/ml 
• 
HCT < 32%.  
• 
history of malignancy (except non-melanoma skin carcinoma) or radiation therapy. 
• 
history of gouty arthritis. 
• 
significant cardiopulmonary disease including unstable coronary artery disease, stage D 
ACC/AHA heart failure or any other condition that the investigator deems may preclude the 
subject from participating safely or completing the protocol procedures. 
• 
major psychiatric disease that in the opinion of the investigator would preclude the subject 
from providing adequate informed consent or completing the protocol procedures. 
• 
excessive alcohol use or substance abuse that in the opinion of the investigator would 
preclude the subject from providing adequate informed consent or completing the protocol 
procedures. 
• 
known congenital or acquired bone disease other than osteoporosis (including osteomalacia, 
hyperparathyroidism, Paget’s disease) 
• 
current use or use in the past 6 months of oral bisphosphonate 
• 
current use or use within the past 3 months of estrogens, selective estrogen receptor 
modulators, or calcitonin. 
• 
Current use or use in the past 6 months of denosumab 
• 
use of oral or parenteral glucocorticoids for more than 14 days within the past 6 months 
• 
any current or previous use of strontium, teriparatide, or any parenteral bisphosphonate. 


 
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• 
known sensitivity to mammalian cell-derived drug products. 
• 
known sensitivity to teriparatide or any of its excipients. 
• 
known sensitivity to densoumab or any of its excipients. 
• 
Extensive dental work involving extraction or dental implant within the past 2 months or 
planned in the upcoming 2 months. 
 
 
DATA-2-EX criteria: 
Subjects completing DATA-2 will be offered enrollment in DATA-2-EX if they meet the same entry 
criteria outlined in DATA-2 with the following exceptions related to fracture risk. Subjects currently 
enrolled will be offered enrollment in DATA-2-EX by letter and a follow-up phone call at least 2 months 
prior to their 4th study visit. Subjects being recruited will be informed of the optional extension during 
the screening phone call. 
 
All subjects enrolled in DATA-2 will be eligible for DATA-2-EX or the optional observational visit. 
 
In addition to these DATA-2 criteria, to be enrolled in DATA-2-EX, women will be required to have an 
estimated GFR >35 (mL/min), a 25-(OH) Vitamin-D level >20 (ng/mL), and no known allergy to 
bisphosphonates. Laboratory testing of Cr, GFR and 25-OH vitamin D will be performed within 3 
months of receiving zoledronic acid. The exclusion criteria will remain the same as the original DATA-
2 exclusion criteria, as outlined above, with the exception that prior exposure to denosumab and 
teriparatide as part of the DATA-2 protocol are permitted and renal function criteria will be assessed 
by estimated GFR (rather than the creatinine level). Zoledronic acid will not be infused if the 25-OH 
vitamin D level is <20 ng/mL or GFR is <35 mL/min.   
 
 
IV. Subject Enrollment 
 
This outpatient study will either be conducted at one or more of the following sites:  the General 
Clinical Research Center (GCRC), the Osteoporosis Research Center or the Endocrine Unit Clinical 
Space (all within the Massachusetts General Hospital.   
 
The general design is a randomized, 2-arm, open label study.  
 
Groups and Randomization 
Subjects will first be screened, and those who appear eligible will have a medical history and interview 
with a study investigator. Those who remain eligible will be formally accepted into the study by a study 
investigator, assigned to one of 4 strata based on age (above or below 65) and previous 
bisphosphonate use (previous use or none) and then randomly assigned within each strata to one of 
the 2 treatment groups by computer-generated cards.  (1:1: ratio).  Within each of the four strata, the 
randomization block size will vary randomly to minimize the predictability of treatment assignments.  
 
The study period lasts 15 months. There will be 35 subjects in each group. 
 
All subjects completing the 15-month DATA-2 trial be offered enrollment in the DATA-2-EX study.  
 
For subjects who do not enroll in DATA-2-EX, subjects may enroll for an optional observational visit. 
The observational period will start immediately after the DATA-2 study’s 15-month visit and will last an 
additional 12 to 24 months. During that interval, each subject will be contacted by phone.  
 
All subjects will be asked if: 
- 
They continued osteoporosis treatment and if so, with what drug 


 
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- 
They have sustained any new fractures. 
 
We will request that all subjects return for one visit to complete one bone density scan of the spine 
and hip (by DXA) within 12 to 24 months of the completion of the 15-month study. Informed consent 
for this visit will be obtained by a research assistant. The DXA will be performed at no cost to the 
study subjects.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: (Optional one-time observational visit for only DXA may occur between month 27 and month 39 for 
subjects who do not receive zoledronic acid.) 
 
All subjects who report dietary intake of less than 1200mg of calcium daily will be given calcium 
supplementation (600mg elemental calcium) with Vitamin D (400IU). Subjects with a dietary intake > 
1200 mg will receive Vitamin D only. 
 
V. Study Procedures 
 
Telephone screening and Screening Visit: 
Members of research staff will screen all interested subjects over the telephone.  If subjects meet 
initial criteria and are interested in the study, a member of the study staff will schedule a screening 
visit wherein the subject will sign a separate “screening only” consent form.  This consent form will 
allow for a blood draw and bone mineral density testing. 
 
Prior to signing this screening only consent form, subjects will be offered the option to speak with a 
physician investigator if they wish or if they have questions that can't be answered by the RA. 
 
At this visit, bone mineral density of the spine and hip will be obtained and the following will be 
measured in serum or blood: 
• 
PTH 
• 
25-(OH) Vitamin D 
• 
Routine chemistries (Calcium, Phosphate, electrolytes, BUN, creatinine, ALT)  
• 
Complete Blood Count 
• 
FSH (if necessary because of prior hysterectomy) 
 
Visit 1: 
If the subject meets the above BMD and laboratory criteria, she will then be scheduled for  visit 1.  At 
this visit, a study physician will obtain written informed consent for participation in the complete study.  
If subjects require more time to consider participating after reading the consent form the screening 
 


 
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visit will not continue.  If the subject is ready to sign the consent form, the study physician will then 
perform a history and physical on her. If all inclusion/exclusion criteria are met, subjects will then 
continue visit 1 and the subsequent visits.  
 
Visit 1-6: 
These visits will occur at the following times: 
Visit 1 (month 0) 
Visit 2 (month 3 +/- 2 weeks)  
Visit 3 (month 9 +/- 2 weeks) 
Visit 4 (month 15 +6/- 2 weeks) 
Visit 5 (month 27 +/-2 weeks) 
Visit 6 (month 42 +/-2 weeks) 
 
If enrolled in optional observational study, these visits will occur at the following times: 
Visit 1 (month 0) 
Visit 2 (month 3 +/- 2 weeks)  
Visit 3 (month 9 +/- 2 weeks) 
Visit 4 (month 15 +/- 2 weeks) 
Visit 5 (month 27, up to month 39) Visit 5 will consist of obtaining informed consent and DXA hip and 
spine scan only. A blood draw will not be performed. 
 
 
Subjects will be seen at MGH prior to 10 a.m. and will be instructed to be fasting, and to skip that 
day's PTH injection (if any).  The following blood/serum tests will be measured: 
 
• 
Routine chemistries (Calcium, Phosphate, electrolytes, BUN, creatinine, ALT, PTH, 25OH vit 
D) 
• 
Complete Blood Count 
• 
Serum CTX (pooled assay of de-identified samples at end of study to be analyzed by 
collaborator Dr. Richard Eastell) 
• 
Serum osteocalcin (pooled assay of de-identified samples at end of study to be analyzed by 
collaborator Dr. Richard Eastell) 
• 
Serum PINP (pooled assay of de-identified samples at end of study to be analyzed by 
collaborator Dr. Richard Eastell) 
 
After which the subjects will be given breakfast, and then have the following procedures per table 
below: 
 
The following procedures are performed at each visit: 
 
Screen 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Month 
 
0 
3 
9 
15 
27 
42 
 
 
 
 
 
 
 
 
Routine and hormonal lab 
testing 
X 
X 
X 
X 
X 
√ 
√ 
History and Physical Exam 
X 
 
 
 
√ 
 
 
Dispense Medications 
 
X 
X 
X 
√ 
 
 
Bone Turnover Markers 
 
X 
X 
X 
X 
√ 
√ 
BMD by DXA of PA spine, hip, 
and 1/3 distal radius 
X 
X 
X 
X 
X 
√ ,* 
√ 
HR-pQCT of radius and tibia 
 
X 
X 
X 
X 
√ 
√ 
QCT of the hip and spine 
 
X 
 
 
X 
 
√ 


 
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X = DATA-2 procedures 
√ = DATA-2-EX procedures 
*= observational visit, DXA spine and hip only 
 
After blood sampling, denosumab (sold under the brand name Prolia) will be administered (visits 2 
and 3 only).  Additionally, at visit 1 subjects will be trained in the use of the teriparatide pen (sold 
under the brand name Forteo) and will give themselves the first injection while observed by a 
member of the study staff. At each visit participants will return their used and unused Forteo 
injection pens, so we can estimate and record the unused volume in each pen and thereby estimate 
her compliance with Forteo use.  All subjects in DATA-2-EX receive a single 5-mg infusion of 
zoledronic acid at month 15. 
 
Study funds and NIH funding will cover the costs of all study procedures, ancillary medications and 
the costs of the study drugs if not covered by insurance or the manufacturer. 
 
Note:  Any remaining serum samples will be saved and may be used to measure other variables 
related to bone metabolism at a future time. Samples will be stored with subject code number and 
date and time of sampling in a locked –80 degree freezer and only approved study personnel will 
have access to the samples. It is understood that any future use of samples must be reviewed and 
approved separately by the HRC prior to their use.  Personal-Identifying information will be removed 
before any sample is sent out for analysis to a non-Partners affiliated institution. 
 
Note: The Principal Investigator may end the subject's participation without the subject's consent in 
order to protect the health of the subject, if the subject is unable to attend to study visits, if the sponsor 
decides to stop the study, or due to other administrative reasons. 
 
 
Interpretation of results and study limitations of the proposed clinical trial: 
This 15-month RCT will provide scientifically important and potentially groundbreaking clinically 
relevant findings. The combination of anabolic therapy with BPs has not been promising but the 
DATA study demonstrates that DMAB, through its distinct mechanism of action, may prove to be a 
more effective inhibitor of osteoclast activity in the presence of a potent anabolic stimulus. By 
increasing the TPTD dose, we hypothesize that we will maintain or improve bone formation rates 
while resorption remains powerfully inhibited. If the combination of this higher TPTD dose and 
DMAB increases BMD, improves bone quality, and increase estimated bone strength more than the 
combination of high-dose TPTD and alendronate and the combination of standard-dose TPTD and 
DMAB, it will represent a significant step forward in osteoporosis therapy. Additionally, analysis of 
the QCT and HR-pQCT assessments will potentially confirm the robust effects of DMAB and TPTD 
co-administration on the cortical compartment of the axial and appendicular skeleton.  
 
 
VI. Study Endpoint and Statistical Analysis 
 
The primary endpoint is the change in PA spine BMD (DXA) between treatment groups at 15 months. 
The method of analysis will be a longitudinal mixed effects ANOVA. This model includes the subject 
level random intercept, time, fixed treatment effect, and the (group)X(time) interaction term. The 
inference of the regression coefficient associated with the interaction term (difference in slopes) will 
determine differences between treatment groups. The model will allow us to include all available 
partial observations for the non-completers and this approach will provide more valid estimates (with 
increased efficiency) of the time effects than the last value carried forward method.  
 


 
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Calculation of Power  
For purposes of estimation, we calculated the sample based on a between-group comparison of the 
mean intra-individual treatment effect over the treatment period for the primary and secondary 
endpoints based on the our observations of the standard deviation of the 12-month treatment effects 
observed in the DATA study. We predict that 30 subjects in each group will complete the study. This 
represents an 86% completion rate, a conservative estimate based on our current withdrawal rate of 
less than 6% in DATA.  With this group size, the table below shows our estimated power calculations 
using the Hsu (With Best) multiple comparison test at a 5% significance level and assuming 80% 
power. The Hsu completers-based power analysis is conservative, and the actual analysis will likely 
attain greater power as the full analysis set can be utilized. 
 
These detectable between-group differences are at the lower limit of what is considered clinically 
important and generally correspond to the between-group difference that we observed in the DATA 
study.  
 
VII. Risk and Discomforts 
 
Denosumab 
DMAB is an FDA approved medication used to treat osteoporosis in various populations, including 
postmenopausal women. More than 13,500 patients have been treated with DMAB in clinical studies, 
and it is generally well tolerated. In clinical studies, it has been reported that DMAB may uncommonly 
produce the following side-effects: eczema, serious skin infections, low blood calcium (which can 
cause tingling in the fingers or around the mouth, muscle cramps, or abnormal heart rate), pain in the 
joints or extremities, high blood cholesterol, dizziness, cough, difficulty emptying the bladder, and 
decreased skin sensation. Hypocalcemia has been very rarely reported in absence of renal failure. 
Osteonecrosis of the jaw has been reported in the oncology clinical trial program in patients treated 
with DMAB but its relative incidence compared to placebo is unclear. Atypical, low-energy, or low 
trauma fractures of the femoral shaft have been reported patients who received DMAB. The incidence 
of atypical femur fractures is not well-defined but appears to be extremely rare. If a study subject 
presents with thigh or groin pain, she will be immediately evaluated to rule out an incomplete femur 
fracture.  
Parameter  
Standard Deviation of 12-month 
change in subjects receiving 
combination therapy in DATA. 
Minimum detectable 
difference at a 5% 
significance level assuming 
80% power 
DXA PA Spine (primary 
endpoint) 
3.8% 
2.5% 
DXA Fem. Neck 
4.3% 
2.8% 
DXA Total Hip 
2.8% 
1.9% 
Distal Radius Total vBMD 
2.2% 
1.5% 
Distal Radius HR-pQCT Cortical 
vBMD  
1.5% 
1.0% 
Distal Radius HR-pQCT Cortical 
Thickness 
4.5% 
2.9% 
Distal Tibia Total vBMD 
2.1% 
1.4% 
Distal Tibia HR-pQCT Cortical 
vBMD  
1.5% 
1.0% 
Distal Tibia HR-pQCT Cortical 
Thickness 
3.1% 
2.4% 
CTX 
35% 
23% 
Osteocalcin 
27% 
18% 
P1NP 
32% 
21% 


 
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Teriparatide 
TPTD is an FDA approved medication used to treat postmenopausal women with osteoporosis who 
are at high risk of fracture. The most commonly reported side effects of TPTD are overall pain, 
asthenia, nausea, headache, leg cramps, sinus tachycardia, arthralgia, rhinitis), and dizziness. TPTD 
can cause transient hypercalcemia, which is generally mild, even with the 40-μg dose 13. Repeated 
daily administration of TPTD in high doses to rodents causes dose-dependent osteosclerosis, bony 
obliteration of the marrow space, and extra-medullary hematopoiesis, followed by osteosarcomas.   
The relevance of these findings to humans is unclear and will remain so for many years, because 
osteosarcoma is rare in adults (4 cases/million/year). Eli Lilly and the FDA are monitoring the 
incidence of osteosarcoma in TPTD treated patients and have not reported a linkage thus far. 
 
The dose of TPTD chosen (40-μg) is higher than that currently approved by the U.S. Food and Drug 
Administration (20-μg once daily) but the same as doses used in other clinical studies, including our 
own. Studies from our group were performed under an IND to Dr Robert Neer (co-investigator) and 
include the following: 
 
Study 
Population 
Total subjects 
receiving TPTD 
40-μg SC daily 
Duration 
Hypercalcemia 
incidence (24-hrs 
post-dose) 
Finkelstein et al. 
NEJM 2003 24 
men 
55 
24 months 
<1% 
Finkelstein et al. 
JCEM 2010 23 
postmenopausal 
women 
62 
24 months 
<2% 
 
In the largest study of the 40-μg dose of teriparatide 13, 541 women received the 20-μg dose and 544 
women received the 40-μg dose for a mean if 19 months. In this study, both doses were generally well 
tolerated and differences in side effects between doses were small. Side effects included nausea (40-
μg 18%, 20-μg 8%, placebo 8%), headache (40-μg 13%, 20-μg 8%, placebo 8%), dizziness (40-μg 
6%, 20-μg 9%, placebo 6%), and leg cramps (40-μg 1%, 20-μg 3%, placebo 1%). Additionally, the 40-
μg dose was well-tolerated in a group of 122 postmenopausal women when co-administered with 
hormone replacement therapy for 24 month 15. 
 
Zoledronic Acid 
The most common side effects associated with zoledronic acid include flu-like symptoms (e.g., fever, 
chills, muscle/joint aches) occurring after the infusion. The majority of these symptoms occur within 
the first 3 days following drug administration and usually resolve within 3 days of onset but resolution 
can take up to 7-14 days. Taking acetaminophen or ibuprofen after the infusion can mitigate these 
symptoms. Other common side effects include nausea, tiredness, dizziness, headache, or 
pain/redness/swelling at the injection site.  
 
Renal toxicity: Zoledronic acid, has been associated with renal impairment and in rare cases, acute 
renal failure. There is a transient increase in serum creatinine within 10 days of dosing in 1.8% of 
zoledronic-acid treated patients versus 0.8% of placebo-treated patients.  Renal function is being 
monitored closely in both DATA-2 and DATA-2-EX and patients will be required to have an estimated 
GFR >50 (mL/min) to receive zoledronic acid 5mg. Subjects with GFR 35-50 would receive zoledronic 
acid 2 mg. As per the approved product labeling, the infusion time for zoledronic acid will be at least 
15 minutes and will be followed by a 10 mL normal saline flush of the intravenous line. 
 
Hypocalcemia: In clinical trials of zoledronic acid without Vitamin D pre-treatment, approximately 0.2% 
of patients had notable declines of serum calcium levels to values less than 7.5 mg/dL after each 
zoledronic acid administration. No symptomatic cases of hypocalcemia were observed in clinical trials 


 
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if they had been pretreated with Vitamin D. All patients in DATA-2-EX are being treated with Vitamin D 
and Vitamin D levels are being monitored in both DATA-2 and DATA-2-EX. Patients are required to 
have a pre-treatment 25-(OH) Vitamin-D level ≥20 (ng/mL). Patients who are administered the renal 
dose of zoledronic acid (2mg) will be asked to return for bloodwork 10 days (+/- 3 days) post-infusion 
to assess calcium and creatinine levels. 
 
Osteonecrosis of the Jaw: Osteonecrosis of the jaw is an extremely rare side effect of zoledronic acid 
when given at the doses recommended for osteoporosis treatment. Subjects will not be enrolled in 
DATA-2-EX if they have any major dental work planned during the projected course of the study 
(extractions or implants). An oral examination will be performed by a study doctor prior to 
administration of zoledronic acid. 
 
Atypical Femur Fractures: Atypical, low-energy, or low trauma fractures of the femoral shaft have 
been reported in bisphosphonate-treated patients. Atypical femur fractures may be unilateral or 
bilateral and some patients report prodromal dull or aching pain in the thigh in the weeks to months 
before a complete fracture occurs. The incidence of atypical femur fractures is not well-defined but 
appears to be extremely rare and at least somewhat dose-dependent. If a study subject presents with 
thigh or groin pain, she will be immediately evaluated to rule out an incomplete femur fracture.  
 
 
Imaging studies 
Over the 15-month study period, subjects will receive the following imaging studies: 
 
Study Type 
DATA-2 
DATA-2-EX 
Radiation 
exposure per 
scan 
DXA of the lumbar spine, hip, 
and radius. 
5 (including 
screen) 
2 
1 mrem 
HR-pQCT of the distal tibia 
and radius 
4 
2 
<0.5 mrem 
QCT of the hip and spine 
2 
1 
510 mrem 
 
The total dose for the DATA-2 15-month study is therefore ~1000 mrem . The total dose for DATA-2-
EX (months 15-42)  is ~500 mrem..  This amount of radiation is equal to the background radiation one 
is exposed from the earth and sky over 3.25 years (for DATA-2) and 1.5 years (for DATA-2-EX).  
 
The total dose for the observational visit alone is 0.05 mSv, equal to background radiation one is 
exposed from the earth and sky over 3 days.  
 
VIII. Potential Benefits 
The medications given in this study have been shown to reduce fracture risk as well or better than all 
other approved osteoporosis therapies and subjects can expect to derive the benefit from these 
medications. It is hoped that the knowledge gained from this study will improve osteoporosis care. 
 
IX. Monitoring and Quality Assurance 
 
A study physician will review all laboratory test results. Subjects will be discontinued from the study if 
they have any finding that in the opinion of the study physician requires withdrawal from the study. 
Disqualifying findings will be communicated to both the subject and her primary care physician. If the 
subject does not have a primary care physician, the principal investigator will coordinate appropriate 
follow-up with a physician of the subject's choosing. Hypercalcemia is a well-described complication of 
teriparatide treatment.  Elevated blood calcium levels will be handled in the manner recently 


 
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recommended by Antoniucci et al (see below) 57.  
 
 
 
If serum calcium concentration is above 11.2 mg/dl, teriparatide will be stopped and serum calcium 
measured at least daily until normal.  Thereafter teriparatide will be resumed every other day and the 
above algorithm followed, starting at "Reduce PTH to every other day". 
 
The Data Safety Monitoring Board (DSMB) that is currently monitoring DATA 1 will monitor DATA 2. 
This DSMB is comprised of experienced clinical investigators: Dr. Deborah Wexler (Chair), Dr. Carl 
Pallais, and Douglass Hayden (biostatistician). Adverse events and serious adverse events will be 
reported to all appropriate regulatory bodies as required by current regulations.  
 
A NIAMS-appointed DSMB will provide safety oversight for DATA-2-EX. This DSMB will meet as per 
NIAMS/KAI guidelines. As per NIAMS reporting requirements, all adverse events will be reported in 
the routine safety reports and all serious adverse events regardless of relatedness will be reported to 
the DSMB Safety Officer and the NIAMS, through KAI (NIAMS Executive Secretary), within 48 hours 
of the PI receiving notification of the events. 
 
Adverse events or other unanticipated problems will be reported to the Partners Human Research 
Committee (PHRC) within 7 calendar days/5 working days of the date the investigator first becomes 
aware of the problem as described in the PHRC policy on Adverse Event Reporting and 
Unanticipated Problems Involving Risks to Subjects or Others.


 
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