Conditions: Osteoporotic Fractures Osteoporosis, Postmenopausal
Keywords: Bone loss Frail Geriatric Women Nursing Home Patients Long-term Care Patients Osteoporosis Osteoporotic Fractures
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 310
Healthy volunteers: no

Brief summary:
The goal of this study is to perform the first fracture reduction clinical trial with a potent antiresorptive agent (intravenous zoledronic acid) in the most vulnerable long-term care population.

Detailed description:
Although close to 85% of frail women in long-term care (LTC) facilities have osteoporosis and the risk of osteoporotic fractures is nearly 10 times that of community dwelling elderly, few are treated and studies are scarce. It is postulated that in frail, LTC women an annual infusion of zoledronic acid, an antiresorptive therapy for osteoporosis, will:

1. be effective demonstrated by fracture reduction;
2. be safe.

To address these hypotheses, up to 1000 female LTC residents age 65 and older will be screened in order to enroll 310 eligible for randomization in a 3 year, randomized, double-blind, calcium and vitamin D controlled trial with the antiresorptive agent zoledronic acid. Use of an intravenous, once yearly agent avoids concerns of oral bisphosphonate side effects, poor absorption and burden on staff. Participants will reside in the long-term care settings associated with the Division of Geriatric Medicine, University of Pittsburgh and will include women with multiple comorbid conditions, functional and cognitive impairment, and limited mobility.

Arms:
arm 1: Annual dose: intravenous zoledronic acid (Reclast) 5.0 mg; vitamin D (800 IU/daily) and calcium (approximately 1200 mg/daily, dietary + supplements) arm 2: Annual dose: intravenous saline; vitamin D (800 IU/daily and calcium (approximately 1200 mg/daily, dietary + supplements)

Interventions: intervention 1: Zoledronic acid intervention 2: vitamin D intervention 3: calcium intervention 4: Saline
Intervention descriptions: intervention 1: Annual intravenous 5.0 mg intervention 2: 800 IU daily intervention 3: approximately 1200 mg (dietary and supplement) intervention 4: Annual intravenous saline placebo

Protocol document:
ICF_002.pdf: 
University of Pittsburgh STUDY19040149 
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Study Consent 
 
 
 
 
 
 
Official Title: Zoledronic Acid for Osteoporotic Fracture Prevention 
(ZEST II) 
  
 
 
ClinicalTrials.gov ID (NCT number): NCT02589600 
 
 
 
Protocol Date: 3/30/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


University of Pittsburgh STUDY19040149 
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Expires: 5/3/2022 
 
 
 
 
 
Division of Geriatric Medicine 
 
Osteoporosis Prevention 
and Treatment Center 
 
1110 Kaufmann Medical Building 
3471 Fifth Avenue 
Pittsburgh, PA 15213 
412-692-2220 
 
CONSENT TO ACT AS A SUBJECT IN A RESEARCH STUDY 
Title: ZEST II for Osteoporotic Fracture Prevention 
 
Principal Investigator: 
Susan Greenspan, MD 
Professor of Medicine 
Director of Osteoporosis Prevention and Treatment Center 
University of Pittsburgh 
3471 Fifth Avenue, Suite 1110 
Pittsburgh, PA 15213 
(412) 692-2477 
 
Co-Investigator: 
David Nace, MD 
Director of Long Term 
University of Pittsburgh Institute on Aging, Medical Director 
3471 Fifth Avenue, Suite 500 
Pittsburgh, PA 15213 
412-692-2360 
 
Study Coordinator: 
Julie Wagner, PA-C, MPA 
412-692-2478 
E-mail: wagnerjm@pitt.edu 
 
Sources of Support: NIH Grant # 1R01AG050302 - 01A1 
 
Why is this research study being done? 
The purpose of this research study is to find if a yearly intravenous (IV) 
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drug called Zoledronic acid (Reclast®) works to reduce fractures in female 
long-term care (LTC) residents with osteoporosis. Osteoporosis is a 
thinning and weakening of the bones that can cause fractures (broken 
bones). An IV drug is one that is given through a vein in your arm. 
Zoledronic acid (Reclast®) is approved by the U.S. Food and Drug 
Administration (FDA) for the treatment and prevention of osteoporosis in 
postmenopausal women and to reduce the incidence of fracture in 
postmenopausal women with osteoporosis. 
 
This 3-year research study is being done at your facility by the 
Osteoporosis Prevention and Treatment Center at the University of 
Pittsburgh and will involve 5 study visits over the next 3 years. 
 
Who is being asked to take part in this research study? 
You are being asked to participate because you are a female LTC resident, 
age 65 or older, with osteoporosis or at risk for fracture. Approximately 514 
female LTC residents will be eligible to take part in the research study. 
Participants will be randomly assigned (by chance, a 50-50 chance 
such as with flipping a coin) to either Zoledronic Acid 5mg IV 
(Reclast®) or placebo (an intravenous solution containing no study 
drug). Of the 514 participants, 257 will receive the study drug and 257 will 
receive the placebo. All participants will receive calcium and vitamin D 
supplements. 
 
What procedures will be done for research purposes? 
If you decide to take part in this research study, the study visits will be done 
at your facility where you will go through some procedures that are not part 
of your standard medical care. The screening visit that you already had 
done determined that you are eligible to take part in this research study 
which will involve 5 study visits over the next 3 years, plus up to 6 
safety checks before and after your yearly dose of zoledronic acid 
5mg IV (Reclast®) or placebo. We will obtain your written informed 
consent before any research study procedures are done. If you would like 
to take part but are not able to make decisions alone, we will obtain written 
informed consent from your legal guardian (the person legally responsible 
for your care) with your agreement. 
 
 
Baseline / Randomization Visit 
This visit will take a total of approximately 1 ½ hours of your time and will 
 
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involve the following procedures which may occur over several days: 
1. Brief physical exam (blood pressure, pulse, temperature). 
2. You will be asked about changes in your health since the screening 
visit and if you have had any broken bones or falls since then. 
3. Approximately 4 teaspoons of blood will be drawn from your arm for 
tests that measure your bone health. A sample of your blood will be 
frozen and saved for later testing and for possible future tests which 
may include research on aging, function, bone and muscle health, 
and overall health. 
4. If you are able to take acetaminophen (Tylenol®) (i.e. if you have no 
liver abnormalities), you will be given acetaminophen (two 500 mg 
tablets, to be taken by mouth) 1 hour before the IV infusion and then 
every 6 hours for the next 72 hours to manage possible flu-like 
symptoms such as fever. 
5. Individual single packets of Biofreeze® may also be made available 
to you (at no cost to you) if needed to manage possible muscle aches 
and pains following the infusion. The ointment may be rubbed onto 
the skin up to 2 times per day for 2-3 days. 
6. You will receive IV study drug [zoledronic acid 5 mg IV 
(Reclast®) or placebo]. The study drug infusion will be given by a 
nurse or physician’s assistant who is a member of the research team. 
This requires a small catheter (a thin tube) be placed in a vein in your 
arm using a needle. The study drug IV solution will be given through 
the IV catheter. There is approximately ½ cup of solution which will 
be given over approximately 60 minutes. After the infusion is 
complete, the IV catheter will be removed. This IV study drug is given 
yearly including at baseline, Month 12, and Month 24. 
7. You will receive calcium and vitamin D supplements as needed 
based on your dietary calcium questionnaire to achieve the Institute 
of Medicine and National Osteoporosis Foundation recommended 
calcium of approximately 1200 mg/daily (divided dose from diet or 
supplement) taken at meals and vitamin D (at least 800 IU/daily). 
 
Monitoring/Follow-up Procedures 
Procedures done for your safety and to check how well the study drug 
works and whether or not you have any side effects are called “monitoring” 
or “follow-up” procedures. You will have brief safety checks done up to 2 
days prior to receiving the annual IV study drug and 1-3 days after. A 
member of the research team will visit you to do a safety check up to 2 
days prior to the infusion when samples of blood (approximately 4 tsp.) 
 
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will be drawn from your arm for safety measures. Another safety check will 
be done 1-3 days after the study drug infusion, when a member of the 
research team will make a telephone call to check on how you are feeling. 
 
Months 12, 24, and 36 
Visits at Months 12, 24, and 36 will each take a total of approximately 3-4 
hours of your time and will involve the following procedures which may 
occur over several days: 
1. At months 12, 24, and 36: Brief physical exam (blood pressure, 
pulse, temperature). 
2. At months 12, 24, and 36: You will be asked about changes in your 
health since your previous visit and if you have had any broken bones 
or falls since then. 
3. At months 12, 24, and 36: You will have blood tests for safety 
checks. Blood will also be saved and frozen for tests of bone health 
and for possible future testing which may include research on aging, 
function, bone health, and overall health. No more than approximately 
4 teaspoons of blood will be drawn at each of these study visits. 
4. At Months 12, 24 and 36: Bone density test of your spine (front and 
side, and trabecular bone score [TBS] which is an indicator of bone 
strength), hip (total hip) forearm, and total body. This bone density 
test, known as a DXA scan, uses a special low-radiation x-ray 
machine. This will inform us about your bone health and the amount 
of muscle and fat in your body, and it will also include vertebral 
fracture assessment (VFA) to show if any of the small bones in your 
spine are broken. For the DXA procedure, you will be asked to lie on 
a padded table for a total of approximately 50 minutes. You will need 
to lie still for several minutes at a time while the arm of the machine 
passes over these body regions to measure the thickness of your 
bones. For the DXA scan of your wrist, you will sit in a chair with your 
arm on the table for approximately 10 minutes. 
5. At Months 12, 24 and 36: You will be asked some questions about 
your daily activities, energy level, your ability to do physical 
tasks, and about your thinking ability (remembering words, 
identifying objects, following instructions), mood, outlook and recent 
falls. This information will be gathered using questionnaires. 
6. At months 12, 24 and 36: We will test your grip strength, balance 
and physical ability and your ability to do routine daily tasks 
such putting on a sweater. You may be asked to do things like get 
up from a chair or walk down a hallway. 
 
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7. At months 12 and 24: If you are able to take acetaminophen 
(Tylenol®) (i.e. if you have no liver abnormalities), you will be given 
acetaminophen (two 500 mg tablets, to be taken by mouth) 1 hour 
before the IV infusion and then every 6 hours for the next 72 hours to 
manage possible flu-like symptoms such as fever. Biofreeze® single 
packets may also be made available to you (at no cost to you) if 
needed to manage possible muscle aches and pains following the 
infusion. The ointment may be rubbed onto the skin up to 2 times per 
day for 2-3 days. 
8. At months 12 and 24: You will receive IV study drug [zoledronic 
acid 5 mg IV (Reclast®) or placebo]. This requires a small catheter 
(a thin tube) be placed in a vein in your arm using a needle. The 
study drug IV solution will be given through the IV catheter. There is 
approximately ½ cup of solution which will be given over 
approximately 45 minutes. After the infusion is complete, the IV 
catheter will be removed. 
 
Possible Repeat Tests 
It is possible that the blood tests performed as part of the research study 
procedures may need to be repeated. Due to the fragile nature of the 
samples, which must be transported back to the UPMC Clinical Laboratory 
for processing, the specimens may deteriorate or become damaged 
despite the best precautions. These repeat blood tests would be done at 
your LTC facility by the research staff as soon as possible after the need 
for retesting became known. The risks remain the same as outlined in the 
risks section of this consent form; however, repeat testing would increase 
the total amount of blood drawn for that study visit’s tests to approximately 
8 teaspoons. 
 
What will happen to your blood samples? 
Your blood samples and any components of your cells not used for the 
tests listed above may be frozen and stored indefinitely for possible future 
research, which may include research on aging, function, bone health, and 
overall health. These samples will be labeled with a unique code to de- 
identify them, and the de-identified samples may be available to secondary 
investigators not listed on the consent form. 
 
Participants in this research study may experience the following 
risks: 
• Risks of the Study Drug. As with any drug, there may be adverse 
 
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events or side effects that are currently unknown, and it possible that 
certain of these unknown risks could be permanent, serious, or life- 
threatening. 
Zoledronic Acid (Reclast®): 
 
The most common side effects are fever; pain in your bones, joints or 
muscles; pain in your arms and legs, and headache. 
 
Other side effects include flu-like symptoms (fever, chills, bone, joint, 
or muscle pain, fatigue); nausea, vomiting, and diarrhea. The majority 
of flu-like symptoms occurs within 3 days following the dose of 
Reclast® and usually lasts about 3 days but can last up to 7-14 days. 
These temporary fever and flu-like symptoms can be treated with 
acetaminophen (Tylenol) to be taken every 6 hours, as needed, for 
72 hours following the IV study drug, for participants who are able to 
take acetaminophen. 
 
Allergic reactions, such as hives, swelling of your face, lips, tongue, 
or throat may occur. A rare side effect is eye inflammation. Serious 
and rare side effects can include: 
• Low calcium levels in your blood (hypocalcemia). The study 
doctor may prescribe calcium and vitamin D to help prevent low 
calcium levels in your blood while you take Reclast®. Take the 
calcium and vitamin D as your study doctor tells you to do. 
• Severe kidney problems. You should drink at least 2 glasses of 
fluid within a few hours before receiving Reclast® to reduce the 
risk of kidney problems. 
• Severe jaw bone problems (osteonecrosis). You should let your 
study doctor know if you are scheduled for a tooth extraction 
before receiving the study drug. It is important for you to 
practice good mouth care during treatment with Reclast®. 
• Unusual thigh bone fractures. Tell your study doctor if you have 
new or unusual pain in your hip, groin, or thigh. 
 
You should not receive Reclast® if you are already receiving 
Zometa® because both Reclast® and Zometa® contain zoledronic 
acid. Do not take Reclast® if you have low levels of calcium in your 
blood, have kidney problems, or have a history of allergic reaction to 
bisphosphonates (such as Fosamax® and Actonel®). 
 
 
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Placebo: Subjects in the placebo group will have the same risks as 
described in this risks section except for those associated with 
zoledronic acid (Reclast®) as described above. There is a potential 
risk for bone loss in not receiving the study drug, however you will 
receive calcium and vitamin D supplements which have been shown 
to reduce bone loss. If we find that you have significant bone loss 
during the study, you will be informed and appropriate treatment 
options will be discussed with you. You will be allowed to continue in 
the study for follow-up visits on a therapy chosen by your physician. 
 
Intravenous (IV) line placement: The risks of IV insertion may include 
pain, infection, inflammation of the vein (phlebitis), and IV fluid 
accidentally entering the surrounding tissue (infiltration). 
 
Acetaminophen: Common side effects include itchiness or rash, 
constipation, nausea, and vomiting. Serious side effects include liver 
failure. 
 
Biofreeze® : The main ingredients of this mild topical ointment are 
camphor and menthol. Get emergency medical help if you have any of 
these signs of an allergic reaction: hives; difficult breathing; swelling of 
your face, lips, tongue, or throat. Stop using and call us at once if you 
have severe burning, stinging, or irritation. 
 
Calcium and vitamin D supplements: Mild constipation from the calcium 
supplement occurs commonly. This may be eliminated by adding fiber to 
your diet. There are no known side effects for vitamin D when taken 
within the recommended daily allowance of up to 800 IU, or up to 4000 
IU daily. 
 
Participation in this research study will involve radiation exposure from 
the dual-energy x-ray absorptiometry (DXA) scans. You will have DXA 
scans of your spine (front and back, and TBS which is a measure of 
bone strength), vertebral fracture assessment (VFA), hip (total hip), 
forearm, and total body. If you complete all the DXA scans for the study 
as outlined above, the total radiation dose to your spine will be about 
240 mrems (an mrem is a unit of radiation). The radiation dose to your 
hip will be about 30 mrems. The radiation dose to your wrist will be 
about 15 mrems, and the radiation dose to your total body would be 
about 3 mrem. For comparison, these radiation doses are a very small 
fraction of the maximum annual whole body radiation dose (5000 
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mrems) permitted by federal regulation to adult radiation workers. There 
is no known minimum level of radiation exposure that is recognized as 
being totally free of the risk of causing genetic defects (cellular 
abnormalities) or cancer. However, the risk associated with the amount 
of radiation exposure from participation in this study is considered to be 
low and comparable to everyday risks. 
 
Blood draws: The risks and discomforts of having blood drawn may 
commonly include pain, feeling lightheaded or fainting, and the 
possibility of bruising or soreness at the site of the blood draw. In rare 
instances, infection at the site of the blood draw may occur. 
 
Walking and Balance tests: There is a risk of falling or of discomfort 
(pain) while doing the walking and balance tests. The study coordinator 
is trained to intervene to prevent a fall from happening. You can decline 
to do any of the balance or walking tests that you do not want to do or 
that you feel is too painful. To protect your privacy, these tests will be 
done in a private room except for the walking test, which will be done in 
a cleared hallway. 
 
There are possible benefits from taking part in this research study: 
Some direct benefits from taking part in this research study are that you will 
also be given calcium and vitamin D supplements, therapies that have 
been shown to help prevent bone loss and broken bones. However, there 
is no guarantee that you will receive such a benefit. This study involves a 
placebo group and participants assigned to the placebo group are expected 
to receive no direct benefit from the intravenous placebo infusion. You will 
also know the mineral content of your bones from your DXA results and the 
composition of your body in terms of percentage of muscle and fat. The 
knowledge gained from your part in this study may help people who have 
osteoporosis in the future, particularly LTC residents. 
 
What treatments or procedures are available if you decided not to 
take part in this study? 
You may choose not to participate in this research study and either 
continue your current health treatment plan or discuss other therapies with 
your physician. Evaluations and treatments for osteoporosis are available 
outside of this study. 
 
None of the tests or procedures done for research study purposes 
 
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will be billed to you or your health insurance (blood tests, DXA scans, 
calcium and vitamin D supplements, physical assessments and 
questionnaires, study drug). If you receive a bill or believe your health 
insurance has been billed for something that is part of the research study, 
notify the study coordinator as soon as possible. 
 
Other tests and procedures that would normally be done as part of your 
conventional care will be your responsibility and charged to you or your 
health insurance, in the standard manner, for services and procedures that 
are done as part of your routine care. Any deductible or copayments that 
are part of your insurance coverage will apply. 
 
 
Are participants paid for taking part in this study? 
You will not be paid for participating in this research study. You will receive 
a study lap blanket as a thank you gift after your randomization visit has 
been completed. 
 
 
If you believe that the research study procedures have resulted in an 
injury to you, immediately contact the Principal Investigator or Study 
Coordinator (see first page for contact info). Emergency medical 
treatment for injuries solely and directly related to your participation in this 
research study will be provided to you by the hospitals of UPMC. Your 
insurance provider may be billed for the costs of this emergency treatment, 
but none of these costs will be charged directly to you. If your research- 
related injury requires medical care beyond this emergency treatment, you 
will be responsible for the costs of follow-up care. At this time, there is no 
plan for any additional financial compensation. 
 
 
Will this research study involve the use or disclosure of my 
identifiable medical information? 
This research study will result in identifiable information that will be placed 
into your medical records held at UPMC and at the Osteoporosis 
Prevention and Treatment Center. The nature of the identifiable information 
resulting from your participation that may be recorded in your medical 
record includes DXA scan reports, past medical history, medications, lab 
values, physical exam, X-rays, dental exam reports, demographic 
information, questionnaires, physician order sheets, and progress notes 
 
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performed for research purposes and information related to any adverse 
events you may experience related to the study procedures. 
 
This research study will also involve the recording of past, current and/or 
future identifiable medical information from your hospital and/or other 
health care provider (e.g. physician office) records. Information that may be 
recorded from your medical records for research purposes includes 
medical history, medications, lab values, X-rays, dental exam reports, 
hospitalizations, physical exam reports, physician order sheets, progress 
notes, and information related to any adverse events experienced. 
 
To protect your privacy and maintain the confidentiality of information 
we obtain from you and from your medical records, we will keep all 
information about you in a secure location. All paper records that could 
identify you will be stored in a locked file cabinet, and all electronic records 
will be stored in password-protected files. Your identity on these records 
will be indicated by a case number rather than your name, and the code 
linking your name to this number will be maintained separately with very 
limited access by research team members. 
 
Although we will do everything in our power to protect your privacy and the 
confidentiality of your records, just as with the use of your medical 
information for health care purposes, we cannot guarantee the 
confidentiality of your research records, including information that we 
obtained from you medical records. 
 
In addition to the investigators listed on the first page of this consent 
document and their research team, the following individuals may have 
access to your identifiable medical information related to this 
research study: 
 
• UPMC hospitals may have access to identifiable information only for 
the purposes of (1) filling orders made by the researchers for hospital 
and health care services (e.g. laboratory tests) associated with the 
study, (2) addressing correct payment for tests and procedures 
ordered by the researchers, and/or (3) for internal hospital operations 
(e.g. quality assurance). 
• Authorized representatives of the University of Pittsburgh Research 
Conduct and Compliance Office may review your identifiable 
research information for the purpose of monitoring the appropriate 
 
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conduct of this research study. 
• Authorized representatives of the sponsor(s) of this research study 
(see page 2), such as outside laboratories assaying blood samples, 
may review and/or obtain identifiable information related to your 
participation in this study for the purposes of monitoring the accuracy 
and completeness of the research data and for performing requires 
scientific analyses of the research data. 
• In unusual cases, the investigators may be required to release 
identifiable information related to your participation in this research 
study in response to an order from a court of law. If the investigators 
learn that you or someone with whom you are involved is in serious 
danger or potential harm, they will need to inform the appropriate 
agencies as required by law. 
• Authorized representatives of the U.S. Food and Drug Administration 
(FDA) may review and/or obtain identifiable information related to 
your participation in this research study for the purpose of monitoring 
the accuracy of the research data. While the FDA understands the 
importance of maintaining the confidentiality of your identifiable 
research and medical information, the University of Pittsburgh and 
UPMC cannot guarantee the confidentiality of this information after it 
has been obtained by the FDA. 
 
According to University of Pittsburgh policy, all research records must be 
maintained for at least 7 years following the final reporting or 
publication of a project. 
 
Your doctor may be involved as an investigator in this research study, 
but you are not under any obligation to participate in any research 
study offered by your doctor. As both your doctor and a research 
investigator, s/he is interested both in your medical care and the conduct of 
the research study. Before agreeing to participate in this research study, or 
at any time thereafter, you may wish to discuss participation with another 
health professional that is not associated with the research. 
 
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will 
not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
Your participation in this research study is completely voluntary. You 
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may want to discuss this research study with your family and friends and 
your personal physician before agreeing to participate. If there are any 
words you do not understand, feel free to ask us. The investigators will be 
available to answer your current or future questions. Whether or not you 
participate will have no effect on your current or future relationship with the 
University of Pittsburgh, UPMC, or its affiliated health care providers or 
health insurance providers. 
 
If you decide you no longer wish to participate after you have signed 
the consent form, you should contact the principal investigator or the 
research coordinator (contact info on page 1). To formally withdraw your 
consent for participation, you should provide a written and dated 
notice of this decision to the principal investigator listed on the first 
page of this form. You may also withdraw, at any time, your authorization to 
allow the research team to review your medical records, but if you do so, 
you will no longer be able to participate in this research study. Any 
information obtained from you up to that point will, however, continue to be 
used by the research team. Your decision to withdraw from this research 
study will have no effect on your current or future relationship with the 
University of Pittsburgh or with UPMC or its affiliated health care and 
insurance operations. 
 
 
The investigators may withdraw you from the research study if they 
feel that you cannot complete the study requirements safely (for example, if 
you need other treatment, cannot undergo the study procedures, do not 
follow the investigators’ instructions, experience adverse events). You 
might also be removed from the research study for other medical or 
administrative reasons (for example, the research resources are no 
longer available or no longer funded by the research sponsor). We will 
notify you should this arise and advise you if there are available 
alternatives that may be of benefit at the time. 
 
 
****************************** 
 
 
VOLUNTARY CONSENT 
The above information has been explained to me and all of my current 
questions have been answered. I understand that I am encouraged to 
 
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ask questions about any aspect of this research study during the course of 
this study, and that any future questions, concerns, or complaints will be 
answered by a qualified member of the research team listed on the first 
page of this consent document at the telephone numbers given. I 
understand that I may always request that my questions, concerns or 
complaints be addressed by a listed investigator. At any time I may also 
contact the Human Subjects Protection Advocate at the IRB Office, 
University of Pittsburgh (toll-free at 1-866-212-2668) to discuss problems, 
concerns, and questions; obtain information; offer input; or discuss 
situations in the event that the research team is unavailable. By signing 
this form I agree to participate in this research study and allow the 
use and disclosure of my medical record information for the purposes 
described above. A copy of this consent form will be given to me. 
 
 
 
Participant’s Signature 
Date 
 
 
 
Participant’s Name (Print) 
 
 
The above-named individual is unable to provide direct consent for study 
participation because 
 
 
 
Therefore, by signing this form, I give my consent for participation in this 
research study. 
 
 
 
Representative’s Name (Print) 
Representative’s Relationship to 
Participant 
 
Representative’s Signature 
Date 
 
 
 
Witness Signature 
Date 
 
 
VERIFICATION OF EXPLANATION: 
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I certify that I have carefully explained the purpose and nature of this 
research study to the above-named participant in appropriate language. 
He/she has had an opportunity to discuss it with me in detail. I have 
answered all his/her questions and he/she has provided affirmative 
agreement (i.e., assent) to participate in this study. 
 
 
 
 
Investigator’s Signature 
Date (Time if placed in medical 
record) 
 
CERTIFICATION OF INFORMED CONSENT: 
I certify that I have explained the nature and purpose of this research to the 
above individual and/or their proxy representative, and I have discussed 
the potential benefits and possible risks of study participation. Any 
questions the individual has about this study have been answered, and we 
will always be available to address future questions as they arise. I further 
certify that no research component of this protocol was begun until after 
this consent form was signed. 
 
 
 
Printed Name of Person 
Role in Research Study 
Obtaining Consent 
 
 
 
Signature of Person Obtaining Consent 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Prot_000.pdf: 
Page 1 of 8 
 
Study Protocol  
 
 
 
 
 
 
Official Title: Zoledronic Acid for Osteoporotic Fracture Prevention 
(ZEST II) 
  
 
 
ClinicalTrials.gov ID (NCT number): NCT02589600 
 
 
 
Protocol Date: 3/30/2023 
 
 
 
 


Page 2 of 8 
 
Scientific Background 
 
Impact of Osteoporosis and Fractures in Long-Term Care Residents: 
Osteoporosis is devastating, particularly for the elderly. Each year 250,000 Americans suffer a 
hip fracture, of whom 20% die in the subsequent year, 25% are institutionalized, and ≤50% fully 
recover. Because the fastest-growing segment of the U.S. population is women >85 years, and 
1/3 of those who fracture are over age 90, the number of patients with hip fractures will double 
in the next 15 years (1,2) and the current annual cost of $17 billion will double by 2040 (3). 
Osteoporosis’ impact for America’s 2 million long-term care (LTC) residents is even more 
dramatic, with a prevalence of 85% (4) and an 11% annual incidence of nonvertebral fractures. 
Such residents were hospitalized ≥15 times as often as those without fracture (5) and those with 
hip or vertebral fractures are at 2-3x greater risk for future fracture (6,7). A vertebral fracture is 
associated with back pain (8-11), decreased mobility, increased bed rest (12), and higher rates 
of hospitalization and mortality (13,14). A recent review of 60,000 nursing home patients 
reported that following a hip fracture, 36% died and 53% died or developed new total 
dependence in 6 months (15). 
 
Osteoporosis Therapy in the Elderly: 
Osteoporosis Therapy is Safe and Efficacious in Healthy Elderly: The PI reported on the first 
prospective, randomized, placebo-controlled, multi-center trial of daily bisphosphonate therapy 
in healthy LTC residents (16). At 2 years, spine and femoral neck bone density had increased 
by 4.4% and 3.2%, respectively, with the bisphosphonate alendronate. This study demonstrated 
that daily alendronate was safe, well-tolerated, and improved bone mass in independent, 
ambulatory, cognitively intact women, able to take a daily oral bisphosphonate by themselves. 
The study excluded women with multiple medical problems, limited mobility, cancers, cognitive 
impairment, or diseases that impact bone and did not address the question if such therapy was 
safe or efficacious in institutionalized elderly. 
Post-hoc pivotal trial subgroup analyses comparing those >75 to those <75 years suggest 
zoledronic acid (17), teriparatide (18) and denosumab (19) are efficacious in older very healthy 
women who qualify for a clinical trial. These trials only included women who were healthy, 
cognitively intact, fully ambulatory, and able to sign their own consent. Fracture reduction data 
in frail elderly are lacking. 
 
Osteoporosis Therapy in Frail Elderly may not be Clinically Effective: 
There are little data on frail elderly or non-healthy LTC residents (20,21). In addition, the limited 
available data questions the efficacy of bisphosphonate in frail elderly. For example, in the HIP 
study, fracture reduction was not demonstrated with an oral bisphosphonate in women over age 
80 enrolled based on clinical risk factors only (22). Furthermore, the PI’s ZEST study in frail LTC 
residents, demonstrated improvement of BMD at the hip and spine with zoledronic acid, 
however no fracture reduction trend was observed. The majority of these patients were 
cognitively impaired, sedentary and had multiple comorbid conditions, excluding them from an 
industry trial. Fracture reduction data are lacking in these vulnerable patients. The March 2011 
NIH/ASBMR Forum on Aging and Skeletal Health echoed the critical need for osteoporosis 
research, a fracture reduction study and treatment for frail LTC residents (23). 
 
Why would therapy fail in frail elderly? Both skeletal and nonskeletal factors in frail elderly may 
mask a fracture reduction benefit from a potent bisphosphonate. Despite the improvement in 
bone density and reduction in bone turnover (both independent contributors to fracture 
reduction), frail individuals may not benefit due to severely compromised skeletal integrity from 
poor trabecular connectivity (disconnected rods and plates), increased trabecular fragments, 


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perforations in trabecular and cortical bone, impaired microstructure, or unhealed stress 
fractures (24-27). This concept was hypothesized by Parfitt (28,29). Bisphosphonates can’t 
reconnect broken fragments. Alternatively, nonskeletal factors may contribute to lack of benefit 
including minimal mobility (less weight bearing) or short life expectancy (too short to see a 
benefit), in addition to other factors such as increased falls (27). Our previous ZEST 1 study was 
not powered to examine fracture reduction. However, neither the limited statistical power nor the 
point estimates observed can be used to infer that fracture reduction would or would not be 
seen in a larger study (30); strong computational evidence suggests that only a fracture 
reduction study will suffice. Based on our data demonstrating a positive impact on both bone 
mass and bone turnover, we believe a fracture reduction study is justified and essential. 
 
Study Objectives 
 
Primary Outcome: 
Effectiveness of fracture reduction will be demonstrated by total non-traumatic incidental 
fractures (vertebral and nonvertebral [identified by x-ray, CT, MRI, VFA imaging) except those 
viewed as severe trauma (fall from a height higher than a stool or chair or severe trauma other 
than a fall), cancer-related or fractures of the toes, finger or facial bones. Incident morphometric 
vertebral fractures will be defined using the Genant criteria (134) as a reduction in vertebral 
height of at least 20% by quantiative morphometry or by an increase of one severity grade or 
more on semiquantitative analysis (134, 135). We will be able to assess primary outcome in all 
randomized women, optimally obtaining partial data in terms of person months of exposure and 
corresponding counts of fractures for analysis from those expiring/dropping out/moving before 3 
years. 
 
Secondary/Exploratory Outcomes: 
(1) New nonvertebral fractures 
(2) New vertebral fractures 
 
Other Secondary/Exploratory Skeletal Outcomes: 
(1) Hip and Spine BMD 
(2) Trabecular bone score (TBS) 
(3) Markers of bone turnover (CTX and P1NP) 
 
Laboratory Safety Outcomes: 
(1) H&H 
(2) Serum Calcium 
(3) Albumin 
(4) Alkaline phosphatase 
(5) Serum 25 OH Vitamin D 
(6) eGFR 
 
Adverse Events Outcomes: 
(1) All and serious adverse events, both by MedRA category and any-event basis 
(2) All and serious acute phase adverse events ≤3 days from an infusion 
(3) Special attention to falls, atrial fibrillation, stroke and symptomatic hypocalcemia 
 
 


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Study Design & Methods 
 
This is a 3-year, randomized, double-blind, calcium and vitamin D controlled trial with the 
antiresorptive agent zoledronic acid (Reclast). 
 
The study consists of 5 main visits (Screening, Randomization, Month 12, Month 24, and Month 
36), with pre and post infusion safety check visits. Pre-infusion safety check visits will be done 
up to 2 weeks prior to receiving the annual IV study drug or placebo. Post-infusion safety check 
visits will be done 1-3 days after infusion. 
 
We have chosen yearly intravenous zoledronic acid because it has been shown to significantly 
reduce vertebral fractures by 70%, all clinical fractures by 35%, hip fractures by 41% in the 
pivotal trial that included older healthy women. Additionally, in a sub-analysis including women ≥ 
75 years old, yearly zoledronic acid decreased vertebral fractures by 66% over 3 years. 
Moreover, fracture reduction after 2 and 3 infusions were 47% and 39%, respectively. Because 
nursing home patients are difficult to treat and resources are limited, the intravenous injection 
has several advantages. It does not require fasting, administration at a specific time of day, or 
sitting up, which are all significant practical advantages over a weekly oral bisphosphonate. All 
patients without liver abnormalities will be offered acetaminophen prior to the infusion and for 2 
days post-infusion to decrease acute phase reactions and maintain the blind. 
 
Rationale for yearly dose versus single dose: Despite the improvement in density over 2 years 
after a single dose in our initial ZEST study, we will follow conventional yearly dosing that 
demonstrated fracture reduction in the pivotal trials. In the event we do not find a fracture 
reduction benefit, we wanted to be certain that it would not be due to under-dosing. 
 
At the request of the DSMB, we will be offering a Follow-up Extension phase to this study to 
continue data collection on the skeletal health of participants in the ZEST II study. Therapy and 
blood work will not be provided throughout the follow-up extension. There will be a maximum of 
three visits in the follow-up extension. The number of visits that a participant will have can be 
determined by when they have completed their Month 36 visit. Participants who have completed 
the Month 36 visit on or before July 31, 2019 will have three follow-up visits. Participants who 
have completed the Month 36 visit on or before July 31, 2020 will have two follow-up visits. 
Participants who have completed the Month 36 visit on or before July 31, 2021 will have one 
follow-up visit. Participants who do not complete the Month 36 visit before August 1, 2021 will 
not be eligible to participate in the follow-up extension. 
 
SKELETAL ASSESSMENTS 
 
Fragility Fractures: From baseline to the end of follow-up, nonvertebral and clinical vertebral 
fractures will be identified by the electronic medical record alert and by Theradoc (a real-time, 
stand-alone clinical alert and decision support application used at UPMC LTC facilities, with 
custom rules to be written for this study to provide detection and identification of participants 
presenting to any UPMC facility so that generated alerts will be sent to the study team via e-
mail). In addition, participants/charts will be queried at approx. 6 month intervals for clinical 
fragility fractures defined as a fracture following a fall from a standing or sitting height. All 
reported fractures will be verified by obtaining the radiology report confirming the fractures. We 
exclude fingers, toes, face, and skull fractures. All femur fractures will be examined for atypical 
fractures using ASBMR criteria (128). 


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Vertebral Fractures: We will use the presence of thoracic or lumbar vertebral fractures as 
determined by Vertebral Fracture Assessment (VFA is DXA-derived) as the primary 
classification of vertebral fracture performed annually (53, 73, 129). The fractures will be scored 
according to the method of Genant (130, 131) and considered a grade 1 mild vertebral 
deformity, a grade 2 moderate vertebral deformity, or a grade 3 severe vertebral deformity. We 
will assess vertebral fractures at baseline, 12, 24, and 36 months, as well as at follow-up visits 
1, 2, and 3. Conventional x-rays or a MRI that demonstrates a fracture will also be used. 
Indices of Bone Mineral Metabolism: Serum will be assayed for 25-hydroxyvitamin D2/D3 for the 
secondary aim. We will collect serum for bone turnover markers at baseline and M36 for 
responder analysis for the exploratory aim (60, 65-67, 132, 133). To assess bone resorption, we 
will measure serum CTX. We will assess bone formation with P1NP. Serum will be archived for 
future analyses. 
 
Trabecular Bone Score (TBS): TBS, a new gray-level texture measurement is evaluated in the 
same region of interest as the spine BMD using the iNsight Software version 1.9 (54-58). TBS 
utilizes the 2-D DXA spine images and provides 3-D microarchitectural images and parameters 
(57, 59). The precision for TBS ranged from 1.1 to 1.9% (55). In previous studies, TBS was 
independent of BMD for fracture prediction and significantly improved risk protection (80, 81). 
TBS is only minimally affected by sclerosis/osteoarthritis (57). For the exploratory aim, we will 
examine TBS from DXA images. 
 
Eligibility Criteria  
 
Inclusion Criteria:  
Our goal is to include older women with osteoporosis or low bone mass (with fracture 
risk) unless there is a known contraindication to therapy. We will enroll ambulatory 
women age ≥65 years including those using assistive devices to maximize 
generalizability, if they: 
1) Reside in long-term care (LTC) including Managed Senior Communities which 
provide the following: (a) An environment engineered to prevent falls (handrails, ramps) 
and are ADA accessible; (b) Facilitate access to medical attention (pull cords, life-alerts, 
or other electronic means); (c) ADA accessible transportation services available; (d) 
Provide or coordinate meals; (e) Secure building (automatically locked door or buzzer 
system, security cameras). 
2) Have a) osteoporosis by axial bone density (spine, hip or forearm BMD T-score ≤ -
2.5 SD)(99,100); or b) a previous adult fragility fracture of the spine or hip; or, c) would 
be treated based on FRAX (101,102) NOF treatment thresholds of a 10 year risk of ≥ 
20% for a major osteoporotic fracture or ≥ 3% for hip fracture using femoral neck BMD 
(103). 
 
Follow-up Extension Inclusion Critera: 
1) Complete Month 36 Visit on or before July 31, 2021. 
Exclusion Criteria:  


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We will exclude: 
1) Men because osteoporosis is less common in men and our initial ZEST 1 study only 
included women. 
2) Institutionalized women with subacute illnesses surviving or discharged in < 3 years. 
3) Women currently on bisphosphonate, denosumab, or teriparatide therapy or who 
have been on a bisphosphonate for greater than 1 year during the previous 2 years 
because bisphosphonates are long acting (104). 
4) Patients with a calculated creatinine clearance < 35 ml/min (105,106) or who have a 
contraindication for bisphosphonates (allergy, hypocalcemia). 
5) Women scheduled for a tooth extraction to avoid jaw osteonecrosis (107-109). 
 
We will screen with a detailed history, chart review, and baseline laboratory analyses. 
Women with vitamin D levels <25 ng/mL (110,111) will be treated with vitamin D 50,000 
IU/wk for 8 weeks (112,113). The patient will be enrolled if the follow-up vitamin D level 
is ≥ 25 ng/mL. Vitamin D levels <25 ng/mL are associated with falls (114,115) and our 
prior ZEST 1 Study data supports a level ≥ 25 ng/mL for better performance and 
improved walking (98). Patients can continue on glucocorticoids and anticonvulsants 
because their use is common (116). Women on raloxifene, calcitonin or using protective 
hip pads will be allowed to participate. 
 
Exclusion Criteria #3, #4, and #5 will not apply to participants in the Follow-up Extension 
phase of this study. 
Statistical Considerations 
 
Overview: All statistical analyses will use SAS® version 9 (SAS Institute, Inc., Cary, North 
Carolina) based on intention-to-treat. First, appropriate descriptive statistics will be computed 
and graphical summarizations made for all variables for each treatment group for each time 
point as well as raw and percent change scores from baseline to obtain an overall sense of the 
distributional characteristics, missing values and general data quality. Second, baseline 
measures will be compared across arms using independent samples t- and a Wilcoxon rank 
sum tests, as appropriate, for continuous variables and chi-square and Fisher’s exact tests, as 
appropriate, for categorical variables. Although no significant differences are expected due to 
randomization and large sample size, any variables found to be significantly different will be 
accounted for by including them as covariates in sensitivity analyses. Third, main analyses will 
be performed using a negative binomial regression model. Finally, exploratory analyses will be 
performed. 
 
Main Analyses: First, we will fit a series of negative binomial regression implemented in the 
SAS® GENMOD procedure with each fracture outcome as the dependent variable; duration of 
follow-up as an offset to account for each participant's exposure; treatment arm as the main 
independent factor of interest; and any covariates deemed important as additional independent 
variables in sensitivity analyses. The incident rate ratio and its statistical significance at α=0.05 
level for the primary outcome of all new fractures will serve as a formal test of the main fracture 
reduction hypothesis (H1). Second, we will fit a series of linear mixed models using the SAS® 
MIXED procedure with raw and percent change each from baseline in each of the continuous 
outcomes representing laboratory measures related to safety as the dependent variable; 
treatment arm, follow-up time point (12-/24-/36-month, as available) and their interaction as the 


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fixed effects of interest; and a subject random effect. For some measures, we will fit simpler 
models (due to only one planned post-infusion assessment) using the GLM procedure with raw 
and percent change each as the dependent variable, and treatment arm as the main factor of 
interest. We will appropriately construct sets of contrasts to test various hypotheses of interest 
by comparing the said change over time between the two arms. Third, we will fit a series of 
logistic regression models using the SAS® LOGISTIC procedure with each incident 
dichotomous adverse event during the 36-month follow-up (any and specific types of adverse 
events) as the dependent variable, and treatment arm as the independent factor of interest. The 
resulting odds ratios and levels of significances will be used to test the specific hypotheses for 
Aim 2. We will repeat all main analysis after stratification by institutional setting (assisted 
living/nursing home). 
 
Findings from the proposed trial will be most useful if (a) we can also identify a target sub-
population of the long-term care that is most likely to benefit from zoledronic acid and/or least 
likely to experience side effects; and (b) we can speculate whether fracture reduction or non-
reduction in women, despite improvement in BMD, depends on bone microstructure as 
measured by TBS. Therefore, using several techniques, some with an exploratory data mining 
philosophy, we will identify such sub-populations to address Aim 3(a). First, we will include all 
baseline clinical and laboratory characteristics, one-at-a-time, as an additional fixed effect in the 
models above, along with an interaction term with treatment group. Statistical significance of the 
interaction term will be interpreted as a patient baseline characteristic whose levels exhibit 
potentially differential treatment effects and/or safety profiles. Second, we will stratify analyses 
by such baseline criteria to actually obtain preliminary estimates of subgroup-specific treatment 
effects/safety differences. Third (data mining), using only the active arm, we will fit a series of 
logistic regression models using the SAS® LOGISTIC procedure and classification tree models 
using Salford Predictive Miner® software (Salford Systems, Inc., San Diego, California) with 
incident fracture as the dichotomous response variable; and baseline characteristics as 
predictors. Logistic models are more efficient when associations are linear, and hard-to-discover 
higher order interactions and non-linearity and/or multicollinearities among predictors do not 
exist, while classification tree models are more efficient when they do exist. Thus we will use 
both methods to obtain areas under the receiver operator characteristic curve (AUROCC) to 
quantify predictive accuracy, and use the results from the method with a greater AUROCC. For 
logistic regression we will use the backward elimination and for classification trees minimum 
misclassification-complexity cost tree to guard against overfitting. We will use the method of 
DeLong to obtain statistical significance of the differences in predictive accuracy between the 
models. For predicting improvements in continuous BMD change outcomes, we will employ a 
similar approach but with standard multiple linear regression and regression tree models and 
proportion of explained variance (R2) to quantify predictive accuracy. 
 
For Aim 3(b), the association between zoledronic acid, BMD, TBS and fracture reduction will be 
explored in two ways. First, we proposed above to examine the effect of the study drug on TBS 
with standard linear models. Second, using only the active arm of the trial, we will fit a negative 
binomial model with number of fractures within 3 years as the dependent variable; and baseline 
BMD, 3-year change in BMD, baseline TBS, and 3-year change in TBS as independent 
variables. The statistical significance of regression coefficients for TBS measures will be 
interpreted as evidence supporting that fractures over a 3-year period depend on TBS and its 
changes over the same period independent of BMD. 
 
Exploratory Analyses: We will perform exploratory analyses to assess the robustness of results 
and make more refined conclusions. For example, we will stratify adverse event and fracture 


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analyses to identify any differences between short- and long-term effects and/or within organ 
systems. 

SAP_001.pdf: 
 
 
Study Statistical Analysis 
 
 
 
 
 
 
Official Title: Zoledronic Acid for Osteoporotic Fracture Prevention 
(ZEST II) 
  
 
 
ClinicalTrials.gov ID (NCT number): NCT02589600 
 
 
 
Document Date: 3/30/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
All statistical analyses will use SAS® version 9 (SAS Institute, Inc., Cary, North Carolina) based on 
intention-to-treat. First, appropriate descriptive statistics will be computed and graphical 
summarizations made for all variables for each treatment group for each time point as well as raw and 
percent change scores from baseline to obtain an overall sense of the distributional characteristics, 
missing values and general data quality. Second, baseline measures will be compared across arms using 
independent samples t- and a Wilcoxon rank sum tests, as appropriate, for continuous variables and chi-
square and Fisher’s exact tests, as appropriate, for categorical variables. Although no significant 
differences are expected due to randomization and large sample size, any variables found to be 
significantly different will be accounted for by including them as covariates in sensitivity analyses. Third, 
main analyses will be performed using a negative binomial regression model. Finally, exploratory 
analyses will be performed.