Clinical trial NCT00904033
Conditions: Breast Neoplasms Bone and Bones
Sponsor: University of Rochester
Start date: 2008-12-01; Completion date: 2018-01-01
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
Both the calcitriol and exercise interventions are aimed at reducing fracture risk by maintaining proper bone density, thereby preventing osteoporotic/osteopenic conditions and increasing muscle mass. Both calcitriol and exercise are efficacious in maintaining proper bone health and muscle mass among the general population, but little research has been done on breast cancer patients and survivors. The combination of calcitriol and exercise, which function through different but similar mechanisms, could produce interactive effects in reducing fracture risk among breast cancer survivors.

Hypothesis: A combination of calcitriol along with a structured home-based walking and progressive resistance exercise program will be efficacious in preventing bone resorption and in increasing bone formation among survivors of invasive breast cancer.

Detailed description:
Primary Objective

To collect data on the efficacy and feasibility of a supplementation of calcitriol with/without an accompanying structured home-based walking/progressive resistance exercise program for improving bone health among breast cancer survivors.

Secondary Objectives

To collect data on the efficacy and feasibility of a supplementation of calcitriol with/without an accompanying structured home-based walking/progressive resistance exercise program for increasing strength among breast cancer survivors.

To collect data on the efficacy and feasibility of a supplementation of calcitriol with/without an accompanying structured home-based walking/progressive resistance exercise program for improving skeletal muscle mass among breast cancer survivors.

Arms: arm 1: Multivitamin used as control group. arm 2: Exercise consisting of progressive walking and resistance band training. arm 3: Calcitriol pill taken once per week. arm 4: Calcitriol pill taken once per week plus Exercise consisting of progressive walking and resistance band training.
Interventions: intervention 1: Calcitriol intervention 2: Exercise intervention 3: Multivitamin
Intervention descriptions: intervention 1: Calcitriol tablet taken once per week. intervention 2: Exercise consisting of progressive walking and resistance band training intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
UNIVERSITY OF ROCHESTER CANCER CENTER 
 
 
 
 
 
 
A Pilot Study of the Effects of High-Dose Oral Calcitriol and Physical Activity  
on Bone Health in Breast Cancer Survivors 
 
 
 
 
 
 
 
 
 
 
STUDY CHAIR:   
 
Luke J. Peppone, Ph.D. 
 
 
 
 


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Study Schema ................................................................................................................. 3 
1.0  Background .............................................................................................................. 4 
2.0  Objectives .............................................................................................................. 11 
3.0  Subject Eligibility .................................................................................................... 11 
4.0  Treatment Assignment ........................................................................................... 13 
5.0  Treatment Protocol ................................................................................................. 15 
6.0  Treatment Evaluation ............................................................................................. 25 
7.0  Statistical Considerations ....................................................................................... 29 
8.0  Records to be Kept ................................................................................................. 31 
9.0   Patient Consent and Peer Judgment ..................................................................... 32 
10.0  References ........................................................................................................... 32 
 
 
 




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structured home-based walking/progressive resistance exercise program 
for improving bone health among breast cancer survivors.  
 
 
Secondary Objectives 
 
To collect data on the efficacy and feasibility of a 12-week 
supplementation of calcitriol 45 μg with/without an accompanying  
structured home-based walking/progressive resistance exercise program 
for increasing strength among breast cancer survivors.  
 
To collect data on the efficacy and feasibility of a 12-week 
supplementation of calcitriol 45 μg with/without an accompanying  
structured home-based walking/progressive resistance exercise program 
for improving skeletal muscle mass among breast cancer survivors.  
 
The primary analyses will consist of calculating mean change scores (i.e., baseline 
assessment minus final assessment) and standard deviations for both NTx and BAP.  In 
addition, a paired-sample t-test will be used to calculate the differences between the 
baseline and end of trial values for both BAP and NTx. 
 
 
1.0  Background 
 
1.1  Incidence and Survival Rate for Invasive Breast Cancer 
Breast cancer is, by far, the leading type of cancer among women in the United 
States, with an estimated 182,460 new cases in 2008 alone.1  In addition to the 
incident cases of invasive breast cancer, 62,000 cases of cancer in situ will be 
diagnosed.2  In 2008, breast cancer will claim the lives of 40,480 American 
women, which represents 15% of the total cancer deaths.3  In the United States, 
approximately 17% of breast cancer patients are under the age of 50 
(premenopausal) at time of diagnosis, while the remaining 83% of patients are 50 
years of age or older.4  The incidence rate for estrogen receptor positive (ER+) 
breast cancer is approximately 190 per 100,000 women, but the incidence rate for 
estrogen receptor negative (ER-) breast cancer is about 4 times less at 47 cases per 
100,000 women.  Overall, over 70% of all breast cancers display some sort of 
estrogen receptor activity.5  The mortality rate for breast cancer is lower than that 
for other cancer sites, with an overall 5-year survival of 89% for all stages of 
breast cancer and 98% for localized breast cancer.2  Due to the decreasing 
mortality rate of cancer, there are more than 10 million cancer survivors in the 
United States alone and more than 2 million breast cancer survivors.6, 7  Because 
many of these survivors do not succumb to cancer, other health problems, such as 
bone loss, have become a concern. 
 


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1.2  Bone Health Complications in Breast Cancer Patients 
We propose to conduct an efficacy and feasibility pilot of breast cancer patients 
studied over 12 successive weeks to determine whether breast cancer patients can 
safely participate in a high-dose oral calcitriol (a vitamin D analog) intervention.  
Additionally, we will evaluate the influence of the intervention on bone health 
biomarkers.  Recently, the American Cancer Society joined the Canadian Cancer 
Society, along with 6 other health groups, in urging more vitamin D research.8  
Numerous studies have demonstrated that proper supplementation with vitamin D 
and its main analog (calcitriol) can improve bone health in a wide variety of 
populations.  The majority of trials have focused on post-menopausal women, 
who are generally at higher risk for bone loss.  Peri-menopausal women lose 3%-
5% of their bone mass annually, while postmenopausal women lose 
approximately 2% of their bone mass annually, compared with just 0.5% annual 
loss in men.9, 10  Progressive bone loss can lead to osteoporosis, a skeletal disorder 
characterized by diminished bone strength.  Women with this condition are 
predisposed to increased risk of fracture, and this disorder can result in suffering 
and functional decline for the individual and drain health-care resources.11   
 
Treatment for various types of cancer can have deleterious effects on bone health.  
A 1990 study was one of the first to demonstrate that those who were treated for 
breast cancer had lower bone mineral density compared to women without cancer 
of similar age.12  Other studies have shown that both pre and postmenopausal 
women treated for breast cancer have a significantly lower bone mineral density 
than women of similar age without breast cancer.13-15  Increased rates of bone loss 
and osteoporosis lead to increased fracture risk for many breast cancer survivors.  
A study from the Women’s Health Initiative found that survivors of breast cancer 
were more likely to suffer an osteoporosis related fracture compared to women 
with no history of cancer.16  A 1999 study in the British Journal of Cancer found 
that women with breast cancer were almost 5 times more likely to suffer a fracture 
than healthy controls.17  The study also found women were more than 6 times 
more likely to suffer a fracture than controls.  This evidence demonstrates that 
breast cancer survivors are more likely to have bone loss and fractures compared 
to women with no history of breast cancer. 
 
 
In 2004, there were an estimated 10 million American women with osteoporosis 
and an addition 34 million women with its precursor, osteopenia.18  The effects of 
osteoporosis can be devastating.  Every year, hip fractures are responsible for 
300,000 hospitalizations.19  Studies have shown that up to 25% of the elderly who 
fracture a hip die within one year.20  Over 30% of survivors will be permanently 
disabled, and approximately 20% of survivors will need long-term care in a 
nursing home.21-24  The cost attributed to hip fractures can exceed $80,000 per 
person and costs the United States between $13 and $25 billion annually, along 
with 550,000 years of lost life.25 


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1.3  Calcitriol and Bone Health 
Calcitriol could prove to be a safe, low-cost treatment for preserving bone health 
in breast cancer patients.  Human beings obtain Vitamin D from sunlight, food, 
and supplementation.26  Vitamin D plays a vital role in maintaining proper bone 
health and works in conjunction with calcium.  Higher levels of vitamin D have 
been shown to increase the intestinal absorption of calcium.27  One study 
demonstrated that an increase in serum vitamin D produced a 45%-65% increase 
in intestinal absorption of calcium.28  Although no consensus exists on optimal 
vitamin D levels, most experts agree a 25-hydroxyvitamin D level of less than 20 
ng per milliliter is deficient.29  Based on this level, it is estimated more than 1 
billion people worldwide and between 40%-100% of elderly U.S. residents are 
vitamin D deficient.30-33  More than 50% of postmenopausal women already under 
treatment for osteoporosis have deficient vitamin D levels.34, 35   
 
Bone health is a major concern in women undergoing treatment and who have 
completed treatment for breast cancer.  Cancer-treatment-induced bone loss 
(CTIBL) is a long-term side-effect of various breast cancer treatments.36  
Chemotherapy, hormone therapy, and irradiation frequently lead, either directly or 
indirectly, to bone mass depletion in breast cancer patients.37  Studies have 
documented accelerated bone loss in breast cancer patients, and this bone loss 
frequently goes undiagnosed.38-40  Breast cancer survivors have greater bone loss 
than women of similar age who were not diagnosed with cancer.41-43  Risk factors 
for bone loss are already present in many women prior to a breast cancer 
diagnosis.44  Treating bone loss in a prophylactic manner leads to greater success 
than delayed treatment.45, 46   The Women’s Health Initiative (WHI) and other 


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studies have found that postmenopausal breast cancer survivors had increased risk 
of fractures.47,48, 49   
 
 
 
The American Society of Clinical Oncology (ASCO), however, recommends 
pharmaceutical interventions (bisphosphonates) only after a severe amount of 
bone loss in patients considered osteoporotic.50   Bisphosphonates produce a host 
of side effects, including poor GI absorption, nausea, and diarrhea for the oral 
medications.51 Fever, flu-like symptoms, and myalgia are seen in treatment with 
iv bisphosphonates.52  Among the most serious side-effects is osteonecrosis of the 
jaw, which can require surgical intervention.53, 54  All of these side-effects lead to 
poor compliance.  Studies have shown that compliance with bisphosphonate 
therapy is low, with 57% of patients considered non-compliant after 2 years.55 
 
While bone loss is a significant problem for breast cancer patients and 
pharmaceutical interventions result in less than ideal compliance, vitamin D and 
calcitriol supplementation could be an effective intervention for bone health.  A 
review of clinical trials found vitamin D supplementation had a positive effect on 
bone mineral density.56  Trials that used a low-dose vitamin D intervention (≤ 400 
IU/d) failed to significantly reduce bone fractures.57, 58  In contrast, interventions 
that used a higher dose of vitamin D (≥ 700 IU/d) produced significant positive 
effects on fracture prevention.59-63  A pooled analysis of those trials found vitamin 
D significantly reduced the risk of hip fracture by 26% and any nonvertebral 
fracture by 23%.64  Other interventions used the active vitamin D analog, 
calcitriol, because of its higher efficiency and quicker absorption.  These trials 
demonstrated calcitriol is effective in maintaining bone mineral density and 
reducing fractures.65-71  A pooled analysis revealed calcitriol interventions 
significantly reduced the rate for nonvertebral fractures by 48% and all fractures 
by 48%.  A comparative analysis found that calcitriol was significantly more 
effective at reducing bone loss and fractures than native vitamin D.72  A pooled 
analysis also concluded that vitamin D analogs (calcitriol) were more effective in 
preserving BMD than placebo, no treatment, plain vitamin D3 and/or calcium 


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alone.73 
 
In addition to regulating bone health, vitamin D also protects against falls and 
helps maintain muscular strength.74, 75  A meta-analysis of 5 randomized clinical 
trials reported a 22% reduction in falls in those receiving vitamin D 
supplementation.76  Similarly, calcitriol protects against falls.  One trial found 
those supplemented with calcitriol, in addition to having adequate calcium intake, 
had a 55% reduction in falls.77  A 2001 intervention trial reported a significant 
reduction in the number of falls for those treated with calcitriol compared to 
placebo.78  A recent comparative meta-analysis concluded that calcitriol was more 
effective at preventing falls than native vitamin D.79 
 
 
1.4  Calcitriol Dosing 
To date, the maximum tolerated dosage of 
vitamin D has not been clearly established.  
Many clinical trials have failed to produce 
protective bone health effects from vitamin D 
because the supplementation level was too 
low.80, 81  Some researchers have suggested that 
interventions should use high, intermittent 
doses of vitamin D to increase serum levels and 
overcome low adherence.82  Trials that 
supplemented with ≥ 700 IU/d of vitamin D 
were able to show protection against bone 
loss.83-87  In both North America and Europe, 
the upper limit for vitamin D intake is 
considered to be 2,000 IU/d.88, 89  However, 
many 
researchers, 
even 
government 
committees, believe numerous individuals are 
vitamin D deficient and this upper limit is too 
low.90-92  These recommendations were 
formulated out of concern for safety and to 
prevent toxicity such as hypercalcemia.93  
However, 
many 
clinical 
trials 
have 
administered vitamin D doses well above the 
upper limit.  One trial administered 100,000 IU 
of vitamin D every four months for five years 
without reports of toxicity.94  Another 
intervention administered 50,000 IU/d of 
vitamin D for a period of 8 weeks without a change in serum calcium.95  A long-
term trial was able to administer 18,000 IU/d (9 times higher than the upper limit) 
of vitamin D for a period of 5 years without evidence of adverse events.96  A review 
of these trials shows that vitamin D is not toxic at intakes much greater than 
previously considered unsafe.97 


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98 
 
The pattern is similar in terms of dosing for calcitriol.  Higher doses of calcitriol 
were typically not possible when given on a daily dosing schedule because of the 
development of hypercalcemia and hypercalcuria.99, 100  In recent years, 
researchers discovered that a less frequent dosing schedule allowed them to 
circumvent dose-limiting toxicities.101, 102  A weekly administration of high-dose 
oral calcitriol was shown to be safe in cancer patients.103, 104  The dosage was not 
limited by toxicities, but rather by nonlinear pharmacokinetics.105  Subsequent 
studies have shown substantial dose escalation was possible when calcitriol was 
administered once a week.106-113  Trump et al. were able to administer 12 μg of 
calcitriol daily for three consecutive days (36 μg/week) without any dose-limiting 
toxicities.114  A trial of prostate cancer patients found that 60 μg/week of calcitriol 
was well tolerated .115  Recently, 7 separate clinical trials were able to administer 
45 μg/week (or 0.5 μg/kg/week) of calcitriol to patients undergoing adjuvant 
cancer therapy.116-122  In the larger trials, participants remained on calcitriol for 
one year or longer.123, 124  These studies demonstrated that this dose was well 
tolerated, and adverse events were extremely rare.  In fact, a number of studies 
have demonstrated the safety of doses much greater than 45 μg/week.  A phase I 
study in patients with cancer found calcitriol was well tolerated at a dose of 165 
μg/week.125  Another phase I trial administered calcitriol at doses up to 38 μg/d 


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for three consecutive days (114 μg/week) without dose-limiting toxicity.126  These 
trials established intermittent oral dosing of calcitriol as a method of significant 
dose escalation and produced potentially therapeutic levels.127  Additionally, 
calcitriol enhances the effects of radiation, chemotherapy, hormone therapy, and 
other antineoplastic treatments.128-131  Based on previous trials, the 45 μg/week of 
calcitriol is an ideal dose to elicit positive effects and should pose only a minimal 
risk to the subject enrolled in this study.  Nonetheless, potential toxicities related 
to calcitriol will be closely monitored.  
 
1.5  Exercise and Bone Health 
Exercise and physical activity, in general, have beneficial effects on bone health.  
Several clinical trials demonstrate that various exercise interventions have 
positive effects on bone mineral density.132-138  These trials found that exercise 
was beneficial in postmenopausal women, who are those at the highest risk for 
osteoporosis.  A pooled analysis found a mean difference of 1.79 (p<0.01) in 
spinal bone mass density when an exercise intervention was compared to 
controls.139  In terms of specific exercises, walking interventions are effective in 
preventing bone loss.140-142  Interventions examining the effect of exercise on 
bone health in breast cancer patients have been limited.  Nevertheless, exercise 
interventions in breast cancer patients are also protective against bone loss.143, 144  
One single-arm clinical trial in breast cancer patients found a combination 
exercise and vitamin D had significant effects on bone health.145  In addition to 
the benefits of aerobic exercise on bone health, resistance training has also been 
shown to be effective.146-149  A pooled analysis revealed a weighted mean 
difference of 2.50 (p=0.02) in spinal bone density when resistance training was 
compared to placebo.139  The literature shows that improvements in bone mineral 
density for resistance training were greater with a higher resistance/lower 
repetition regimen in older populations.150-152  Therefore, it is recommended that 
women at higher risk for osteoporosis (e.g. breast cancer patients) train with 
higher resistance and fewer repetitions, which is the regimen that this protocol 
will follow.153  
 
1.6  Summary 
We propose to conduct a feasibility and efficacy pilot in breast cancer patients 
studied over 12 weeks to identify the ability to participate in a high-dose oral 
calcitriol and exercise intervention and to investigate the subsequent effects on 
bone health.  The study will accrue 54 patients and is intended to provide pilot 
data for a later grant submission.  The anticipated results could provide important 
information with clinical and methodological applications.  Acquiring a better 
understanding of treatments capable of preserving bone health in breast cancer 
patients could lead to a higher quality of life and functional independence for 
these survivors. 
 


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2.0  Objectives 
 
Both the calcitriol and exercise arms are aimed at reducing fracture risk by maintaining 
proper bone density, thereby preventing osteoporotic/osteopenic conditions and 
increasing muscle mass.  Both calcitriol and exercise are efficacious in maintaining 
proper bone health and muscle mass among the general population, but little research has 
been done on breast cancer patients and survivors.  The combination of calcitriol and 
exercise, which function through different but similar mechanisms, could produce 
interactive effects in reducing fracture risk among breast cancer survivors. 
 
Hypothesis: A combination of calcitriol 45 μg/week along with a structured home-
based walking and progressive resistance exercise program will be 
efficacious in preventing bone resorption, as defined by NTx level, and in 
increasing bone formation, as defined by BAP level, among survivors of 
invasive breast cancer. 
 
2.1 Primary Objective 
 
2.1.1  To collect data on the efficacy and feasibility of a 12-week 
supplementation of calcitriol 45 μg with/without an accompanying  
structured home-based walking/progressive resistance exercise program 
for improving bone health among breast cancer survivors.  
 
 
2.2 Secondary Objectives 
 
2.2.1 To collect data on the efficacy and feasibility of a 12-week 
supplementation of calcitriol 45 μg with/without an accompanying  
structured home-based walking/progressive resistance exercise program 
for increasing strength among breast cancer survivors.  
 
2.2.2  To collect data on the efficacy and feasibility of a 12-week 
supplementation of calcitriol 45 μg with/without an accompanying  
structured home-based walking/progressive resistance exercise program 
for improving skeletal muscle mass among breast cancer survivors.  
 
 
3.0  Subject Eligibility 
Inclusion Criteria: 
 
3.1 
Must be female. 
 
3.2 
Women of child-bearing potential (i.e. women who are pre-menopausal or not 


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surgically sterile) must use acceptable contraceptive methods (abstinence, 
intrauterine device (IUD), or double barrier device) and must have a negative 
serum or urine pregnancy test within 1 week prior to beginning treatment on this 
trial.  Contraceptive use needs to be continued at least 1 month after the trial has 
ended. 
 
3.3 
Must provide informed consent.  
 
3.4  
Must be willing to discontinue use of calcium and/or vitamin D supplements. 
 
3.5  
Participants must have an ionized serum calcium level within normal limits (1.19-
1.29mmol/L) and a total corrected serum calcium of < 10.2mg/dl. 
 
3.6 
Must have a functional capacity rating of ≤ 2 on the Eastern Cooperative 
Oncology Group (ECOG) performance status when assessed at baseline.154  
 
3.7 
Must have the approval of their treating physician (or physician’s nurse 
practitioner or physician’s assistant) to participate in sub-maximal physiological 
fitness testing and a low to moderate home-based walking and progressive 
resistance exercise program and to receive the 12-week supplementation of 
calcitriol 45 μg.  Participants assigned to either of the calcitriol treatment arms 
will be instructed to stop taking calcium and/or vitamin D supplements. 
 
3.8 
Must be less than five years from the diagnosis of breast cancer and have received 
chemotherapy, radiation therapy, and/or hormonal therapy.  Chemotherapy and 
radiation therapy, if received, must have been completed prior to study 
enrollment. Hormonal therapy may be ongoing. 
 
 
Exclusion Criteria: 
 
3.9 
Subjects with life-threatening conditions that would preclude them from breast 
cancer treatment including chronic cardiac failure, which is unstable despite 
medication use, uncontrolled hypertension, uncontrolled diabetes mellitus, or 
unstable coronary artery disease.   
 
3.10 
Patients who had a myocardial infarction within the past year. 
 
3.11 
Patients with severe metabolic disorders, which includes phenylketonuria (PKU), 
homocystinuria, and Fabry's disease, that would preclude them from taking 
calcitriol. 
 
3.12 
Patients with impaired renal function (CRCL < 60 mL/min) or who had kidney 
stones (calcium salt) within the past 5 years. 
 
3.13 
Patients with hypercalcemia (corrected serum Ca > 10.2 mg/dl) or a history of 


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hypercalcemia or vitamin D toxicity. 
 
3.14 
Patients currently taking calcium supplements or aluminum-based antacids must 
be willing to discontinue their use if they are to enroll in the study.   
 
3.15 
Patients currently taking vitamin D supplements must immediately discontinue 
their use if they are to enroll in the study.   
 
3.16 
Patients with a known sensitivity to calcitriol. 
 
3.17 
Women who are pregnant or lactating. 
 
3.18 
 
 
3.19 
 
 
3.20 
Patients not capable of participating in an exercise intervention due to severe knee 
arthrosis or ligament/cartilage injuries of the lower extremities. 
 
3.21 
Women currently using oral contraception. 
 
3.22 
Women with malabsorptive syndromes (i.e. cystic fibrosis, chronic pancreatitis) 
or taking medications that decrease the absorption of fat soluble vitamins (i.e. 
Orlistat, Questran). 
 
3.23 
 
 
 
 
 
4.0  Treatment Assignment 
 
4.1 
All patients who meet the eligibility criteria, sign the patient informed consent 
form, obtain physician consent, and complete baseline assessments will 
immediately be randomized to one of four treatment arms.  Randomization will be 
determined by means of a computer-generated random number table. 
 
4.1.1 This study will use a block-randomized scheme with block sizes of 8 to 
ensure an equal distribution among the four arms. 
 
4.1.2 A total enrollment of 72 patients is planned (18 in each treatment arm). 
 
4.1.3 Treatment sequence in the four trial arms will be as follows: 


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Treatment Arm  
 
Condition 
 
 
1 
 
 
Calcitriol 45 μg:  Patients will be given 45 μg/week of 
calcitriol beginning at baseline for a period of 12 weeks. 
 
2 
Home-Based Exercise:  Patients will be given a progressive 
walking and resistance band exercise treatment and a daily 
multivitamin for a period of 12 weeks. 
 
3 
Calcitriol 45 μg and Home-Based Exercise:  Patients will 
be given 45 μg/week of calcitriol along with a progressive 
walking and resistance band exercise treatment for a period 
of 12 weeks. 
 
4 
Usual Care:  A daily multivitamin plus standard care 
monitoring. 


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5.0  Treatment Protocol 
 
5.1 
This will be a four-arm clinical trial of an intervention examining the feasibility 
and efficacy of calcitriol 45 μg alone, a structured home-based 
walking/progressive resistance exercise program alone, along with the 
combination of calcitriol 45 μg and a structured home-based walking/progressive 
resistance exercise program for the maintenance of proper bone health among 
invasive breast cancer survivors.   
 
5.2 
Potentially eligible subjects at Strong Memorial Hospital will be approached by 
their physician either at a regularly scheduled oncology appointment or by 
standardized letter in the mail.  The initial contact will assess whether the patient 
has any interest in participating in a clinical trial to preserve bone health.  If 
interested, patients will be invited to call or come to our research center for 
screening to determine their eligibility for the study.  If the patient is eligible, 
study personnel will explain the details of the study and obtain informed consent 
from patients who agree to participate.  
 
5.3 
Consent Process and Initial Assessments 
 
5.3.1 Cancer survivors less than 5 years removed from the diagnosis of breast 
cancer who meet the eligibility criteria including approval from their 
physician will be invited to participate in the trial. 
 
Upon consent, with help from the study coordinator, the patient will 
complete an On-Study Data Form, a Clinical Record Form, and a 
Medication Form, providing clinical and demographic data.  Questions 
concerning the patient’s sun exposure history, medical history, supplement 
usage history, exercise history, and baseline brief symptom inventory are 
also included.  The study coordinator will obtain information necessary to 
complete these three forms from the patient’s medical records when the 
patient is unable to provide this information in sufficient detail (e.g., 
staging, Karnofsky Performance Scale, surgical procedures, types and 
doses of treatments).  Additionally, patients will be evaluated on vitals 
(Resting Heart Rate, Height, Weight & Blood Pressure), aerobic capacity 
(VO2max Treadmill Test and Resting Metabolic Rate (RMR) test) 
muscular strength (Handgrip Dynamometry and 7-10 repetition maximum 
test), skeletal muscle mass (Bioelectrical Impedance Analysis), and 
physical activity.  (Note: Baseline measures of physical activity involve 
fitting each participant with a Pedometer for a 5-day baseline assessment).  
Patients will also provide a blood sample at this time.  
 
5.3.2 Patients will be randomized to one of four treatment arms.  Study 
medication and instructions for calcitriol 45 μg will be given and reviewed 
with all patients.  Arm 2 and arm 3 patients will also receive instructions 
and an Exercise Kit for the home-based walking and progressive 


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resistance exercise program. 
 
5.3.2.1 Patients assigned to Treatment Arm 1 will receive a 12-week supply 
of calcitriol, which consists of twelve 45μg pills of calcitriol to be 
taken once a week (QW). 
 
5.3.2.2 Patients assigned to Treatment Arm 2 will receive a 12-week supply 
of daily multivitamins and a home-based walking and progressive 
resistance exercise regimen to follow for a total duration of 12 
weeks. 
 
5.3.2.3 Patients assigned to Treatment Arm 3 will receive a 12-week supply 
of calcitriol, which consists of twelve 45μg pills of calcitriol to be 
taken once a week (QW) and a home-based walking and progressive 
resistance exercise regimen to follow for a total duration of 12 
weeks. 
 
5.3.2.4 Patients assigned to Treatment Arm 4 will receive a 12-week supply 
of daily multivitamins but will not receive an exercise regimen to 
follow during the study period.   
 
 
 
 
5.4 
Physiological and Psychological Assessments 
 
5.4.1 Blood sampling at four time points (baseline, day 5, week 6, and week 12) 
will be done to estimate bone resportion and formation and as a safety 
check for hypercalcaemia.  Measures of bone pathology will be performed 
through the Associated Regional and University Pathologists (ARUP) 
Laboratories.  Pre and post-intervention tests for Cross-linked N-
teleopeptide of type I collagen (NTx), a specific indicator of bone 
resorption will be performed.  In addition, pre and post-intervention tests 
for bone-specific alkaline phosphatase (BAP), an indication of bone 
formation, will be performed. 
 
5.4.2 The blood draws for estimation of NTx and BAP will use 2 red top tubes 
for serum.   
 
5.4.3 All blood draws will occur in the General Clinical Research Center 
(GCRC) and the blood will be drawn by research personnel in the GCRC.  
The time of day will be noted, with future assessments at approximately 
the same time of day during post-testing and follow-up.   
 
5.4.4 All patients will be given a measure of physical activity (Aerobics Center 
Longitudinal Physical Activity Questionnaire (ACLS)), fatigue 


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(Functional Assessment of Chronic Illness Therapy Fatigue Subscale 
(FACIT-F); Brief Fatigue Inventory (BFI); Multidimensional Fatigue 
Symptom Inventory (MFSI)), QOL (Functional Assessment of Chronic 
Illness Therapy with Fatigue (FACIT-F)), to complete at home at the 
appropriate times (i.e. during baseline and post-testing).  (Note: Pilot use 
of the questionnaire packet indicates an average completion time of ≤ 30 
minutes). 
 
5.4.5 All patients will be evaluated on aerobic capacity (VO2max Treadmill 
Test), muscular strength (handgrip dynamometry, 7-10 repetition 
maximum test), gait (tandem walk test), and skeletal muscle mass 
(bioelectrical impedance).  All physiological fitness testing will be 
administered according to the Guidelines for Exercise Testing and 
Prescription (GETP) as outlined by the American College of Sports 
Medicine (ACSM).   
 
5.5 
Calcitriol 45 μg Arms 1 & 3 
 
5.5.1 The calcitriol 45 μg arms 1 & 3 will follow the guidelines listed below: 
 
5.5.1.1 The calcitriol 45 μg pills will be supplied by Roswell Park Cancer 
Institute and the State University of New York at Buffalo.  The 
pills will be placed in a tamper-proof blister pack.  Research 
subjects will be instructed to take the calcitriol on an empty 
stomach, 1 to 2 hours prior to or after any meal.  Subjects will also 
be advised to increase their intake of water by 4 cups on the day of 
taking the pill and the day after.  Subjects will take 1 capsule 1 day 
a week for a duration of 12 weeks.  Subjects will be supplied with 
the full 12 weeks of capsules that will be dispensed by the 
University of Rochester Medical Center pharmacy. 
 
5.5.1.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.5.1.3 The study coordinator will contact each subject on the day she is 
scheduled to take calcitriol 45 μg as a reminder. The study 
coordinator will use this opportunity to assess any potential 
complications or toxicities due to the intervention. 
 
5.5.1.4 Because of improved calcium absorption from the gastrointestinal 
tract caused by calcitriol, most participants may be maintained on a 
lower calcium intake.  Most patients on calcitriol require only 
dietary sources of calcium and need no supplementation.  
Therefore, participants must not take multivitamin or calcium 
supplementation while on the study medication.  In addition, 
ingestion of large amounts of foods containing dairy products 
should be avoided.  Participants assigned to calcitriol who are 
routinely taking a multivitamin supplement may continue the 
supplement as long as the amount of vitamin D in the supplement 
is not in excess of the RDA (recommended daily allowance) of 400 
IU or 10 μg.  If they are not taking a multivitamin supplement, 
they will be asked to not start supplementation while on study. 
 
5.5.2 Toxicity Monitoring: 
 
After the first dose of calcitriol is administered on day 0, the patients will 
return for blood collection on day 5.  On day 5, any patient displaying any 
grade ≥ 3 toxicity related to the study drug will be removed from the 
study.  The patients will return at 6 weeks and 12 weeks for blood 
collection.  These visits will be coordinated with surgical oncology visits, 
medical oncology visits, or radiation oncology visits, when possible, to 
reduce patient burden.  Following her appointment, the patient will 
proceed directly to phlebotomy. 
 
Removal from study:  Patients will be removed from the study for any of 
the following reasons: 
 
1. Any grade ≥ 3 toxicity related to the study drug. 
2. A grade 2 toxicity that persists for more than 2 weeks. 
3. Withdrawal of consent. 
 


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For any clinically adverse event, the toxicity grading scale established by 
the FDA will be used.  It is as follows: 
 
Grade 1 toxicity (Mild): No interference with activity 
Grade 2 toxicity (Moderate): Some interference with activity not requiring 
medical intervention. 
Grade 3 toxicity (Severe): Prevents daily activity and requires medical 
intervention. 
Grade 4 toxicity (Potentially Life Threatening): ER visit or hospitalization. 
 
For hypercalcemia, the FDA toxicity grading scale specific to serum 
calcium will be used: 
 
Grade 1 toxicity (Mild): 10.3-11.0 mg/dL 
Grade 2 toxicity (Moderate): 11.1-11.5 mg/dL 
Grade 3 toxicity (Severe): 11.6-12.0 mg/dL 
Grade 4 toxicity (Potentially Life Threatening): > 12.0 mg/dL 
 
The FDA toxicity grading scale will be used for determining all adverse 
events. 
 
In addition to blood safety checks throughout the study, a research 
coordinator will call each patient at on the day of the week she is 
scheduled to take calcitriol 45 μg to ensure compliance and assess side 
effects.  The nurse will record any adverse events (AE) and/or serious 
adverse events (SAE).  Any patient who reports an AE or SAE will be 
scheduled for a clinical visit.  In addition, the research coordinator will 
inquire as to any change in over the counter supplement usage.  Reports 
regarding potential toxicities, patient safety, and outcomes will be 
submitted to the University of Rochester Medical Center Research 
Subjects Review Board (RSRB).  The potential risks and side effects of 
calcitriol include:155 
 
Because calcitriol is the active analog of vitamin D, adverse effects are 
similar to those found with excessive vitamin D intake.  Because of the 
short biological half-life of calcitriol, elevated serum calcium levels 
normalize within a few days, much more quickly than with native vitamin 
D supplementation. 
 
Early signs and symptoms of vitamin D intoxication: Weakness, headache, 
somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone 
pain, metallic taste, anorexia, abdominal pain, or stomach ache. 
 
Late signs and symptoms of vitamin D intoxication:  Polyuria, polydipsia, 
anorexia, weight loss, nocturia, conjunctivitis, pancreatitis, photophobia, 
rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, 


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20 
albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic 
calcification, nephrocalcinosis, hypertension, cardiac arrhythmias, 
dystrophy, sensory disturbances, dehydration, apathy, arrested growth, 
urinary tract infections, and, rarely, overt psychosis. 
 
This protocol requests a Comprehensive Metabolic Profile (Panel 14) from 
the GCRC.  Of main concern is serum calcium, specifically 
hypercalcemia.  A serum calcium level between 8.4 and 10.2 mg/dL is 
considered normal.  Any level > 10.2 mg/dL or < 8.4 mg/dL is considered 
outside the safety range and the investigators should be notified. 
 
 
 
5.5.3 Adverse Events 
 
5.5.3.1 An adverse event (AE) is any untoward medical occurrence in a 
patient administered a pharmaceutical product, which does not 
necessarily have a causal relationship with the treatment.  An 
adverse event can be any unfavorable and unintended sign (eg, 
including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the drug, whether or not it is 
considered to be drug related.  This includes any newly occurring 
event or previous condition that has increased in severity or 
frequency since the administration of drug. 
 
5.5.3.2 A serious adverse event (SAE) is any adverse event, occurring at 
any dose and regardless of causality that: 
• Results in death. 
• Is life-threatening.  Life-threatening means that the patient was at 
immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction which hypothetically might have 
caused death had it occurred in a more severe form. 
• Requires inpatient hospitalization or prolongation of existing 
hospitalization.  Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned 
prior to study entry are not considered AEs if the illness or disease 
existed before the patient was enrolled in the trial, provided that it 
did not deteriorate in an unexpected manner during the trial (eg, 
surgery performed earlier than planned). 
• Results in persistent or significant 
disability/incapacity.  Disability is defined as a substantial 
disruption of a persons’ ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  An important medical event is an 
event that may not result in death, be life-threatening, or require 
hospitalization but may be considered an SAE when, based upon 
appropriate medical judgment, it may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent 


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one of the outcomes listed in the definitions for SAEs.  Examples 
of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug 
abuse.   
 
5.5.3.3 An unexpected adverse event is any drug experience, the 
specificity or severity of which is not consistent with the risk 
information described in the investigators brochure or general 
investigational plan (see section 5.91). Unexpected as used in this 
definition refers to an adverse drug event that has not been 
previously observed rather than from the perspective of such 
experience not having been anticipated from the pharmacological 
properties of the drug.  
 
 
5.5.4 Adverse Event Reporting 
 
 
University of Rochester Medical Center Reporting  - Serious adverse 
events that are associated with the study and occur while a subject is on 
study until 14 days after the date the subject goes off study must be 
reported in writing to the Strong Memorial Hospital IRB within 10 
working days. They are also reported to the Data Safety Monitoring 
Committee within the same time frame. Adverse events that are both 
unexpected fatal or life-threatening events must be reported 
immediately to the IRB. 
 
 
5.5.5 Data Safety Monitoring Plan 
 
 
Investigators will conduct continuous review of data and patient safety.  
The review will include for each treatment arm level:  the number of 
patients, significant toxicities as described in the protocol, dose 
adjustments, and responses observed.  The Investigator will submit twice 
yearly summaries of this data to the Clinical Trials Monitoring Committee 
for review.   
 
Clinical Trials Data Safety Monitoring Committee:  The Director of the 
Cancer Center delegates responsibility for continued review and 
monitoring of all clinical trials conducted by the URCC to the Clinical 
Trials Data Safety Monitoring Committee.  This committee provides 
oversight of study progress and safety by review of accrual and adverse 
events at annual meetings. Any adverse event requiring expedited review 
per protocol will be submitted to the Data Safety Monitoring Committee 
(DSMC) for determination as to whether further action is required.  The 
study PI and the study medical monitor determine if the adverse event 


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requires expedited review.  Interim meetings are scheduled, as needed, to 
address specific issues that require immediate attention to assure patient 
safety.   
 
 
 
The Committee:   
 
a) 
Reviews assigned clinical trials conducted at the URCC for progress and 
safety. 
 
b) 
Reviews all adverse events requiring expedited reporting as defined in the 
protocol. 
 
c) 
Reviews reports generated by the URCC data quality control review 
process. 
 
d) 
Submits recommendations for corrective actions to the Protocol Review 
Committee and the PI 
 
e) 
In general, outcome data is not made available to individuals outside of 
the DSMC until accrual has been completed and all patients have 
completed their treatment.  At this time, the DSMC may approve the 
release of outcome data on a confidential basis to the trial PI for planning 
the preparation of manuscripts and/or to a small number of other 
investigators for purposes of planning future trials.  Any release of 
outcome data prior to the DSMC’s recommendation for general 
dissemination of results must be reviewed and approved by the DSMC. 
 
 
 
 
 
 
 
Safety Coordinator:  The Medical Director of the Cancer Center Clinical Trials 
Office appoints the Safety Coordinator.  The Safety Coordinator monitors adverse 
event rates utilizing the URCC Clinical Trials database.  If any assigned study has 
had two or more of the same SAEs reported in a month or more than six of the 
same SAEs in six months, the DSMC will review the summary of SAEs, discuss 
events with the Study Chair, and conduct a more detailed review with the Study 
Chair.  The Data Safety Monitoring Chair will determine if further action is 
required. 
 
5.5.6 All study drugs will be dispensed and all biological specimens will be 
collected at the University of Rochester Medical Center. 
 
5.5.7 There will be no cost to the patient for the study medication, the 
pathological tests, blood tests, or bone health tests.  All costs will be paid 
from funds controlled by Dr. Gary R. Morrow within the James P. Wilmot 


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23 
Cancer Center. 
 
 
 
5.6 
Walking and Progressive Resistance Exercise Arms 2 & 3 
 
5.6.1 The Home-Based Walking and Progressive Resistance Exercise Program 
is designed by an Exercise Scientist certified by the American College of 
Sports Medicine (ACSM) and is in accordance with the guidelines for 
exercise testing and prescription as set forth by the ACSM.   
 
5.6.2 The Home-Based Walking and Progressive Resistance Exercise Program 
will follow the guidelines listed below. 
 
5.6.2.1 The Home-Based Walking Prescription will be based on a patient’s 
baseline pedometer assessment.  
 
 
 
 
 
 
 
5.6.2.2 The Home-Based Progressive Resistance Prescription will be 
based on a patient’s optimal level of challenge.  Patients will be 
instructed on the proper use of resistance bands. 
 
 
 
 
 
 
 
  
 
5.6.2.3 The study coordinator will talk with each patient on a 
weekly basis by telephone as a reminder to take calcitriol.  


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24 
He/she will also answer any questions the patient may have 
regarding the exercise program in order to facilitate proper 
adherence and compliance to the exercise intervention.   
 
5.6.3 All Walking and Progressive Resistance Exercises will be performed off-
site from the University of Rochester Cancer Center in a home-based 
patient-selected environment.   
 
5.6.4 There will be no costs to the patient for the physiological assessments (e.g. 
serum collection and muscular strength), resistance bands, pedometers, or 
Home-Based Walking and Progressive Resistance Exercise Prescription.  
All costs will be paid from funds controlled by Dr. Gary Morrow in the 
Behavioral Medicine Unit within the James P. Wilmot Cancer Center. 
 
5.7 
Commencement of a low to moderate walking and progressive resistance exercise 
program is not associated with any severe side effects and risks are minimal for 
individuals with no cardiopulmonary, orthopedic, or age-identified high risk 
factors as determined by the patient’s treating physician (or designee).  The 
chance of a cardiac event is rare once coronary disease has been excluded with 
reasonable certainty.  Approximately 1 death per 15,000-20,000 healthy men per 
year occurs during jogging; this risk is much lower in women.  A transient 
increase in blood pressure may occur with all types of exercise.  Although 
unlikely, the risks involved in a low to moderate walking and progressive 
resistance exercise program are musculoskeletal— possibly mild muscle soreness, 
a muscle strain, or related injuries such as tripping.  Overall, the risk level for 
participation in a low to moderate Home-Based Walking and Progressive 
Resistance program is minimal.  Risks associated with a 6-minute walk test are 
similar to participation in a low to moderate walking exercise program and are 
minimal for individuals with no cardiopulmonary, orthopedic, or age-identified 
high risk factors as determined by the patient’s doctor.  7-10 Repetition maximum 
tests for strength may cause minor stiffness and/or tenderness in muscles for a few 
days following testing.  The nature of these assessments will require a level of 
exertion causing temporary changes such as an increase in heart rate and blood 
pressure, both of which are normal responses to moderate exercise.  There is a 
small risk of irritation to the skin from the electrodes used for the BIA analysis.  
Lying under the canopy for resting metabolic testing creates a risk for some 
subjects to feel anxious or claustrophobic.  Every effort will be made to minimize 
the risks for all study procedures through the approval of the treating physician to 
enter the study, supervision of all testing and exercise prescription by an 
American College of Sports Medicine certified Health and Fitness Instructor or a 
physician (or physician’s designee) when necessary according to American 
College of Sports Medicine Guidelines, the use of standardized guidelines for 
exercise testing and prescription provided by the American College of Sports 
Medicine and resting metabolic rate testing and bioelectrical impedance analysis. 
Regarding the risks for resting metabolic testing, if patients feel claustrophobic 
during the resting metabolic test it will be stopped.  Electrodes will be removed 


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25 
immediately after the bioelectrical impedance test by the patient to minimize skin 
irritation.  Risks will also be minimized by following the documented and 
approved procedures for the tests that are performed in the NIH-funded and 
approved University of Rochester General Clinical Research Center, and trained 
staff will perform these tests. 
 
5.8 
Multivitamin Arm 
 
 
 
5.8.1 New Formula Centrum® 
   
Study participants assigned to arm #4 will receive a daily multivitamin and 
mineral supplement.  They will be instructed to take one (1) tablet of New 
Formula Centrum® (Wyeth Consumer Healthcare) daily for the duration of the 
intervention.  The supplement contains: Vitamin A 3500 IU (70% Daily Value 
(DV), Beta-Carotene 25 µg, Vitamin C 90 mg (150% DV), Vitamin D 10 µg 
(100% DV), Vitamin E 30 IU (100% DV), Vitamin K 25 µg (31% DV), Thiamin 
1.5 mg (100% DV), Riboflavin 1.7 mg (100% DV), Niacin 20 mg (100% DV), 
Vitamin B6 2 mg (100% DV), Folic Acid 500 µg (125% DV), Vitamin B12 6 µg 
(100% DV), Biotin 30 µg (10% DV), Pantothenic Acid 10 mg (100% DV), 
Calcium 200 mg (20% DV), Iron 18 mg (100% DV), Phosphorus 109 mg (11% 
DV), Iodine 150 µg (100% DV), Magnesium 100 mg (25% DV), Zinc 11 mg 
(73% DV), Selenium 55 µg (79% DV), Copper 0.9 mg (45% DV), Manganese 2.3 
mg (115% DV), Chromium 35 µg (29% DV), Molybdenum 45 µg (60% DV), 
Chloride 72 mg (2% DV), Potassium 80 mg (2% DV), Boron 150 µg, Nickel 5 
µg, Silicon 2 mg, Tin 10 µg, Vanadium 10 µg, Lutein 250 µg, and Lycopene 300 
µg.  Patients will be provided with the first 6 weeks worth of multivitamins at the 
start of the trial and the remainder of the multivitamins at the week 6 visit.  There 
are no dietary restrictions for participants assigned to this arm.  Participants 
assigned to this arm who normally use calcium supplementation are free to 
continue. 
6.0  Treatment Evaluation 
6.1 
Measures 
 
 
6.1.1 Bone health  
 
 
 
6.1.1.1 Levels of bone resorption will be measured by Cross-linked N-
teleopeptide of type I collagen (NTx).  NTx is a specific indicator 
of bone resorption.  It is generated from bone by osteoclasts as a 
degradation product of type I collagen, and it can easily be 
measured in urine or serum.  NTx is a valid and reliable measure of 
bone resorption.156  Researchers believe that markers of bone 
resorption are superior to markers of bone formation and more 
accurately predict changes in bone mass.157  Bone resorption 
markers are also able to predict failing bone health in advance of 
BMD.  Laboratory assay methods of NTx levels are well 


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26 
established and considered reliable.158 
 
6.1.1.2 Levels of bone formation will be measured by bone-specific 
alkaline phosphatase (BAP).  Bone formation markers, 
specificially (BAP), are also considered a valid measure of bone 
health.159, 160  Although BAP is a valid measure of bone health, 
measures of bone resorption tend to be better predictors of bone 
health.  Laboratory assay methods of BAP levels are well 
established and considered reliable.161 
 
 
6.1.2 Physical activity will be assessed subjectively using the Aerobic Center 
Longitudinal Study Physical Activity Questionnaire and questions on the 
daily journal.  In addition, objective assessments of physical activity will 
be obtained via the pedometer. 
 
 
6.1.2.1 The Aerobic Center Longitudinal Study Physical Activity 
Questionnaire (ACLS) is a measurement instrument that includes 
assessment of lifestyle physical activity.  The questionnaire 
requests that participants report their engagement (frequency, 
intensity and duration) in fourteen different physical activities over 
the last three months.  Estimates of energy expenditure are 
calculated using the following equation: (sessions/week) * 
(min/session)* (hour/min) * MET [Note: MET = metabolic energy 
expenditure rate] for each activity and then summed to provide 
total MET hours of energy expenditure for a week.  The index of 
walking, jogging, and running predicted treadmill performance 
time β = 0.31 and there is a moderate relationship between energy 
expenditure estimates and treadmill performance (r =0.41).  The 
accuracy and reliability of the ACLS has been previously 
demonstrated.162 
 
6.1.2.2 The Pedometer device will be used to assess duration of physical 
activity via steps walked during the time out of bed.  [Note: 
Participants NOT assigned to the exercise arm will give back their 
pedometer after the 5-day baseline measure and will have the 
pedometer reissued for the 5-day measure at the end of the trial.] 
 
6.1.2.3 The Daily Journal is designed to track daily physical activity.  
The participant will be asked to complete the journal each night 
immediately prior to sleeping and record steps and miles walked, 
caloric expenditure, and a Rating of Perceived Exertion. 
 
6.1.3 Aerobic capacity will be assessed using a VO2max Treadmill Test as a 
measure of compliance using a modified “Branching Treadmill Protocol”. 
Participants begin at a normal walking speed (2.5 mph) and 0% grade. 


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27 
After 2 min. the speed is increased to a faster walking speed (3.0 mph) and 
0% grade. After 2 min, the speed is increased to 3.5 mph and 2% grade. 
Thereafter, only the grade is increased by 2% every 2 min. Oxygen 
consumption (VO2), carbon dioxide production (VCO2), and flow rate 
will be measured continuously. The test is ended when the participant 
wants to stop. An MD is available onsite in the hospital during all tests as 
outlined by the ACSM fitness testing guidelines.  In preparation for the 
exercise treadmill test, subjects will be instructed to fast for 4 hrs prior to 
the test and they will be asked to rest quietly on a bed in a quiet room for 
30 minutes under a clear canopy which is placed over their head.  During 
this 30 minute period, they will have their resting metabolic rate measured 
for 30 minutes using continuous, computerized open-circuit indirect 
calorimetry (Sensormedics® Vmax).  A 6-Minute walking test may be 
substituted for the treadmill test in the event the person is not able to 
complete it.  This is a sub maximal measurement using a 6 minute walk 
protocol.  Participants are given a short warm up and cool down walking 
protocol in the test walking area in the University of Rochester.  
Participants walk for a total of 6 minutes and cover as much distance as 
they can during this time.  Upon completion of the test, the total distance 
walked is used to calculate an estimate of aerobic capacity 
(VO2max:Maximal Oxygen Consumption). 
 
6.1.4 Muscular fitness will be assessed using two measures: a handgrip 
dynamometer test and a 7-10 repetition maximum strength test. 
 
6.1.4.1 The Handgrip Dynamometer Test is a grip strength test used to 
assess the maximal voluntary contraction generated by the arm 
muscles.  The test is administered with the patient standing in 
anatomical position, the elbow joint angle will be held constant at 
180 degrees with the medial distal humeral epicondyl held 2 inches 
from the torso.  Trials will be performed in an alternating bilateral 
sequence for a total of six attempts (three with each arm).  The best 
score of the three trials will be used for right and left limbs to 
calculate static strength.  The surgically involved arm(s) will be 
noted for data analysis.  The handgrip dynamometer test has been 
previously used in a number of URCC CCOP protocols and has 
shown to be a reliable clinical method of assessing strength.163 
 
6.1.4.2 The standard 7-10 Repetition Maximum Dynamic Strength 
Testing Protocol will be used to estimate patients’ 1-repetition 
maximums for the leg extension (quadriceps) and bench press 
(pectoralis and deltoid). The patients will receive a full orientation 
to the fixed resistance machines and proper lifting form by a 
certified (ACSM) exercise testing professional.  Participants will 
perform a light warm up consisting of 8 lift repetitions employing 
the lightest weight on the machine.  After the warm up, patients 


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28 
will be given a 2-3 minute rest break.  A weight will be selected by 
the exercise testing staff based on the ease or difficulty of 
completing the warm up for each patient, and this weight will be 
lifted until subjective fatigue.  Alternating rest breaks (2-3 
minutes) and lifting bouts will continue with the resistance weight 
adjusted by the exercise testing staff until the patient reaches a 
level of resistance that results in subjective fatigue between 7-10 
repetitions.   Established algorithms employing the weight lifted 
and the number of repetitions completed will then be used to 
estimate the patients’ 1-repetition maximum.164  The 7-10 
Repetition Maximum Dynamic Strength Testing Protocol has been 
previously used in a number of URCC CCOP protocols and is used 
by ACSM as a method of assessing strength.165 
 
 
6.1.5 Skeletal muscle mass is assessed using the following measure: 
 
6.1.5.1 The RJL Bioelectrical Impedance System is a non-invasive, 
easy-to-administer and safe method of assessing lean body mass.  
BIA involves passing a small electrical current through the body 
and evaluating the reactance and resistance to flow, which are 
related to fat-free mass (FFM) and total body water.  Prediction of 
lean body mass from BIA is as reliable as skin-fold measurements 
and hydrostatic weighing.  Participants need to be 4-hours fasted, 
abstained from physical exercise for 12 hours, abstained from 
alcohol and diuretics (unless prescribed) for 48 hours, well 
hydrated (water only), and voided completely prior to assessment.  
Participants lie supine on a flat surface for approximately 5 
minutes prior to the test to ensure a resting metabolic state.  
Electrodes are attached to the right hand (distal end of the 3rd and 
4th metacarpal and distal end of the ulnar and radius) and the right 
foot (distal end of the 3rd and 4th metatarsal and distal end of the 
tibia and fibula).  Skeletal muscle mass will then be calculated 
from the lean body mass.166  BIA is considered an accurate and 
reliable test in determining skeletal muscle mass among the 
general population, including older adults.167-169 
 
6.1.6 For the resting metabolic rate, subjects will be instructed to fast for 4 hrs 
prior to the test, and they will be asked to rest quietly on a bed in a quiet 
room for 30 minutes under a clear canopy which is placed over their head.  
During this 30 minute period, they will have their resting metabolic rate 
measured for 30 minutes using continuous, computerized open-circuit 
indirect calorimetry (Sensormedics® Vmax). 
 
6.1.7 Gait and balance is assessed using the following measure: 
 
6.1.7.1 The Tandem Walk Test (TWT) is a non-invasive, easy-to-
administer, and safe method of assessing gait.  The TWT involves 


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29 
testing a woman’s ability to walk with the heel of her front foot 
touching the big toe of her rear foot.170, 171  The scores for this test 
are: 1=able to do four consecutive tandem steps; 2=unable to do 
four consecutive tandem steps without stepping off or touching the 
examiner’s arm; 3=unable or unwilling to put feet in tandem 
position. Women who use walking assistance and do not take the 
test will be assigned a score of 4.  
 
 
7.0  Statistical Considerations 
 
7.0 
Primary measures and analyses:  
 
 
7.0.1 Bone Resorption: NTX 
 
7.0.2 Bone Formation: BAP 
 
Since the primary objective of this pilot study is to gather preliminary efficacy 
and feasibility data for the development of a planned career development grant 
application, the primary analyses will consist of calculating mean change scores 
(i.e., baseline assessment minus final assessment) and standard deviations for the 
two variables above.  In addition, a paired-sample t-test will be used to calculate 
the differences between the baseline and end of trial value for both BAP and 
NTX.  An independent t-test will be used to calculate the difference between the 
baseline and end of trial value for both BAP and NTx between the trial arms.  
Lastly, ANCOVA models will be used for BAP and NTx with the addition of 
relevant covariates collected during the study.  Results of these two analyses will 
be interpreted cautiously because of the limited sample size.  
 
7.1 
Secondary measures and analyses: 
 
 
7.1.1 Physical Activity: ACLS and Pedometer 
 
7.1.2 Aerobic Capacity: VO2max Treadmill Test 
 
7.1.3 Muscular Fitness: Handgrip Dynamometer and 7-10 Repetition Maximum 
 
7.1.4 Muscle Mass: Bioelectrical Impedance Analysis 
 
  
7.1.5 Since the secondary aims relating to physical activity, aerobic capacity,  
muscular fitness, and muscle mass, respectively, are intended to gather 
preliminary efficacy data for the development of a planned K07 
submission, the secondary analyses will consist of calculating mean 
change scores (e.g., baseline assessment subtracted from the final 
assessment, and baseline subtracted from the follow-up assessment), 
standard deviations, and correlations on these variables for the two study 
arms. Additional exploratory analyses will use mixed effects models, to 
compare mean bone health within the four treatment arms during the 
intervention time and follow-up period of the study.  The mixed effects 




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31 
 
7.2.2 Based on a discussion with breast cancer clinicians at the University of 
Rochester Medical Center about patient volume and projecting an accrual 
rate of 50%, it will take approximately ten months to enroll 72 women. 
8.0  Records to be Kept  
 
 
8.1 
All hardcopy research records will be stored onsite in the University of Rochester 
Medical Center, in the Behavioral Medicine Unit of the James P. Wilmot Cancer 
Center.  The Cancer Center is secured by electronic key cards.  Offices within the 
Cancer Center are again secured by key and data is kept in locked file cabinets.  
Electronic research records are stored on the University of Rochester Medical 
Center’s password secured and firewall protected networks.  These are the same 
methods of security used for patient medical records.  Human serum samples and 
biopsy samples are stored in locked freezers, within locked and alarmed 
laboratories that are accessible by key codes and electronic card swipes.  All study 
data will be kept for a period of 10 years after the study and all reports and 
publications are complete.   
 
8.2 
All data (information, human blood samples, and human tissue samples) collected 
for the current study will be used in post hoc analyses as appropriate.  No blood or 
biopsy samples will be banked.  The patient is provided the opportunity to be 
contacted for future research studies in the informed consent.  The patient’s 
individual research record will not be shared with their treating physician, unless 
they provide consent or the patient’s treating physician is a study physician, in 
Schedule of Clinical Visits, Data and Specimen Collection 
Procedure
0
5 Days
6 Weeks 12 Weeks
Eligibility Interview
+
Informed Consent
+
Medical History
+
+
+
Assess Supplement Use
+
+
+
+
Blood CBC Levels
+
+
+
+
Serum 1, 25 OH2 D3 Levels
+
+
+
+
Bone Biomarkers
+
+
+
On Study Data (Demographics and Clincal Data)
+
+
Phone call reminders
Weekly
Weekly
Weekly
Weekly
Toxicity monitoring
+
+
+
+
Daily Diary
Daily
Daily
Daily
Daily
Functional Assessment of Chronic Illness Therapy (FACIT) (28-item 
QOL measure & 13-item fatigue subscale)
+
+
Brief Fatigue Inventory (BFI)  (Severity of fatigue and level of 
interference in activities of daily living - 9 items)
+
+
Symptom Inventory (13-item symptom rating scale)
+
+
VO2max Treatmill Test
+
+
Aerobic Center Longitudinal Study Physical Activity Questionnaire 
(ACLS) (15-item physical activity history measure)
+
+
Pedometer
+
+
Tandem Wallk Test (TWT)
+
+
Handgrip Dynamometer
+
+
7-10 Maximum Repetition
+
+
Bioelectrical Impedance Analysis
+
+
Time Since Randomization


RSRB #25478 
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32 
which case they will have access to study data as a study co-investigator.  Overall 
study results will be presented to participants, faculty and staff at the University 
of Rochester Medical Center after completion of the study.  Study results will be 
presented at professional meetings and published.   
 
8.3 
The study coordinator will assign a numerical Study ID to each participant once 
they have signed the consent form.  All study forms and questionnaires will use 
this number and the participant’s first, middle, and last initials as identifiers, to 
ensure data integrity.  Other identifying information will not exist on these forms.  
A complete list of study participants with study ID, name, and contact information 
will be maintained separately. This linkage information will only be accessible to 
the study coordinator, study investigators, and the individual responsible for 
maintaining the database. 
9.0   Patient Consent and Peer Judgment 
 
9.1 
Current, state, federal, and institutional regulations concerning informed consent 
will be followed.   
10.0  References 
 
Reference List 
 
 
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6.  Ganz PA. A teachable moment for oncologists: cancer survivors, 10 million strong and growing! J Clin 
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7.  Chen Z, Maricic M, Pettinger M et al. Osteoporosis and rate of bone loss among postmenopausal survivors of 
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8.  A call for more vitamin D research. CA Cancer J Clin 2006; 56(5):250-251. 
 
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RSRB #25478 
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33 
 
11.  Andersen SJ. Osteoporosis in the older woman. Clin Obstet Gynecol 2007; 50(3):752-766. 
 
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14.  Greep NC, Giuliano AE, Hansen NM, Taketani T, Wang HJ, Singer FR. The effects of adjuvant 
chemotherapy on bone density in postmenopausal women with early breast cancer. Am J Med 2003; 
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15.  Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone 
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16.  Chen Z, Maricic M, Bassford TL et al. Fracture risk among breast cancer survivors: results from the 
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17.  Kanis JA, McCloskey EV, Powles T, Paterson AH, Ashley S, Spector T. A high incidence of vertebral 
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28.  Heaney RP, Dowell MS, Hale CA, Bendich A. Calcium absorption varies within the reference range for 
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29.  Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, wson-Hughes B. Estimation of optimal serum 


RSRB #25478 
Amended 05/04/09 
34 
concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006; 84(1):18-28. 
 
30.  Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006; 
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31.  Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss 
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32.  Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet 1998; 351(9105):805-
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33.  O'Shea D, Carter GD. Hypovitaminosis D in medical inpatients. N Engl J Med 1998; 339(5):345-346. 
 
34.  Lips P, Hosking D, Lippuner K et al. The prevalence of vitamin D inadequacy amongst women with 
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35.  Holick MF, Siris ES, Binkley N et al. Prevalence of Vitamin D inadequacy among postmenopausal North 
American women receiving osteoporosis therapy. J Clin Endocrinol Metab 2005; 90(6):3215-3224. 
 
36.  Michaud LB, Goodin S. Cancer-treatment-induced bone loss, part 1. American Journal of Health-System 
Pharmacy 2006; 63(5):419-430. 
 
37.  Pfeilschifter J, Diel IJ. Osteoporosis due to cancer treatment: Pathogenesis and management. Journal of 
Clinical Oncology 2000; 18(7):1570-1593. 
 
38.  Chen Z, Maricic M, Pettinger M et al. Osteoporosis and rate of bone loss among postmenopausal survivors of 
breast cancer. Cancer 2005; 104(7):1520-1530. 
 
39.  Greep NC, Giuliano AE, Hansen NM, Taketani T, Wang HJ, Singer FR. The effects of adjuvant 
chemotherapy on bone density in postmenopausal women with early breast cancer. Am J Med 2003; 
114(8):653-659. 
 
40.  Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone 
loss in women with early-stage breast cancer. J Clin Oncol 2001; 19(14):3306-3311. 
 
41.  Hadji P. Reducing the risk of bone loss associated with breast cancer treatment. Breast 2007; 16 Suppl 3:S10-
S15. 
 
42.  Hadji P, Bundred N. Reducing the risk of cancer treatment-associated bone loss in patients with breast 
cancer. Semin Oncol 2007; 34(6 Suppl 4):S4-10. 
 
43.  Hu MI, Gagel RF, Jimenez C. Bone loss in patients with breast or prostate cancer. Curr Osteoporos Rep 
2007; 5(4):170-178. 
 
44.  Hadji P. Reducing the risk of bone loss associated with breast cancer treatment. Breast 2007; 16 Suppl 3:S10-
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45.  Brufsky A, Harker WG, Beck JT et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in 
postmenopausal women with early breast cancer. J Clin Oncol 2007; 25(7):829-836. 
 
46.  Gnant MF, Mlineritsch B, Luschin-Ebengreuth G et al. Zoledronic acid prevents cancer treatment-induced 
bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast 
cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 2007; 25(7):820-
828. 


RSRB #25478 
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35 
 
47.  Chen Z, Maricic M, Bassford TL et al. Fracture risk among breast cancer survivors: results from the 
Women's Health Initiative Observational Study. Arch Intern Med 2005; 165(5):552-558. 
 
48.  Kanis JA, McCloskey EV, Powles T, Paterson AH, Ashley S, Spector T. A high incidence of vertebral 
fracture in women with breast cancer. Br J Cancer 1999; 79(7-8):1179-1181. 
 
49.  Hadji P, Body JJ, Aapro MS et al. Practical guidance for the management of aromatase inhibitor-associated 
bone loss. Ann Oncol 2008. 
 
50.  Hillner BE, Ingle JN, Chlebowski RT et al. American Society of Clinical Oncology 2003 update on the role 
of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003; 21(21):4042-
4057. 
 
51.  Morris GJ, Mitchell EP. Bisphosphonate therapy for women with breast cancer and at high risk for 
osteoporosis. J Natl Med Assoc 2007; 99(1):35-45. 
 
52.  Conte P, Guarneri V. Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. 
Oncologist 2004; 9 Suppl 4:28-37. 
 
53.  Bamias A, Kastritis E, Bamia C et al. Osteonecrosis of the jaw in cancer after treatment with 
bisphosphonates: incidence and risk factors. J Clin Oncol 2005; 23(34):8580-8587. 
 
54.  Yarom N, Yahalom R, Shoshani Y, Hamed W, Regev E, Elad S. Osteonecrosis of the jaw induced by orally 
administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. 
Osteoporos Int 2007; 18(10):1363-1370. 
 
55.  Siris ES, Harris ST, Rosen CJ et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic 
women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc 
2006; 81(8):1013-1022. 
 
56.  Cranney A, Horsley T, O'Donnell S et al. Effectiveness and safety of vitamin D in relation to bone health. 
Evid Rep Technol Assess (Full Rep ) 2007;(158):1-235. 
 
57.  Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss 
and fractures and therapeutic implications. Endocr Rev 2001; 22(4):477-501. 
 
58.  Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI. Can vitamin D supplementation 
reduce the risk of fracture in the elderly? A randomized controlled trial. J Bone Miner Res 2002; 17(4):709-
715. 
 
59.  Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of calcium and cholecalciferol treatment for three 
years on hip fractures in elderly women. BMJ 1994; 308(6936):1081-1082. 
 
60.  Chapuy MC, Pamphile R, Paris E et al. Combined calcium and vitamin D3 supplementation in elderly 
women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II 
study. Osteoporos Int 2002; 13(3):257-264. 
 
61.  Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on 
bone density in men and women 65 years of age or older. N Engl J Med 1997; 337(10):670-676. 
 
62.  Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D 
and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone 
Miner Res 2000; 15(6):1113-1118. 


RSRB #25478 
Amended 05/04/09 
36 
 
63.  Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on 
fractures and mortality in men and women living in the community: randomised double blind controlled trial. 
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64.  Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, wson-Hughes B. Fracture prevention 
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65.  Aloia JF, Vaswani A, Yeh JK, Ellis K, Yasumura S, Cohn SH. Calcitriol in the treatment of postmenopausal 
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66.  Gallagher JC, Riggs BL, Recker RR, Goldgar D. The effect of calcitriol on patients with postmenopausal 
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67.  Gallagher JC, Goldgar D. Treatment of postmenopausal osteoporosis with high doses of synthetic calcitriol. 
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68.  Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the 
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69.  Sambrook P, Birmingham J, Kelly P et al. Prevention of corticosteroid osteoporosis. A comparison of 
calcium, calcitriol, and calcitonin. N Engl J Med 1993; 328(24):1747-1752. 
 
70.  Sambrook P, Henderson NK, Keogh A et al. Effect of calcitriol on bone loss after cardiac or lung 
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71.  Tilyard MW, Spears GF, Thomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or 
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72.  Richy F, Schacht E, Bruyere O, Ethgen O, Gourlay M, Reginster JY. Vitamin D analogs versus native 
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73.  de Nijs RN, Jacobs JW, Algra A, Lems WF, Bijlsma JW. Prevention and treatment of glucocorticoid-induced 
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74.  Bischoff HA, Stahelin HB, Dick W et al. Effects of vitamin D and calcium supplementation on falls: a 
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75.  Kenny AM, Biskup B, Robbins B, Marcella G, Burleson JA. Effects of vitamin D supplementation on 
strength, physical function, and health perception in older, community-dwelling men. J Am Geriatr Soc 2003; 
51(12):1762-1767. 
 
76.  Bischoff-Ferrari HA, wson-Hughes B, Willett WC et al. Effect of Vitamin D on falls: a meta-analysis. JAMA 
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77.  Dukas L, Bischoff HA, Lindpaintner LS et al. Alfacalcidol reduces the number of fallers in a community-
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78.  Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the 
prevention of age-related bone loss. J Clin Endocrinol Metab 2001; 86(8):3618-3628. 


RSRB #25478 
Amended 05/04/09 
37 
 
79.  Richy F, Dukas L, Schacht E. Differential effects of d-hormone analogs and native vitamin d on the risk of 
falls: a comparative meta-analysis. Calcif Tissue Int 2008; 82(2):102-107. 
 
80.  Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss 
and fractures and therapeutic implications. Endocr Rev 2001; 22(4):477-501. 
 
81.  Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI. Can vitamin D supplementation 
reduce the risk of fracture in the elderly? A randomized controlled trial. J Bone Miner Res 2002; 17(4):709-
715. 
 
82.  Bischoff-Ferrari HA. How to select the doses of vitamin D in the management of osteoporosis. Osteoporos 
Int 2007; 18(4):401-407. 
 
83.  Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of calcium and cholecalciferol treatment for three 
years on hip fractures in elderly women. BMJ 1994; 308(6936):1081-1082. 
 
84.  Chapuy MC, Pamphile R, Paris E et al. Combined calcium and vitamin D3 supplementation in elderly 
women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II 
study. Osteoporos Int 2002; 13(3):257-264. 
 
85.  Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on 
bone density in men and women 65 years of age or older. N Engl J Med 1997; 337(10):670-676. 
 
86.  Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D 
and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone 
Miner Res 2000; 15(6):1113-1118. 
 
87.  Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on 
fractures and mortality in men and women living in the community: randomised double blind controlled trial. 
BMJ 2003; 326(7387):469. 
 
88.  Elmadfa I, European Commission, Directorate-General for Health and Consumer Protection. European 
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89.  Institute of Medicine (, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. 
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for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, D.C: National Academy Press; 
1997. 
 
90.  Cranney A, Horsley T, O'Donnell S et al. Effectiveness and safety of vitamin D in relation to bone health. 
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91.  Vieth R. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical 
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92.  Vieth R. Vitamin D toxicity, policy, and science. J Bone Miner Res 2007; 22 Suppl 2:V64-V68. 
 
93.  Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr 2007; 85(1):6-18. 
 
94.  Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on 
fractures and mortality in men and women living in the community: randomised double blind controlled trial. 
BMJ 2003; 326(7387):469. 
 
95.  Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its major metabolites: serum 


RSRB #25478 
Amended 05/04/09 
38 
levels after graded oral dosing in healthy men. Osteoporos Int 1998; 8(3):222-230. 
 
96.  Hasling C, Nielsen HE, Melsen F, Mosekilde L. Safety of osteoporosis treatment with sodium fluoride, 
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97.  Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr 2007; 85(1):6-18. 
 
98.  Bischoff-Ferrari HA. How to select the doses of vitamin D in the management of osteoporosis. Osteoporos 
Int 2007; 18(4):401-407. 
 
99.  Gross C, Stamey T, Hancock S, Feldman D. Treatment of early recurrent prostate cancer with 1,25-
dihydroxyvitamin D3 (calcitriol). J Urol 1998; 159(6):2035-2039. 
 
100.  Rustin GJ, Quinnell TG, Johnson J, Clarke H, Nelstrop AE, Bollag W. Trial of isotretinoin and calcitriol 
monitored by CA 125 in patients with ovarian cancer. Br J Cancer 1996; 74(9):1479-1481. 
 
101.  Beer TM, Munar M, Henner WD. A Phase I trial of pulse calcitriol in patients with refractory malignancies: 
pulse dosing permits substantial dose escalation. Cancer 2001; 91(12):2431-2439. 
 
102.  Beer TM, Javle MM, Ryan CW et al. Phase I study of weekly DN-101, a new formulation of calcitriol, in 
patients with cancer. Cancer Chemother Pharmacol 2007; 59(5):581-587. 
 
103.  Beer TM, Munar M, Henner WD. A Phase I trial of pulse calcitriol in patients with refractory malignancies: 
pulse dosing permits substantial dose escalation. Cancer 2001; 91(12):2431-2439. 
 
104.  Beer TM, Lemmon D, Lowe BA, Henner WD. High-dose weekly oral calcitriol in patients with a rising PSA 
after prostatectomy or radiation for prostate carcinoma. Cancer 2003; 97(5):1217-1224. 
 
105.  Muindi JR, Potter DM, Peng Y, Johnson CS, Trump DL. Pharmacokinetics of liquid calcitriol formulation in 
advanced solid tumor patients: comparison with caplet formulation. Cancer Chemother Pharmacol 2005; 
56(5):492-496. 
 
106.  Beer TM, Hough KM, Garzotto M, Lowe BA, Henner WD. Weekly high-dose calcitriol and docetaxel in 
advanced prostate cancer. Semin Oncol 2001; 28(4 Suppl 15):49-55. 
 
107.  Beer TM. Development of weekly high-dose calcitriol based therapy for prostate cancer. Urol Oncol 2003; 
21(5):399-405. 
 
108.  Beer TM, Myrthue A, Garzotto M et al. Randomized study of high-dose pulse calcitriol or placebo prior to 
radical prostatectomy. Cancer Epidemiol Biomarkers Prev 2004; 13(12):2225-2232. 
 
109.  Beer TM, Javle M, Lam GN, Henner WD, Wong A, Trump DL. Pharmacokinetics and tolerability of a single 
dose of DN-101, a new formulation of calcitriol, in patients with cancer. Clin Cancer Res 2005; 11(21):7794-
7799. 
 
110.  Beer TM, Venner PM, Ryan CW et al. High dose calcitriol may reduce thrombosis in cancer patients. Br J 
Haematol 2006; 135(3):392-394. 
 
111.  Beer TM, Javle MM, Ryan CW et al. Phase I study of weekly DN-101, a new formulation of calcitriol, in 
patients with cancer. Cancer Chemother Pharmacol 2007; 59(5):581-587. 
 
112.  Beer TM, Ryan CW, Venner PM et al. Double-blinded randomized study of high-dose calcitriol plus 
docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the 
ASCENT Investigators. J Clin Oncol 2007; 25(6):669-674. 


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39 
 
113.  Tiffany NM, Ryan CW, Garzotto M, Wersinger EM, Beer TM. High dose pulse calcitriol, docetaxel and 
estramustine for androgen independent prostate cancer: a phase I/II study. J Urol 2005; 174(3):888-892. 
 
114.  Trump DL, Potter DM, Muindi J, Brufsky A, Johnson CS. Phase II trial of high-dose, intermittent calcitriol 
(1,25 dihydroxyvitamin D3) and dexamethasone in androgen-independent prostate cancer. Cancer 2006; 
106(10):2136-2142. 
 
115.  Beer TM, Javle MM, Ryan CW et al. Phase I study of weekly DN-101, a new formulation of calcitriol, in 
patients with cancer. Cancer Chemother Pharmacol 2007; 59(5):581-587. 
 
116.  Beer TM, Hough KM, Garzotto M, Lowe BA, Henner WD. Weekly high-dose calcitriol and docetaxel in 
advanced prostate cancer. Semin Oncol 2001; 28(4 Suppl 15):49-55. 
 
117.  Beer TM, Lemmon D, Lowe BA, Henner WD. High-dose weekly oral calcitriol in patients with a rising PSA 
after prostatectomy or radiation for prostate carcinoma. Cancer 2003; 97(5):1217-1224. 
 
118.  Beer TM, Javle M, Lam GN, Henner WD, Wong A, Trump DL. Pharmacokinetics and tolerability of a single 
dose of DN-101, a new formulation of calcitriol, in patients with cancer. Clin Cancer Res 2005; 11(21):7794-
7799. 
 
119.  Beer TM, Venner PM, Ryan CW et al. High dose calcitriol may reduce thrombosis in cancer patients. Br J 
Haematol 2006; 135(3):392-394. 
 
120.  Beer TM, Javle MM, Ryan CW et al. Phase I study of weekly DN-101, a new formulation of calcitriol, in 
patients with cancer. Cancer Chemother Pharmacol 2007; 59(5):581-587. 
 
121.  Beer TM, Ryan CW, Venner PM et al. Double-blinded randomized study of high-dose calcitriol plus 
docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the 
ASCENT Investigators. J Clin Oncol 2007; 25(6):669-674. 
 
122.  Tiffany NM, Ryan CW, Garzotto M, Wersinger EM, Beer TM. High dose pulse calcitriol, docetaxel and 
estramustine for androgen independent prostate cancer: a phase I/II study. J Urol 2005; 174(3):888-892. 
 
123.  Beer TM, Ryan CW, Venner PM et al. Double-blinded randomized study of high-dose calcitriol plus 
docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the 
ASCENT Investigators. J Clin Oncol 2007; 25(6):669-674. 
 
124.  Tiffany NM, Ryan CW, Garzotto M, Wersinger EM, Beer TM. High dose pulse calcitriol, docetaxel and 
estramustine for androgen independent prostate cancer: a phase I/II study. J Urol 2005; 174(3):888-892. 
 
125.  Beer TM, Javle M, Lam GN, Henner WD, Wong A, Trump DL. Pharmacokinetics and tolerability of a single 
dose of DN-101, a new formulation of calcitriol, in patients with cancer. Clin Cancer Res 2005; 11(21):7794-
7799. 
 
126.  Muindi JR, Peng Y, Potter DM et al. Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 
trial of calcitriol and paclitaxel. Clin Pharmacol Ther 2002; 72(6):648-659. 
 
127.  Beer TM, Myrthue A, Eilers KM. Rationale for the development and current status of calcitriol in androgen-
independent prostate cancer. World J Urol 2005; 23(1):28-32. 
 
128.  Anzano MA, Smith JM, Uskokovic MR et al. 1 alpha,25-Dihydroxy-16-ene-23-yne-26,27-
hexafluorocholecalciferol (Ro24-5531), a new deltanoid (vitamin D analogue) for prevention of breast cancer 
in the rat. Cancer Res 1994; 54(7):1653-1656. 


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40 
 
129.  Dunlap N, Schwartz GG, Eads D et al. 1alpha,25-dihydroxyvitamin D(3) (calcitriol) and its analogue, 19-nor-
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