Incorporating Nutrition, Vests, Education, and Strength Training in Bone Health (INVEST in Bone Health)
Phase: NA
Conditions: Weight Loss, Bone Health
Sponsor: Wake Forest University Health Sciences

Official Title:  Incorporating Nutrition, Vests, Education, and Strength Training in Bone Health (INVEST in 
Bone Health)
NCT04076618
Approval Date:  11/04/2022

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Study Title: Incorporating Nutrition, Vests, Education, and Strength Training in Bone Health (INVEST in 
Bone Health) 
 
Principal Investigator: Kristen M. Beavers, PhD 
 
Co-investigator(s): Barbara J. Nicklas, PhD, Daniel Beavers PhD, Leon Lenchik MD, Ashley A. Weaver PhD, 
and Jason Fanning, PhD 
 
Sponsor or funding source: National Institutes of Health 
 
Background, Rationale and Context 
The prevalence of obesity and its detrimental health effects are increasing rapidly among older adults.1–5 
Medical complications associated with excess fat mass highlight the need to treat obesity in this age group;6 yet, 
intentional weight loss (WL) remains controversial.7–10 Reluctance stems, at least in part, from loss of bone 
mineral density (BMD) known to accompany overall WL,11–21 and the potential exacerbation of age-related22,23 
risk of osteoporotic fracture11,24–28 - a leading cause of injury in older adults that significantly compromises both 
quality and expectancy of life.29–32 Importantly, BMD does not appear to be recovered if lost weight is 
regained,33–35 and bone loss may even continue at an accelerated rate among those who are successful at long-
term WL maintenance.36 Collectively, these findings provide impetus for better understanding of the 
mechanisms underlying WL-associated bone loss, particularly among older adults, so that effective intervention 
strategies can be designed to disrupt them. 
 
Skeletal tissue is highly responsive to mechanical stress;37 thus, WL-associated declines in mechanical 
loading likely contribute to BMD loss.16,19 Clinical trial data consistently demonstrate that the addition of 
exercise training (designed to enhance gravitational or muscle loading38–41) to intentional WL attenuates the 
amount of bone lost compared to WL alone.42–46 We recently reported resistance exercise training (RT) is 
superior to aerobic exercise training in attenuating WL-associated bone and muscle losses, while augmenting 
loss in total body fat mass.47 However, RT was unable to fully prevent bone and muscle loss and, in agreement 
with prior findings,48 intervention effectiveness hinged significantly on exercise compliance. Although intuitive, 
this observation may be especially important for older adults who are less likely49 (i.e., unwilling or unable) to 
perform the volume and intensity of exercise necessary to preserve bone during WL. In addition, conventional 
RT often requires expensive equipment, on-site participation, and (ideally for older adults) safety supervision by 
trained staff, limiting its scalability as an intervention strategy. 
Alternately, treating WL-associated decrease in mechanical load by replacing lost weight externally may 
also preserve bone mass. In animal models, skeletal metabolism responds in a similar fashion to increases in 
actual body, or externally added, mass.50–52 In human studies, wearing weighted vests during exercise improves 
areal BMD (aBMD) and bone turnover, as well as muscle mass and lower extremity strength.53–61 Our pilot data 
suggest this approach is both feasible and likely effective in reducing WL-associated hip aBMD loss by 
increasing bone formation.62 If confirmed, the greater availability, ease of administration, and reduced cost 
associated with weighted vest use to offset WL-associated bone loss, as compared to RT, holds significant 
public health potential as a translatable strategy to maximize the cardiometabolic benefits of WL, while 
minimizing potential harm to the musculoskeletal system. 
 
Objectives 
The main goal of this study is to compare the effects of WL alone with WL plus weighted vest use or 
WL plus RT on indicators of bone health and subsequent fracture risk. This is a 12 month trial in 150 older (60-
85 years) adults with obesity (BMI=30-40 kg/m2 or BMI= 27.0-<30 kg/m² plus one risk factor) randomized to 
one of three interventions (n= 50/group): WL alone (WL; caloric restriction targeting 10% WL with adequate 
calcium, vitamin D, and protein); WL plus weighted vest use (WL+VEST; targeting 8 hours/day, weight 
replacement titrated up to 10% WL); or, WL plus structured RT (WL+RT; targeting 3 sessions/week). In 

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accordance with recent international position statements on the clinical use of computed tomography (CT) of 
the hip in the management of osteoporosis,63,64 total hip trabecular volumetric BMD (vBMD) is the primary 
outcome. This outcome will be complemented by exploratory assessment of several fracture-related risk factors, 
including: (1) femoral neck and lumbar spine vBMD, cortical thickness, finite element modeling of bone 
strength, and regional fat and muscle volumes, measured by CT; (2) aBMD at the total hip, femoral neck, 
lumbar spine, and distal radius; trabecular bone score; and total body fat/lean masses, measured by dual energy 
x-ray absorptiometry (DXA); (3) muscle function and strength; (4) biomarkers of bone turnover; and (5) bone-
regulating hormones/cytokines known to influence bone metabolism during WL. Therefore, our Specific Aims 
are to: 
Aim 1: Determine the effects of WL+VEST compared to WL and WL+RT on 12 month change in total hip 
trabecular vBMD. Despite similar reductions in total body weight, Hypothesis 1: Participants in the WL+VEST 
group will show attenuated losses of total hip trabecular vBMD versus WL; and Hypothesis 2: Loss in total hip 
trabecular vBMD will be no greater in WL+VEST compared to WL+RT. 
Aim 2: Explore the effects of WL+VEST compared to WL and WL+RT on the 12 month change in fracture-
related risk factors. Despite similar reductions in total body weight, we hypothesize that WL+VEST and 
WL+RT will demonstrate improvements in fracture-related risk factors compared to WL. 
 
Methods and Measures 
  
 
We will use a three group randomized design in 150 older (60-85 years), obese (BMI=30-40 kg/m2 or 
BMI= 27.0-<30 kg/m² plus one risk factor), men and women who will undergo a 12 month WL intervention to 
test our overall hypothesis that weighted vest use added to WL will better preserve bone health compared to WL 
alone and similarly to WL plus a structured RT intervention. All groups will receive the same WL intervention 
(caloric restriction targeting 10% WL and with adequate calcium, vitamin D, and protein intake), in accordance 
with national obesity treatment guidelines.65 Thus, treatment groups are: WL alone (WL; n=50); WL plus 
weighted vest use (WL+VEST; targeting 8 hours/d, weight replacement titrated up to 10% WL; n=50); or, WL 
plus structured RT (WL+RT; targeting 3 sessions/week; n=50); Table 1. All outcome assessments occur at 
baseline, six, and 12 months. 
 
Table 1. Proposed Intervention Components by Treatment Group. 
Intervention 
Components 
Intensive WL Phase 
(Months 1-6) 
Reduced Contact WL Phase 
(Months 7-12) 
Weight Loss (WL) 
Weekly behavioral-based group sessions; 10% WL 
goal following national obesity treatment guidelines 
Biweekly behavioral-based group sessions; 10% WL 
goal following national obesity treatment guidelines 
WL + Weighted 
Vest (WL+VEST) 
WL + 8 hours/day weighted vest use  
titrated weekly to adjust for achieved WL  
(up to 10% baseline weight) 
WL + 8 hours/day weighted vest use titrated biweekly 
to adjust for achieved WL (up to 10% baseline 
weight) 
WL + Resistance 
Training (WL+RT) 
WL + 3 days/week progressive, structured RT 
 
Recruitment of study participants: Randomization of 150 participants will ensure at least 85% statistical power 
(with a conservative drop-out rate of ~15%; n=128 completed) to detect significance between group differences 
in our primary outcome (12 month total hip trabecular vBMD). We plan to recruit, screen and enroll during 
Years 1-3.5 of the study. We will target older adults who live in the area via media advertisements and mass 
mailings.  
 
 
 

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Participant screening and randomization 
 
All individuals who respond to our recruitment strategies will call a phone number and a recruiter will 
describe the study and perform a brief screening for general eligibility. All participants must conform to the 
inclusion/exclusion criteria detailed in Table 2. These criteria are in place both to verify our target population 
and to eliminate participants who may be adversely affected by the interventions.  
 
Table 2. Proposed inclusion/exclusion criteria. 
 
Criteria 
Inclusion Criteria 
Exclusion Criteria 
Assessment 
Age 
Age 60-85 years 
 
Self-report 
Obesity status 
BMI=30-40 kg/m2 or 
BMI 27.0-<30.0 kg/m² AND 
at least ONE of the following 
risk factors: 
1) elevated waist 
circumference (>35 inches in 
women, >40 inches in men) 
2) diabetes, 
3) hypertension, 
4) dyslipidemia, 
5) or other obesity-related 
comorbidities: clinically 
manifest coronary artery 
disease [e.g., history of MI, 
angina pectoris, coronary 
artery surgery, coronary 
artery procedures (e.g., 
angioplasty) if not within the 
past year], other 
atherosclerotic disease [e.g., 
peripheral arterial disease, 
abdominal aortic aneurysm, 
symptomatic carotid artery 
disease if not within the past 
year], sleep apnea, or 
osteoarthritis of the knee or 
hip (without prescription 
medication use for at least 3 
months within the past year) 
 
Weight greater than 450 lbs (DXA/CT limit) 
Measured on 
scale 
 
 
1) Measured 
with tape 
measure 
 
 
2-4) Self-
report and 
treatment 
 
5) Self-report 
Functional status 
 
Dependent on cane or walker: >2 falls (injurious on non-
injurious) in past year 
Self-report 
Weight Status 
No weight loss of >5% in 
past 6 months 
Any contraindications for participation in voluntary weight 
loss 
Self-report 
Lifestyle Behaviors 
 
Smoker (>1 cigarette/d or 4/week within year); Drug  
abuse or excessive alcohol use (>14 drinks/week) 
Self-report 
Physical status 
 
Participation in regular resistance training  
and/or high intensity/high impact aerobic exercise for 
 >60 mins per day on > 5 days/week for the past 6 months 
Self-report 
Cognitive status 
  
Evidence of cognitive impairment (MoCA score <20 )  
Questionnaire 
Orthopedic status 
No self-disclosed 
contraindications for safe and 
optimal participation in 
exercise training/vest use. 
 Osteoporosis (any of the below): 
Self-reported and on prescription medication. 
Self-reported prior spine, hip, wrist, or shoulder fracture 
after age 40 (except when caused by trauma or fall from 
height). 
Self-report on  
Medical History 
form, or 
medication use 
or DXA scan 

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T-score ≤ -2.5 at total hip, femoral neck, lumbar spine, or 
distal radius scan at screening visit. 
FRAX 10-year risk scores ≥3% for hip fracture or ≥20% 
for major osteoporotic fracture (TBS adjusted FRAX is 
preferable if available).  
 
Chronic back/shoulder/knee pain with current or past (within 
1 year) prescription medication use for at least 3 months. 
 
Severe, diagnosed arthritis (osteoarthritis, rheumatoid 
arthritis, or gout) with current or past (within 1 year) 
prescription medication use for at least 3 months. 
 
Past (ever) or planned (next 12 months) back surgery. 
 
Past (6 months prior) or planned (next 12 months) joint 
replacement surgery. 
 
Past (ever) unilateral or bilateral hip  
replacement surgery, or metal device or fixation in hip, pelvis
or femur. 
Co-morbidity/health 
status 
Approved for participation by 
Study Coordinator 
Uncontrolled hypertension (BP>160/90 mmHg) 
 
Current or recent past (within 1 year): severe symptomatic 
heart disease, uncontrolled angina, stroke, chronic 
respiratory disease requiring oxygen, neurological or 
hematological disease requiring treatment for at least 3 
months in past year;   
cancer requiring treatment in the past year (except non-
melanoma skin cancer).  
 
Low vitamin D (<20 ng/mL), abnormal kidney or liver 
function (2x upper limit of normal), eGFR<45 
mL/min/1.73 m2,  Anemia (Hb< 13 g/dL in men/< 12 g/dL 
in women); Uncontrolled diabetes (fasting glucose >140 
mg/dl) 
BP measurement
 
 
Self-report on  
Medical History 
Form  
 
 
 
 
 
Metabolic panel/
CBC screening  
blood test 
Medication use 
 
Use of growth hormones, weight  
loss medications, oral steroids, insulin, , or prescription 
osteoporosis medications in the past year (see medication 
list). 
Self-report on  
Medical History 
Form 
 
Technology Status 
Willing to complete 
online/electronic study forms 
and participate in virtual 
group sessions, as needed 
No home computer, laptop, or tablet with reliable home 
internet OR no smartphone (touch-screen enabled phone) 
with reliable unlimited mobile internet. 
Self-report 
Research 
participation 
Willing to provide informed  
consent; agree to all study  
procedures and assessments;  
 
Able to provide own transit to  
assessment/intervention visits 
Involved in another behavioral/interventional  
research study, weight loss program or undergoing physical 
therapy; Unable to tolerate diet, vest, or CT  
scan (claustrophobia). 
 
Judged unsuitable for the trial for any reason by  
clinic staff 
Self-report 
 
Schedule of assessment visits 
Those who pass phone screening will be scheduled for a screening visit (SV1) which is conducted in the 
early morning following a 10 hour fast. Before any data collection, participants provide written informed 
consent and complete a HIPAA authorization form in accordance with our IRB policy. At this visit, weight and 
height will be measured to calculate BMI. Individuals who meet the BMI criteria will be queried on 
demographic information and medical history, undergo medical assessments including a blood pressure and 

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pulse check, comprehensive review of medications, and a fasting blood draw (comprehensive metabolic panel 
and complete blood count); the Center for Epidemiologic Studies Depression Scale (CES-D)66 and the Montreal 
Cognitive Assessment (MoCA)66 to ensure participants are not depressed and do not have impaired cognitive 
function (MoCA score ≥20). Individuals with clinically abnormal results at screening will be referred to their 
primary care providers with their permission. 
Potential participants will also be familiarized with the resistance training protocol and asked to 
complete a dietary and VEST run-in to determine their ability to comply with the intervention protocols. For the 
dietary run-in, all participants will be provided with and oriented to the OPTAVIA® Optimal Weight 4 & 2 & 1 
Plan® guide, sample meal plans, 3 one-day dietary trackers, a sampling of 12 OPTAVIA “Fuelings” (meal 
replacement products), 3 one-day Product Satisfaction Forms, asked to follow the OPTAVIA Optimal Weight 4 
& 2 & 1 Plan for a three day period occurring over the following week, and report on their willingness to follow 
the diet plan. For the VEST run-in, participants will be asked to wear an unloaded vest for 3 days, and report on 
their willingness to wear the vest for 8 hours/day for 12 months, if randomized to that arm (SV2).  
Eligible participants will undergo further testing at two additional screening visits (SV2, SV3) prior to 
randomization (using a web-based system, stratified by sex with random block sizes) and intervention start, 
with outcome assessments repeated at 6 and 12 month testing sessions (see Table 3 for a detailed assessment 
timeline). Briefly, outcome measure assessments include: anthropometric measures, physical function testing 
(grip strength, leg strength, walking tests, stair climb), resting metabolic rate, accelerometry, imaging (DXA and 
CT), self-reported fatigue, fatigability, and pain, physical activity, and self-efficacy, and blood storage.  
 
Following state and institutional guidelines, modifications to screening and assessment visits will occur 
initially, and be conducted with as limited participant contact as possible, to ensure the safety of staff and 
participants, and to decrease the risk of exposure to COVID-19.  Modifications will include dividing SV1 into 
two separate visits: SV1 and SV1-A. Those who pass SV1, will be scheduled for a remote screening visit (SV1-
A) to be conducted by phone. At this remote visit, individuals will be queried on medical history, 
comprehensive review of medications, physical activity status, and the Center for Epidemiological Studies 
Depression Scale (CES-D). Additional modifications to assessment visits (SV3, FV2, and FV4) and 
intervention (INT) will include the administration of certain questionnaires and surveys by phone (see Table 3 
for specific questionnaires and surveys). When permissible by the state and the institution, in-person contact for 
visits will resume following necessary guidelines. Visits will revert back to the original protocol as described 
above and in Table 3, and these changes will no longer be in effect.  
 
Study Interventions 
Contact frequency and goals of each component of the three treatment groups for the intensive WL 
phase (Months 1-6) and the reduced contact WL phase (Months 7-12) are summarized in Table 1 above. 
 
Weight Loss Intervention (WL; provided to all groups). All participants will undergo a dietary WL intervention 
designed to elicit behavioral changes leading to decreased caloric intake sufficient to result in a 10% loss of 
initial body mass (10 kg for a 100 kg individual). This degree of WL is entirely feasible within this timeframe, 
and we have prior success in achieving this goal in older adults.67–69 The WL intervention includes the use of a 
partial meal replacement (MR) program, group nutrition education, state-of-the-art methods for promoting WL 
based on the group dynamics literature, social cognitive theory, and strategies that optimize self-regulation.70–72 
All participants will be asked to initially follow the OPTAVIA® Optimal Weight 4 & 2 & 1 Plan®. This is a 
portion-controlled, reduced calorie (1100-1300 calories/day) weight loss meal plan and includes consumption of 
a total of 4 OPTAVIA MRs, 2 self-prepared lean and green meals, and 1 Healthy Snack per day. Each of the 
OPTAVIA MRs contain ~90-110 kcals, 10-15 g protein, are fortified with at least 20% of the daily value for 24 
vitamins and minerals (including calcium and vitamin D), and contain GanadenBC30 probiotic cultures. All 
OPTAVIA MRs share a similar nutritional profile, allowing them to be used interchangeably, and will be 
shipped directly to participants. Participants will purchase and prepare ingredients for the foods for the lean and 
green meals on their own.  Each lean and green meal will consist of 5-7 oz. lean protein, 3 servings of non-
starchy vegetables and up to 2 servings of healthy fat. The healthy snack will consist of a self-selected serving 

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of fruit, dairy, or grain purchased by the participant, or one of OPTAVIA’s portable, pre-portioned, ready-to-eat 
snacks can be used as a healthy snack.  Participants will be guided by the study RD on their food purchasing 
and preparation of the other meals and will be encouraged to consume only what is approved from the menu.  
 
Once a participant has met or exceeded 10% weight loss for 3 consecutive group session weigh-ins, they will 
be given the option to transition to the OPTAVIA Lean & Green Life™ maintenance meal plan. Any individual 
for whom additional weight loss appears to be a safety concern will be directed to transition to the Lean & 
Green Life Plan immediately.  The Lean & Green Life Plan takes into consideration a participant’s individual 
calorie needs (based on total energy expenditure and monitoring of weight), builds on the principles learned 
during weight loss, and offers flexibility while simultaneously providing boundaries for those who may need 
them. The Lean & Green Life Plan includes a transitional period during which individuals gradually increase 
their daily calories and decrease the number of OPTAVIA MRs consumed.  At the end of the transitional 
period, participants will be recommended to eat 3 OPTAVIA MRs, 2 self-prepared lean and green meals (with 
expanded lean offerings to include more plant-based proteins, such as beans and lentils) and make up the 
balance of their caloric needs with Healthy 100’s (whole food and beverage options derived from the Diabetes 
Exchange List, each with approximately100 calories and up to 15 g of carbohydrate). A list of such 
foods/beverages that meet the requirements for Healthy 100’s will be provided to participants to facilitate their 
food choices.  Participants who would prefer to decrease or discontinue using the OPTAVIA MRs during 
maintenance can substitute them with the equivalent number of Healthy 100’s (e.g., 1 OPTAVIA MR can be 
swapped for 1 additional Healthy 100’s) while on the Lean & Green Life Plan.   
 
 
In addition to receiving dietary counseling, all participants will be asked to attend virtual or in-person 
behavioral counseling group sessions led by the RD. These sessions will be held weekly for the first 6 months 
and bi-weekly for the remainder of the study to provide participants an opportunity to review specific questions 
and problems. The education and counseling component of the intervention will emphasize instruction in 
making healthy, lower-calorie food choices while teaching changes in behavioral habits to promote WL and 
prevent weight regain.73 Specific emphasis will be placed on the acquisition and use of self-management skills, 
particularly self-monitoring of diet and weight, and achieving 150 minutes of aerobic activity/week, in 
accordance with national guidelines.65,74 Throughout the 12 month WL phase, participants will be asked to track 
their food/beverage intake (including the number of meal replacements consumed each day) daily for the first 
three months and then on a reduced schedule as warranted. These will be reviewed routinely by the study 
registered dietitian. Body weight will be measured and recorded at all group sessions to provide additional 
feedback and to increase motivation. Official study weights will occur at SV3, FV2, and FV4. If it is evident 
(either through review of diet records or inadequate WL) that participants are struggling to meet their WL goals 
additional individual counseling sessions with the RD will be held to improve compliance. At FV1 and FV3, 
participants in this group will be asked to complete a program evaluation form to solicit feedback on overall 
WL program satisfaction, desired future usage, and product preferences. Periodically throughout intervention, 
participants will be asked to rate their confidence (i.e., self-efficacy) in meeting the demands of the intervention 
they are receiving. They will also be asked to report changes in their health and medication.  
 
Weight Loss + Weighted Vest Intervention (WL+VEST). The WL component of the intervention is described 
above. Participants assigned to the WL+VEST group will each receive an appropriately-sized weighted vest for 
the duration of the 12 month intervention. The vest fabric and design fits comfortably over or under clothing 
(individual weights are ¼ inch thick), allows for full range of motion and movement, and full chest expansion 
without restricting breathing. An unloaded vest weighs about one pound and is available in several sizes, 
including XXL. The vest firmly and evenly distributes weight over the body’s core when the small (about the 
size of a domino piece) 2.25 oz weight blocks are added into the vest pockets. Participants in this group will be 
asked to wear the vest on a daily basis, progressing to a goal of 8 hours/day (by week 2) during their most active 
part of the day. Initially, the vest will be unloaded (e.g., one-pound vest only without added blocks). The vest 
weight will then be incremented according to each participant’s rate of WL based on their weekly (first 6 
months) and biweekly (final 6 months) body weight assessments. As body mass is lost, the weight of the vest 
will be increased (with the 2.25 oz weight blocks) to replace the lost weight. The goal is to maintain the 

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gravitational loading on the musculoskeletal system throughout the intervention by replacing lost body mass via 
external loading. To objectively monitor wear time, intervention staff will periodically embed a small 
accelerometer into one of the vest pockets during the weekly/biweekly group sessions. These devices collect 
accelerations across the X, Y, and Z axes and conventional wear-time algorithms will be applied to identify 
periods of non-wear time of the vest. Participants will also keep a daily log to record the time worn, vest weight, 
and any complications or comments related to the vest use, with overall satisfaction of vest use assessed at 
study close. Intervention staff will monitor and discuss accelerometer output and daily logs at the end of each 
group session, intervening to enhance compliance to the vest protocol when necessary.  
 
Weight Loss + Structured Resistance Exercise Training Intervention (WL+RT). The WL component of the 
intervention is described above. Participants assigned to the WL+RT group will undergo a progressive RT 
intervention designed to elicit adaptations in the musculoskeletal system. Exercise sessions will take place on 
three non-consecutive days/week, and will be supervised by staff exercise trainer also trained in basic life 
support and emergency management procedures. The RT program is based on recent guidelines with respect to 
intensity, number of repetitions, exercises, sets, and days per week.78 The maximal weight that can be lifted with 
correct form in a single repetition (1RM) will be used to prescribe intensity. Progression of intensity, repetitions 
and sets will be individualized and gradual to allow participants to familiarize themselves with the equipment, 
minimize muscle soreness and reduce potential for injury. The training goal is for participants to complete three 
sets of 10-12 repetitions for 8 different exercises at 70-75% 1RM for that given exercise. Participants will be 
instructed to rest for approximately one minute between each set. The resistance will be incremented when a 
participant can complete 12 repetitions for two of three sets on two consecutive sessions. Heart rate and blood 
pressure will be measured before and after each session. Participants will be instructed to warm-up at the start 
of each session by walking or cycling for 5-10 minutes at a slow pace, and will end each session with a cool-
down of light stretching. The interventionists will ensure that participants adjust the equipment appropriate to 
their body size and complete the exercises with correct form. 
 
Methods for Study Assessments 
Table 3 provides a detailed study assessment timeline. The nature, purpose, and risks of all procedures and 
protocols will be explained to each participant prior to obtaining written consent. All examiners are trained in the 
standardized conduct of all assessments before data collection.  Participants will be instructed to wear appropriate 
and comfortable clothing, and standardized written instructions will be provided prior to each study visit.  

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Table 3. Proposed Assessment Timeline. 
PS=phone screen, SV=screening visit,  FV=follow up visit, INT=intervention; eSPPB =expanded short physical performance battery, RMR=resting metabolic rate, 
TUG=timed up and go, DXA=dual energy x-ray absorptiometry, CT=computed tomography, CBC=complete blood count. 
 
INVEST Measurements 
PS 
SV1 
SV1-A 
SV2 
SV3 
INT 
FV1 
FV2 
INT 
FV3 
FV4 
SV3, INT, 
FV2, FV4 
Participant Status 
 
fasting 
 
 
fasting 
 
 
fasting 
 
 
fasting 
 
Weeks 
 
-8 to 0 
1-24 
22-26 
25-52 
50-54 
 
Location 
 
WFSM 
or WFU 
Phone 
WFU 
WFSM 
WFSM 
or WFU  
WFU 
WFSM 
WFSM 
or WFU  
WFU 
WFSM 
Phone 
Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Screener 
x 
 
 
 
 
 
 
 
 
 
 
 
Informed consent/HIPAA 
 
x 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
x 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
x 
x 
 
 
 
 
 
 
 
 
 
Medications 
 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
x 
Depression (CES-D) 
 
x 
x 
 
 
 
x 
 
 
x 
 
x 
Cognitive Assessment (MoCA) 
 
x 
 
 
 
 
 
 
 
x 
 
 
Pittsburgh Fatigability Scale 
 
 
 
 
x 
 
x 
 
 
x 
 
x 
PROMIS Pain Intensity and Fatigue 
 
 
 
 
x 
 
x 
 
 
x 
 
x 
CHAMPS physical activity 
 
x 
x 
 
 
 
x 
 
 
x 
 
x 
Adverse Events 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical Exams and Physical Performance 
Measures 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (ht/wt/bp/pulse) 
 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
Anthropometric Measures 
 
 
 
x 
 
 
x 
 
 
x 
 
 
eSPPB 
 
 
 
x 
 
 
x 
 
 
x 
 
 
Hand Grip Test 
 
 
 
x 
 
 
x 
 
 
x 
 
 
RMR 
 
 
 
 
x 
 
 
x 
 
 
x 
 
Activity Monitor - thigh 
 
 
 
x 
 
 
x 
 
 
x 
 
 
Activity Monitor - in vest 
 
 
 
 
 
x  
 
 
x  
 
 
 
400 meter Walk – fast 
 
 
 
x 
 
 
x 
 
 
x 
 
 
TUG 
 
 
 
x 
 
 
x 
 
 
x 
 
 
Biodex 
 
 
 
 
x 
 
 
x 
 
 
x 
 
Stair climb 
 
 
 
x 
 
 
x 
 
 
x 
 
 
Radiology/Imaging Tests 
 
 
 
 
 
 
 
 
 
 
 
 
DXA (whole body, hip, spine, forearm) 
 
 
 
x 
 
 
x 
 
 
x 
 
 
CT (hip and spine) 
 
 
 
 
x 
 
 
x 
 
 
x 
 
Phlebotomy 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
 
x 
 
 
 
 
 
 
 
 
 
 
Metabolic Panel 
 
x 
 
 
 
 
 
 
 
 
 
 
Vitamin D 
 
 
 
 
x 
 
 
 
 
 
 
 
Plasma/Serum Storage 
 
 
 
 
x 
 
 
x 
 
 
x 
 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
D3-Creatine muscle mass (dose/collection) 
 
 
 
x 
x 
 
 
 
 
x 
x 
 
Run-in instructions 
 
x 
 
x 
 
 
 
 
 
 
 
 
Participant Satisfaction 
 
 
 
 
 
 
 
 
x 
 
 
x 
Self-Efficacy 
 
 
 
 
 
x 
 
 
x 
 
 
x 
Adherence monitoring (weight, dietary 
trackers, meet with study dietitian as 
needed). 
 
 
 
 
 
x 
 
 
x 
 
 
 

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Study Measure(s) 
 
Methods for Primary Outcome Measure Assessment. Our study is powered to detect group differences in our 
primary outcome of 12 month change in total hip trabecular vBMD measured from CT scans acquired at 
baseline and 12-month follow-up visits. CT scans will also be acquired at a 6-month visit to assess changes in 
the outcomes at the end of the intensive WL phase. For completeness, below we describe the CT scanning 
protocol and vBMD image acquisition and assessment methods for the total hip, femoral neck, and lumbar spine 
regions of interest. 
 
CT Scanning Protocol. A helical CT scan including the femurs and lumbar spine will be obtained at baseline, 6, 
and 12 months on a 64-slice scanner (PET/CT GE Discovery MI scanner housed within the WFSM Translational 
Imaging Program). Scans will be acquired with SFOV 50 cm and 120 kV with standard reconstruction and 
secondary reconstruction using a bone algorithm. The scan will cover from the top of L1 through 3 cm below the 
mid-shaft of the femurs (mid-shaft defined as the midpoint between the superior aspect of the greater trochanter and the 
inferior aspect of the lateral condyle). The 5-port bone mineral calibration phantom (Mindways CT, Austin, TX) 
will be imaged in every scan and must be positioned to cover the lumbar spine through the lesser trochanter. In 
rare instances where the calibration phantom does not properly cover these regions, a scan may need to be 
repeated for proper data collection. The repeat scan will add approximately 975 millirem of radiation or less to 
the participant’s radiation dose. Participants will have the option to decline a repeat scan, if it is determined that 
one is needed. In an effort to avoid repeated scans, trained study staff are present at each scan to ensure that the 
CT protocol is administered correctly. However, there may be times where study staff are not able to be present, 
and a re-scan may be needed if the scan is not acquired properly during these instances. Quality assurance of the 
CT system will be performed according to manufacturer specifications. 
 
vBMD Acquisition and Assessment. vBMD of the total hip, femoral neck, and lumbar spine will be obtained 
using QCT ProTM software (Mindways, Austin, TX). The software automatically segments the proximal femur 
to obtain total hip trabecular vBMD (primary outcome measure), and total hip cortical and integral vBMD. The 
proximal femur is also automatically divided into anatomical compartments to measure trabecular, cortical, and 
integral vBMD of the femoral neck. Bilateral femoral vBMD averages will be reported, when possible. Regions 
of interest (ROIs) are automatically placed within a mid-vertebral slice at each vertebral level to obtain lumbar 
spine trabecular vBMD. Segmentations and ROIs will be manually adjusted as appropriate. The CT Hounsfield 
units (HU) are calibrated using the 5-port bone mineral phantom to derive equivalent aqueous potassium 
phosphate density measures of vBMD in mg/cm3. Elasticity-density relationships will be used to derive subject-
specific material properties from vBMD measurements for inclusion in finite element (FE) models.75–77 
 
Muscle cross-sectional area (CSA), muscle density, and intermuscular fat CSA will be measured for the total 
abdominal muscles and psoas muscle at a single CT slice at the L3 vertebra level. Visceral and subcutaneous fat 
CSAs will also be measured in this slice. Mid-thigh muscle CSA, muscle density, subcutaneous fat CSA, and 
intermuscular fat CSA will be assessed at the mid-shaft position defined as the midpoint between the superior 
aspect of the greater trochanter and the inferior aspect of the lateral condyle measured on an anterior-posterior 
scout of the entire femur. Muscle and fat areas will be semi-automatically segmented from CT using Mimics 
software (v19, Materialise, Plymouth, MI) by thresholding for fat (-190 to -30 HU) and muscle (-29 to 150 HU) 
and then manually refining segmentations 
 
Methods for Exploratory Outcome Measure Assessment. Several exploratory fracture-related risk factors 
will be assessed, including: (1) CT-acquired femoral neck and lumbar spine vBMD (described above), cortical 
thickness, FE modeling of bone strength, and regional fat/lean volumes; (2) DXA-acquired total hip, femoral 
neck, lumbar spine, and distal radius aBMD, trabecular bone score, and total body fat/lean masses; (3) 
objectively measured muscle function and strength; (4) biomarkers of bone turnover; (5) hormones and 

Version  11.4.2022 
 
cytokines known to influence bone metabolism during WL; and (6) D3-Creatine derived muscle mass. As a 
team, we have extensive experience collecting all secondary outcome measures.47,62,78,79,67,80–88 
 
Cortical Thickness Acquisition and Assessment. Variable cortical thickness across the entire surface of the 
proximal femur and lumbar spine will be obtained using an algorithm validated to accurately measure 
thicknesses as small as 0.3 mm from clinical CT scans (Stradview, Cambridge University, UK).87,89,90 A 
mathematical model constrained by a global cortical density and out-of-plane blur is fit to HU intensities 
measured from a line normal to the cortical surface that passes through the soft tissue, cortex, and trabecula. 
Point clouds of the inner and outer cortex surfaces are output, as well as cortical thicknesses (~14,000/femur; 
~3,000/vertebrae). As we’ve done previously, a mapping approach will be applied to assign subject-specific 
cortical thicknesses to each node of the cortical shell elements in the FE models.87 
 
FE Modeling to Generate Strength Estimates. Subject-specific FE models of the proximal femur and lumbar 
spine will be developed using mesh morphing to accelerate model development.88,91,92 Thin-plate spline radial 
basis function interpolation and a relaxation algorithm will be used to morph an existing FE model (i.e. atlas) to 
a subject-specific geometry. Atlases will be the Global Human Body Models Consortium (GHBMC) M50-O 
v4.4 femur and the Total Human Model for Safety AM50 v4.02 lumbar spine.88,91–94 Homologous landmarks 
from analogous locations on the atlas and subject-specific geometries will be used to derive an interpolation 
function and coefficients to morph the atlas FE model nodal coordinates. Homologous landmarks are collected 
using image segmentation and registration to derive atlas and subject-specific point clouds.95 To evaluate the 
quality of the registration and morphing algorithms, a deviation analysis will be completed to quantify the 
point-to-surface distances between the subject-specific landmarks and the morphed FE nodal coordinates and 
the 3D triangulated surface models derived from the CT scan data. The subject-specific FE models will 
incorporate vBMD-derived material properties and variable cortical thicknesses (see above sections). Bone 
strength will be estimated through simulation of the following experimental tests: single-limb stance, sideways 
fall, and quasi-static uniaxial vertebral compression test.93,94 The peak fracture force or bone strength will be 
defined as the peak force recorded between the impactor and femoral head or vertebral body. 
 
Regional Fat and Muscle Volumes. Muscle/fat/bone cross-talk is an emerging area of scientific inquiry,96,97 and 
because little is known regarding the interaction of regional fat/muscle loss and bone density changes during 
intentional WL in older adults with obesity, this study positions us to use the CT-acquired data to generate 
regional fat and muscle volumes, to complement DXA-acquired appendicular lean mass and visceral fat area 
(see section below). Abdominal visceral and subcutaneous fat volumes will be measured using approximately 
60 slices taken within 15 mm centered at the L4–L5 level. Mid-thigh muscle volume and intermuscular fat will 
also be assessed, with mid-shaft position defined as the midpoint between the superior aspect of the greater 
trochanter and the inferior aspect of the lateral condyle measured on an anterior-posterior scout of the entire 
femur. Muscle and fat volumes will be semi-automatically segmented from CT using Mimics software (v19, 
Materialise, Plymouth, MI) by thresholding for fat (-190 to -30 HU) and muscle (-29 to 150 HU) and then 
manually refining segmentations. 
 
DXA-Acquired Outcome Measures. Areal BMD of the whole body, total hip, femoral neck, lumbar spine, and 
distal radius will be determined by dual-energy x-ray absorptiometry (iDXA, GE Medical Systems, Madison, 
WI). Coefficients of variation (CV) from repeated measurements at our institution are <2% for hip and spine 
regions. All scans will be performed and analyzed by an International Society for Clinical Densitometry (ISCD) 
trained DXA technologist, under the supervision of Dr. Lenchik. Every scan will be examined to evaluate for 
proper patient positioning and analysis, and reanalysis or rescanning will be performed if necessary. Any 
artifacts will be noted and, if possible, excluded from the measured region. Daily quality control scans will be 
obtained with a calibration phantom. If results are more than two SD from baseline the phantom scans will be 
repeated. Additional DXA-acquired measures include trabecular bone score (TBS; %CV: 3.3), obtained from 
the lumbar spine scans; total body fat mass (%CV: 1.3); total body lean mass (%CV: 0.9); appendicular lean 
B 

Version  11.4.2022 
 
mass; and visceral fat area (measured from the whole-body scan in a five cm wide region across the entire 
abdomen just above the iliac crest at a level approximate with the 4th lumbar vertebrae). 
 
Objectively Measured Muscle Function and Strength. Gait speed will be assessed using the fast 400 meter 
walk test. The 400 meter walk tests was originally developed in Health ABC98 and used by our group in several 
clinical trials.70,71,99 Participants are asked to walk 10 laps of a 40 meter course (20 meters out and 20 meters 
back) as fast as possible. A script is used to standardize instructions to all participants. Participants can stop and 
rest if necessary, but are not allowed to sit, and are given a maximum of 15 minutes to complete the test. The 
reliability and validity of the 400 meter walk test are excellent.100,101 Physical performance will be assessed 
using the expanded Short Physical Performance Battery (SPPB). The expanded SPPB consists of five 
repeated chair stands, standing balance (semi- and full-tandem stands and a single leg stand for 30 seconds), a 
four meter walk to assess usual gait speed, and a narrow four meter walk test of balance (walking at usual pace 
within lines of tape spaced 20 cm apart).102 Scores for the traditional 0-12 point SPPB can also be obtained from 
these tests. We will also assess physical performance using the Timed-Up-and-Go (TUG). TUG measures the 
time a person takes to stand up from a standard chair, walk three meters, turn, walk back to the chair, and sit 
down again.103 A practice trial is given, followed by two timed trials and the results of the timed trials are 
averaged. Stair climbing time will be assessed by using the participant’s fastest time achieved to climb 12 
steps 12 step staircase in two trials. Lower extremity muscle strength will be measured using an isokinetic 
dynamometer with the participant sitting and the hips and knee flexed at 90°. The dynamometer will be adjusted 
for each participant and all adjustments will be recorded to duplicate the position for subsequent assessments. 
Start and stop angles will be set at 90° and 30°. Participants will be asked to extend the knee and push as hard as 
possible against the resistance pad. Strength is expressed as peak torque (Nm). Grip strength will be measured 
twice in each hand to the nearest two kg using an isometric Jamar Hydraulic Hand Dynamometer (Performance 
Health, Warrenville, IL) with the mean value from the stronger hand used. 
 
Biomarkers of Bone Turnover and Key Regulators of Bone Metabolism. Blood samples will be collected in the 
morning via venipuncture after an overnight fast (of ≥10 hours) and abstinence from physical activity for the 
previous 24 hours for later analyses of bone turnover and other biomarkers. Aliquots of plasma and serum will 
be stored at -70ºC in the Gerontology BioRepository directed by Dr. Nicklas until use in future assays. 
 
D3-Creatine (D3Cr) muscle mass: Participants will be asked to ingest a small tablet containing 30 mg of D3-
creatine, prepared by Wellspring Compounding Pharmacy (Berkeley, CA) to allow for a direct measure of 
muscle mass. 115 Participants will be given the dose at the SV2 and FV3 visits, and instructed to take the dose 
3-6 days prior to their SV3 and FV4 visits (respectively) where they will be asked to provide a fasted urine 
sample.  Urine will be collected either in a specimen cup and aliquoted, or will be collected directly on a filter 
paper strip, which will be frozen until shipment to the central lab at the University of California, Berkeley for 
detection of labeled and unlabeled creatinine by LC/MS. 
 
Descriptive Data, Potential Covariates, and Adverse Events. Covariate assessment will occur at the 
frequency described in Table 3. Briefly, baseline demographic data will be recorded based on participant self-
report (at baseline only). Medical information on prior and existing co-morbidities and hospitalizations will also 
be ascertained by self-report. Collectively, this information will be used to assess 10 year major osteoporotic 
and hip fracture risk using the FRAX tool.104 We will also record medication use by asking participants to bring 
in all medications (including nutritional supplements). Height without shoes will be measured to the nearest 0.1 
centimeter using a stadiometer and body mass will be measured to the nearest 0.1 kilogram using a calibrated 
and certified balance beam scale. Height and body mass will be used to calculate body mass index (BMI). Waist 
circumference will be measured to the nearest 0.1 cm with a Gulick-II spring-retractable steel tape. Resting 
metabolic rate (RMR) will be measured in the morning after an overnight fast by indirect calorimetry. Upon 
arrival, participants are asked to lie quietly for 15-20 minutes before testing.  Measurement of oxygen 
consumption and carbon dioxide production are collected continuously for at least 30 minutes and RMR is 

Version  11.4.2022 
 
calculated using the Weir equation. Accelerometry will be used to objectively assess physical activity over a 
seven day period at baseline, 6 and 12 months using a triaxial accelerometer and inclinometer.105 Finally, 
questionnaires assessing fatigue/fatigability106, pain107, physical activity108, and intervention adherence self-
efficacy (with questionnaire specific to INVEST modeled on prior work109) will be assessed. If covariates are 
found to be unbalanced between groups, and related to study outcomes, these variables will be included as 
covariates in exploratory, secondary statistical analyses. Lastly, adverse events will be assessed and recorded by 
asking participants to complete a bi-monthly health status questionnaire. Spontaneously reported adverse events 
will also be collected and reported by study staff. 
 
Data and Statistical Analyses 
Data Management. Data will be collected on forms at the clinic site and transferred to a secure electronic 
database. Our web-based management system will assure integrity and validity. Dynamic reports and statistical 
analyses will monitor quality. A participant-based inventory system will track recruitment, retention, adherence, 
and missing data from entry through exit, close-out, and lock-down of final datasets. 
 
Statistical Analyses. We will use intention-to-treat principles in full accordance with CONSORT guidelines. 
We will monitor serious adverse events regularly to maintain up-to-date safety information for reporting to the 
DSMB. All data will undergo range checks at the time of data entry and will be examined monthly by 
histograms and bivariate scatterplots to check for inconsistencies, unusual data needing further verification, and 
outliers. Plots of longitudinal observations will be used to inspect for unusual changes requiring verification 
against source documentation. Regression diagnostics and exploratory analyses will be performed to find 
appropriate transformations of variables if needed. Order of priority in choosing a transformation will be to 
satisfy: 1) linearity, 2) homogeneity, and 3) normality assumptions. We will attempt to identify baseline 
covariates that predict attrition and compliance; and if such covariates can be identified, the analyses may need 
to incorporate stratification by these factors to decrease bias. In addition, following the recommendations of the 
2010 National Academy of Sciences report,110 if the outcome is found to be missing at random, we will attempt 
to identify baseline covariates that predict attrition and use these covariates to impute missing data based on 
multiple imputation. Sensitivity analyses, using methods like pattern mixture models, will be carried out to 
explore the effect of missing outcomes on inference (if found to be not at random). Additionally, we will 
conduct sensitivity analyses of efficacy taking into account treatment compliance as a binary (compliers defined 
as >80% of prescribed vest wear time, >80% resistance training attendance, >80% of weight loss target) or 
continuous variable (proportion of treatment received).  
 
Sample Size and Power. A total sample size of 150 (n=50 per group) is optimal to test hypotheses for the 
primary study aims. Using co-primary hypotheses demands use of a conservative Bonferroni correction of 
dividing the Type I error rate (𝛼𝛼) in half for each aim to determine statistical significance. 
 
 Aim 1, Hypothesis 1. Based on our preliminary 
data demonstrating effectiveness of the 
WL+VEST intervention in preserving total hip 
aBMD, as well as effect size estimates generated 
from an 18 month trial of WL versus WL+RT on 
total hip vBMD, we anticipate that the 
WL+VEST group will decrease 3% from a 
baseline total hip vBMD value of 0.300 g/cm3 
over 12 months compared to 5.5-6.0% decrease 
in the WL alone group, leading to a difference range of 2.5-3.0%. In Table 4, we observe that assuming 12 
month group differences in total hip vBMD between 0.0075 and 0.009 g/cm3, we have at least 85% power to 
detect a statistically significant difference for the primary outcome assuming common group standard 
deviations of 0.010 g/cm3 and using a 2-sided t-test under differing retention scenarios over 12 months at a 
Table 4. Power for Aim 1, Hypothesis 1. 
12 Month ∆ Total 
Hip vBMD g/cm3: 
WL+VEST (∆%) 
12 Month ∆ Total 
Hip vBMD g/cm3: 
WL (∆%) 
12 Month Attrition 
15% 
13% 
10% 
Power (%)* 
-0.009 (-3.0%) 
-0.0165 (-5.5%) 
87.7 
88.6 
89.7 
-0.009 (-3.0%) 
-0.018 (-6.0%) 
96.7 
97.1 
97.5 
*Assumes n=50/group and unadjusted SD=0.010 g/cm3 and 𝛼𝛼=0.025 
under 2-sided alternative hypothesis. 

Version  11.4.2022 
 
0.025 level of significance. Although we do not have pilot data specifically assessing total hip trabecular vBMD 
(only total hip vBMD, which is an integral measure of the trabecular and cortical regions), the two are highly 
correlated, with prior studies showing enhanced responsivity of the trabecular region.111,112 Thus, using total 
hip vBMD for our power calculations ensures adequate power for total hip trabecular vBMD as the primary 
outcome measure.  
 
Aim 1, Hypothesis 2. We anticipate that the change in total hip trabecular vBMD among the WL+VEST will be 
noninferior to the change among WL+RT. The noninferiority margin for the difference in 12-month total hip 
vBMD changes is -4% of baseline or -0.012 g/cm3, as used previously.113 Assuming 12-month equivalence 
between WL+VEST and WL+RT (i.e., WL+VEST and WL+RT 12 month mean are each 0.291 g/cm3), then a 
baseline sample size of 50/group provides >95% power to establish noninferiority of WL+VEST compared to 
WL+RT. This assumes 1) the same SD of change (0.010 g/cm3) as in Hypothesis 1; 2) attrition rate is a 
conservative 15% (better retention provides higher power); and 3) the Type I error rate is 0.0125, based on the 
convention of using 0.025 for a one-sided test, which is further divided in half due to having co-primary 
hypotheses.114 Alternately, using a smaller noninferiority bound provides a stricter standard for the trial 
objectives. Using a margin of -2.5% of baseline (-0.0075 g/cm3) difference between WL+VEST vs WL+RT, we 
have 85% power to establish noninferiority assuming the same SD as above (0.010 g/cm3), 15% attrition, and a 
0.0125 Type I error rate. 
 
Aim 2, Hypothesis 1. We note that the CT estimates were partially derived from DXA-measured aBMD loss 
under WL, which results in similar estimated BMD losses assumed between the two groups. We anticipate that 
the WL+VEST group will decrease 3% from a baseline total hip aBMD value of 1.027 g/cm2 over 12 months 
compared to 5.5% decrease in the WL alone group, leading to a difference of 0.0257 g/cm2, or 2.5% of baseline. 
Using this magnitude of difference, 50 participants/group will provide 90% power to detect a statistically 
significant difference for the primary outcome assuming common group standard deviation of change of 0.033 
g/cm2, based on a 2-sided t-test under 85% retention at 12 months using a 0.025 Type I Error rate.  
 
Aim 2, Hypothesis 2. We anticipate that the change in total hip aBMD among the WL+VEST will be noninferior 
to the change among WL+RT. The noninferiority margin (i.e. difference at which a clinically meaningful 
increase of nonvertebral fracture risk may occur115) for the difference in 12 month total hip aBMD changes is -
2.13% of baseline or -0.022 g/cm2. Assuming equivalence between WL+VEST and WL+RT (i.e., WL+VEST 
and WL+RT 12 month mean are each 3% reduced from baseline (0.996 g/cm2)  as used in Hypothesis 1), then a 
baseline sample size of 50/group provides 80% power to establish noninferiority of WL+VEST compared to 
WL+RT such that the lower bound of the one-sided 0.9875 confidence bound of the group mean differences 
will be greater than a -0.022 g/cm2 difference between WL+VEST minus WL+RT. This assumes 1) the same 
common group SD of change (0.033 g/cm2) as in Hypothesis 1; 2) attrition rate is 15%; and 3) the Type I error 
rate is 0.0125, based on the convention of using 0.025 for a one-sided confidence interval, which is further 
divided in half due to having co-primary hypotheses. 
 
 Aim 2, All other outcomes. Due to the challenges of prespecifying noninferiority boundaries for exploratory 
outcomes, all other analyses for the second aim will focus on the three group comparisons of WL, WL+VEST, 
and WL+RT. Based on the same baseline sample size of 50/group (n=150 overall), we will have 80% power to 
detect a relatively modest effect sizes (variance of means/within-group variance) of 0.116 under the attrition 
rate of 15% assumed above, assuming 2-tailed F-test and a 0.05 Type I error rate. 
 
Statistical Analysis Plan. The primary aim for comparisons of total hip trabecular vBMD will be tested using a 
mixed model fit using the change in total hip trabecular vBMD at 12 months versus the treatment effect 
indicator for each of the three groups, adjusted for visit (6 or 12 months), visit by treatment interaction, sex (to 
account for randomization strata) and baseline value. A contrast statement will test change in total hip 
trabecular vBMD at 12 months in WL versus WL+VEST, and a statistically significant difference will be 

Version  11.4.2022 
 
established at p<0.025. Next, the noninferiority of WL+VEST compared to WL+RT will be determined based 
on whether the lower bound of the one-sided confidence interval for the estimated 12 month treatment effect of 
WL+VEST versus WL+RT overlaps the -4.0% non-inferiority boundary for total hip trabecular vBMD. This 
will be performed using α=0.0125 to account for co-primary hypotheses as well as for using a 1-sided 
alternative hypothesis. Tests for both co-primary hypotheses will be based on different contrast statements from 
the same statistical model. Secondarily, we will repeat these analyses with the short-term effect at 6 months of 
both interventions as an exploratory analysis. For Aim 2, we will repeat these analyses for the 12 month effect 
(and secondarily 6 month effect) using total hip aBMD assessed by DXA as the outcome. Comparisons will be 
performed for both superiority of WL+VEST vs. WL as well as noninferiority of WL+VEST vs WL+RT based 
on a 2.13% noninferiority margin using the methods described above. Analytic models for all other Aim 2 
outcomes will mirror the model used in the primary aim, with the important exception that comparisons will 
focus on statistical comparisons of group mean differences. All outcomes are assessed at 6 and 12 months, and 
while both visit time points will be estimated, the 12 month treatment effect will be considered of primary 
interest. Treatment effects for changes in outcome variables are compared using a mixed model fit with 
treatment group, visit, and treatment by visit interaction, adjusted for sex and baseline values of the outcome. 
Tests will be performed using contrast statements at 12 months (primarily) and 6 months (secondarily), and we 
will use the partial F-test p<0.05 for significance. Significant comparisons for secondary outcomes will further 
use comparisons of all three groups at each visit using p<0.0167 for pairwise significance. Lastly, we intend to 
explore the associations between 6 and 12 month change in vBMD or aBMD with change in secondary outcome 
measures (i.e., DXA and CT-acquired body composition, D3Cr muscle mass, biomarkers of bone turnover, 
bone regulating hormones/cytokines) using linear regression methods and adjusted for sex and treatment group, 
to explore potential mechanisms underlying the treatment effect. Secondary comparisons will not be adjusted 
for multiplicity other than for pairwise group comparisons. Statistical analyses will be conducted using SAS 
v9.4 (SAS Institute, Cary, NC) and R software. 
 
Statistical Analysis and Power Considerations for Limb Loading Sub-Study: 
 
Limb Loading Analysis: Data from the insoles will be downloaded from the smartphone and imported into 
MATLAB (Mathworks Inc, Natick, MA, USA). Limb loading outcomes will include peak impact force, loading 
rate, impulse, and cumulative loading. Peak impact force will be calculated as the largest peak in the first 25% of 
all foot contacts. Loading rate will be calculated as the peak impact force divided by the time to reach the peak 
impact force from initial foot contact (>10N). Impulse for each foot contact (e.g. step, exercise repetition) is the 
area under the force curve. Cumulative loading will be defined as the total impulse from all recorded foot contacts. 
These outcomes will be determined for the right limb and will be averaged for each day of use with the daily 
average for each metric used for data analysis. 
 
Femoral Stress and Strain Analysis: The baseline subject-specific proximal femur models developed in the parent 
study will be utilized for the proposed pilot to conduct additional FE simulations that prescribe the insole daily 
limb loads to estimate in vivo femoral stress and strain. The “peak impact force daily average” and “loading rate 
daily average” measured by the insoles will be applied to the femoral head of the FE model by prescribing a 
“force vs. time” curve that ramps up to the peak impact force in the time from initial foot contact (time=peak 
impact force divided by loading rate). The maximum femoral stress and femoral strain attained during the 
simulation will be output from the proximal femur, along with the location of those elements (e.g. femoral neck, 
trochanter, shaft). A strain of approximately 0.04 – 0.10% is estimated to be the minimum effective strain required 
to prevent bone loss. Strain values derived from our simulation will be compared to these values to determine if 
daily limb loading imposes adequate strain for maintenance of BMD. 
 
Feasibility Analysis: Feasibility of wearing force-sensing insoles will be assessed by recruitment, adherence, and 
satisfaction. Recruitment rates and adherence to wearing the insoles over 4 days will be recorded, and overall 
satisfaction will be measured with an overall satisfaction questionnaire.  

Version  11.4.2022 
 
 
To evaluate limb loading, an analysis of covariance (ANCOVA) to test for mean differences between groups in 
daily loading metrics (cumulative loading, peak force, loading rate, impulse). To evaluate femoral stress and 
strain, an ANCOVA will also be used with femoral mechanical stress and strain as the dependent variable. In 
the event of significant differences, post-hoc independent two-sample t-tests using a Bonferroni adjusted alpha 
= 0.025 will further be tested. Fifteen participants per group provides 80% power to detect a moderate effect 
size (Variance between/Variance within) of 0.40 using a 0.05 Type I error rate and 87% retention at  6 months. 
Cohen’s d effect sizes will be calculated to further contextualize group differences and inform future sample 
size calculations. Pearson product moment will also to explore associations between daily limb loading metrics, 
change in areal and volumetric BMD, and changes in physical function separately by group and across all 
groups combined. 
 
Human Subjects Protection 
 
Subject Recruitment Methods: We will recruit individuals using community-based recruitment strategies 
including newspaper ads and mass mailings. We will also advertise in the Sticht Center recruitment newsletter 
(Volunteers in Touch with an Active Lifestyle: VITAL), utilize WakeOne recruitment letters, and participate in 
community outreach events.  
Informed Consent: Written informed consent will be obtained from each subject.  The informed consent process 
will follow the procedures of the WFSM Institutional Review Board.  The study interviewers will explain the 
purpose, methods and extent of the study to prospective participants.  The potential participant is asked to read 
the informed consent form and ask questions. The form is written in simple easy to understand language.  We 
require study staff to review all of the key aspects of the study verbally with the potential participants. Staff is 
provided with a structured checklist for this purpose. Staff is then required to question potential participants to 
ascertain whether s/he has understood the information.  Potential participants who are illiterate or have impaired 
vision must have the consent read to them, followed by review of the checklist, opportunity for questions, and 
discussion. This process will take place in a quiet, private room. A copy of the signed and dated consent form 
will be given to participants, and the original document will be placed in subjects’ individual study files, which 
will be stored in a secure location.  In compliance with the Health Insurance Portability and Accountability Act 
(HIPAA) and the Standards for Privacy of Individually Identifiable Health Information of the Department of 
Health and Human Services, we will access personal health information only after obtaining informed consent. 
 
Potential Risks: There are inherent potential risks to human subjects who participate in any research study and 
the potential risks to study participants in this study are listed below. Any injuries or illnesses (severe adverse 
events) during the course of a participant’s enrollment in the study are monitored regularly as described below 
in the Data Safety Monitoring Plan.   
Intervention risks:  
  
1) Risks of weight loss at any age include the concomitant loss of fat-free (i.e., bone and muscle) tissue 
along with fat mass loss; and in older adults, this may exacerbate age-related risk of osteoporotic 
fracture. Because the individual risk of osteoporotic fracture is highest in those who are underweight, 
this risk is mitigated by excluding individuals who are non-obese and less likely to benefit from weight 
loss and excluding those who are already diagnosed with osteoporosis (identified on any of the 
following: participant self-reported medical history, medication use, or baseline DXA scan). Procedures 
to minimize loss of bone during the weight loss intervention include prescription of a caloric deficit that 
does not result in excessively rapid weight loss (e.g., >2 lb/week), recommendation to engage in daily 
light- to moderate-intensity walking, in accordance with national physical activity guidelines, and 
incorporating meal replacements and meal plans that provide adequate protein, calcium, and vitamin D 
intake.  In addition, because the vast majority of fractures occur subsequent to a fall, intervention staff 

Version  11.4.2022 
 
will hold fall safety discussions with all participants during group sessions, including distribution of 
written fall prevention resource materials. Fall safety instruction will occur during the first week of 
intervention and will be reiterated during the first week of the intervention transition phase (month 7).  
 
2)  OPTAVIA Fuelings utilize a variety of protein sources, including soy protein. Because of this, we will  
     be alert to possible soy allergies and those taking thyroid medications. Most commonly, a soy allergy  
     presents with mild signs and symptoms that may include itching, skin breakouts, or redness, nasal  
     congestion or digestive issues. Additionally, consuming OPTAVIA products containing soy protein may  
     decrease the body’s absorption of thyroid medications, such as Synthroid or Levothyroxine.  Those with  
     a mild soy allergy or intolerance, or those taking thyroid medications, will be informed of the soy  
     ingredients in the OPTAVIA Fuelings, and will be offered soy protein-free Fuelings. Participants taking  
     thyroid medications will also be instructed to avoid eating any Fuelings containing soy protein within  
     one to three hours before and after taking thyroid medication. Soy protein only needs to be avoided  
     around the time thyroid medications are taken.  
 
3) The risks of intervention-related problems with wearing the weighted vests may include: 1) an increased 
fall risk and 2) an exacerbation of prior conditions related to knee/back/shoulder pain. We exclude 
potential participants who report knee/back/shoulder pain with prescription medication use during the 
initial phone screen. Participants will also be advised to not wear the weighted vest during strenuous 
activities. Additionally, at the outset of all group sessions, participants will be queried regarding 
problems or health symptoms they may be experiencing with the vest. The interventionist will record 
the presence or absence of such symptoms and determine whether or not the contact should be handled 
emergently or, in consultation with the study physician, by a scheduled appointment with the primary 
care provider.  
  
4) The risks of the structured resistance exercise intervention may include: 1) musculoskeletal 
complications and muscle soreness in the early phases of the intervention, and 2), an increased fall risk. 
These risks are minimized since all center-based exercise sessions will be supervised by trained exercise 
technicians who will instruct participants in proper balance safety and footwear to use. Procedures to 
minimize musculoskeletal and cardiac injury and muscle soreness include warm-up and cool-down 
activities that include large muscle movements and stretching. Participants will begin with an easier 
exercise stimulus and will gradually increase in intensity over the first few months. Exercise 
physiologists, trained in cardiac life support, will supervise all center-based exercise sessions and 
practice codes are conducted quarterly.   
 
 Assessment risks: Health risks for each of the assessment procedures may include:  
  
1) Exposure to radiation from the DXA and CT scans. The amount of radiation that participants will 
receive from these procedures is equivalent to a uniform whole body dose of 1866 millirem. This is 
equal to 6.22 times the average yearly radiation exposure from background radiation (300 mRem). If a 
repeat CT scan is needed, participants will receive approximately 975 millirem of additional radiation, 
which would increase the uniform whole body dose of radiation to 2841 millitem. This is equal to 9.47 
times the average yearly radiation exposure from background radiation (300 mRem). The potential long-
term risk from these radiation doses is uncertain, but these doses are not associated with any definite 
adverse effects. Thus the risk to participants, if any, is estimated to be slight.    
  
  
 
  
2) A small risk of injury during the muscle strength and function tests, such as muscle strains or pulls, falls, 
or joint injury. However, these tests have been performed in large study populations with no significant 
adverse events reported. Risks will be minimized by having experienced/trained staff conducting these 

Version  11.4.2022 
 
assessments. A warm-up and range of motion practice will be conducted before testing. In addition, if a 
participant reports pain, dizziness, lightheadedness or other medical problem during the test, the test will 
be terminated. During the walking trials with the force-sensing insoles, there is a small risk of fatigue, 
loss of balance, or falls. Breaks will be provided to participants to minimize fatigue, and participants 
will be spotted during the walking tests to prevent falls and injury.    
  
3) Slight discomfort, bruising, and/or infection at the sight of puncture for blood drawing, but blood will be 
drawn only be trained and experienced phlebotomists who will minimize the discomfort as much as 
possible.  
 
4) Risks associated with wearing the activity monitors are minimal, but may include minor skin 
irritations. Participants will be instructed to note these on their log and if it becomes bothersome to 
remove the device and call staff for further instructions. 
 
Safety measures during the interventions: For the dietary intervention, all study participants are monitored for 
compliance to a safe level of caloric deficit. Since the degree of bone and muscle loss is accelerated by the rate 
of weight loss, all participants will be weighed weekly and if weight is being lost at a rate greater than 0.9 
kg/wk (~2 lb/wk), adjustments may be made to the meal plan to increase the level of calories recommended to 
slow down this excess rate of weight loss. As stated previously, at the outset of all group sessions, participants 
will be queried regarding problems or health symptoms they may be experiencing with the vest. The 
interventionist will record the presence or absence of such symptoms and determine whether or not the problem 
requires medical attention and, if so, to determine whether or not the contact should be handled emergently or, 
in consultation with the study physician, by a scheduled appointment with the primary care provider. Supervised 
RT sessions are conducted at a central location and are supervised by trained interventionists who monitor 
potential adverse experiences and symptoms. On-site staff trained in advanced cardiac life support are available 
to deal with medical emergencies. Also, institutional and community EMS services will be activated if needed. 
Procedures to minimize musculoskeletal discomfort to the exercise include teaching proper warm-up and cool 
down activities and providing instruction on correct exercise techniques and fall safety. If for any reason the 
participant reports a fall or other injury, or chest pain, shortness of breath, or dizziness, during a supervised RT 
session, they will be referred to their doctor, or study staff will notify the participant’s doctor or other health 
care provider with their permission. If at any point during a RT session, participants develop chest pain, 
shortness of breath, or dizziness, they will be instructed to stop exercise, and to contact the study staff if these 
symptoms persist or recur. We monitor blood pressure and heart rate before and after all supervised RT 
sessions. If an intervention-related injury or illness does occur, the study medical staff will be consulted 
according to the type of symptom reported. In some instances, it may be appropriate to reduce or to temporarily 
suspend the participant's weight loss, vest use, or RT goals. If the injury or symptoms do not resolve after an 
appropriate period of time, the participant will be referred to his/her primary care provider for further 
evaluation. The participant will be encouraged to follow the primary care provider's instructions regarding 
intervention compliance.  
  
Safety measures during the assessments: All study assessments are conducted by trained and certified staff. 
Safety precautions are taken during all testing by applying standardized stopping criteria. If the participant 
reports pain, tightness or pressure in the chest, feeling faint, lightheaded or dizzy, or any other medical 
problems, the test will be stopped. When there are medically relevant findings, the participant will be told the 
cause for concern, and may be advised to consult his or her physician. If given permission by the participant, a 
letter will be sent to her primary care physician stating the concern.   
  
Confidentiality and Privacy: Confidentiality will be protected by collecting only information needed to assess 
study outcomes, minimizing to the fullest extent possible the collection of any information that could directly 

Version  11.4.2022 
 
identify subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy and 
confidentiality, only a unique study identifier will appear on the data collection form.  Any collected patient 
identifying information corresponding to the unique study identifier will be maintained on a separate master log.  
The master log will be kept secure, with access limited to designated study personnel and Medifast Scientific 
and Clinical Affairs personnel.  Following data collection subject identifying information will be destroyed at 
the earliest opportunity, consistent with data validation and study design, producing an anonymous analytical 
data set.  Data access will be limited to study staff.  Data and records will be kept locked and secured in the 
Department of Health and Exercise Science, WFU and WFSM, with any computer data password protected.  No 
reference to any individual participant will appear in reports, presentations, or publications that may arise from 
the study. Limb loading data will be saved onto the smartphone with a unique ID number. Following each visit, 
data from the smartphone will be downloaded onto a password protected computer. Data on the smartphone will 
be immediately deleted.  
 
Data and Safety Monitoring: The principal investigator will be responsible for the overall monitoring of the data 
and safety of study participants.  The principal investigator will be assisted by other study staff, including the 
study physician.  
 
Reporting of Unanticipated Problems, Adverse Events or Deviations: Any unanticipated problems, serious and 
unexpected adverse events, deviations or protocol changes will be promptly reported by the principal 
investigator or designated member of the research team to the IRB and sponsor or appropriate government 
agency if appropriate. 
 
Use of biological samples by other investigators: Biological samples may be used by investigators other than 
the investigators of the current study.  The use will be limited to non-commercial purposes.  The names and 
other personal identifiers of the study participants will not be sent to any recipients of the blood samples. 
Storage and disposal of biological material: Tissue samples will be stored at Wake Forest University Medical 
Center indefinitely after the end of the trial. Biological specimens will be stored in locked alarmed ultra-low 
freezers located in a locked room, and will be destroyed when they are no longer needed.  The lab coordinator 
and the PI have access to the keys of the freezers.  All the specimens will have numerical study IDs with no 
personal identifiers of the participants. These are stored under the Pepper Center Tissue Repository (IRB#1219). 
 
 

Version  11.4.2022 
 
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