Utilizing Protein During Weight Loss to Impact Physical Function and Bone

The ancillary study to the UPLIFT trial (NCT03074643) will use a 3-group design in 225 obese
(BMI 30-45 kg/m2 or 27-<30 kg/m2 with an obesity-related risk factor), older (65-85 years)
men and women at risk for disability (SPPB ≤10) who will undergo a 6-month weight loss
intervention followed by a 12-month follow-up phase to test the overall hypothesis that a
higher protein (1.2 g/kg body wt/d) / lower carbohydrate (CHO) diet during a 6-month weight
loss intervention improves bone phenotypes compared with an isocaloric lower protein (the
current Recommended Dietary Allowance (RDA), 0.8 g/kg body wt/d) / higher CHO diet, and
whether continuing a higher protein / lower CHO diet for 12-months following weight loss will
result in better maintenance of bone. All participants will undergo a 6-month weight loss
intervention involving caloric restriction and supervised exercise followed by 12 months of
follow-up with randomization to one of three groups (n=75/group): 1) Lower protein / higher
CHO diet for the 6-month weight loss phase only (RecProt); 2) Higher protein / lower CHO diet
for the 6-month weight loss phase only (6-mo HiProt); or 3) Higher protein / lower CHO diet
for the 6-month weight loss and 12-month follow-up phases (18-mo HiProt). Vertebral and
femoral volumetric bone mineral density and cortical thickness (Primary Aim) and bone marrow
adipose tissue (Secondary Aim 1) will be assessed with computed tomography at baseline, 6-,
and 18-months. Bone strength and fracture risk (Secondary Aim 2) will be assessed by finite
element modeling at baseline, 6-, and 18-months.

Subjects are recruited using inclusion and exclusion criteria of the parent trial (UPLIFT;
NCT03074643).

Inclusion Criteria:

- 65-85 years

- BMI: 30-45 kg/m2 or BMI 27.0 - <30.0 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 myocardial infarction, 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.

- No regular resistance training and/or aerobic exercise (>20 mins/d) for past 6 months

- SPPB ≥3 to ≤10

- No contraindications for safe and optimal participation in exercise training

- Approved for participation by Medical Director (Dr. Lyles)

- Willing to provide informed consent

- Agree to all study procedures and assessments

- Willing to consume protein/CHO supplements for up to 18 months

- Able to provide own transportation to study visits and intervention sessions

Exclusion Criteria:

- Weight loss (≥5%) in past 6 months

- Dependent on cane or walker

- Cognitive impairment (MoCA score <22)

- Severe arthritis, or other musculoskeletal disorder

- Joint replacement or other orthopedic surgery in past year

- Uncontrolled resting hypertension (>160/90 mmHg);

- Uncontrolled diabetes (HbA1c ≥8.0%)

- Current or recent past (within 1 year) severe symptomatic heart disease, uncontrolled
angina, stroke, chronic respiratory disease requiring oxygen; uncontrolled
endocrine/metabolic disease; neurological or hematological disease; cancer requiring
treatment in past year, except non-melanoma skin cancers; liver or renal disease; or
clinically evident edema

- Unstable Severe Depression

- Serious conduction disorder, uncontrolled arrhythmia, or new Q waves or ST-segment
depressions (>3 mm at rest or ≥2 mm with exercise)

- Abnormal kidney function (eGFR <30 based on serum creatinine, age, gender, and race)

- Anemia (Hb<13 g/dL in men; <12 g/dL in women)

- Drug abuse or excessive alcohol use (>7 drinks/week women; >14 drinks/week men)

- Use of any tobacco or nicotine products in the past year

- Osteoporosis (T-score < -2.5 on hip or spine scan)

- Regular use of growth/steroid hormones, sex steroids or corticosteroids

- Osteoporosis medication

- Protein supplements (and unwilling to stop using for duration of study)

- Weight loss medications or procedures

- Current participation in another intervention study