Myogenic and Osteogenic Responses to eXercise and Ibuprofen

People are advised to engage in weight-bearing physical activity to help prevent the loss of
bone and muscle mass that occurs with aging. There is evidence from studies of animals that
non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, block some of the bone-
and muscle-building effects of exercise. The aim of this study is to determine whether use
of ibuprofen, either before or after exercise, blocks the benefits of exercise training on
bone and skeletal muscle in older women and men. The hypothesis is that taking ibuprofen
before exercise will block some of the effects of exercise training to increase bone density
and muscle mass.

Women and men aged 60-75 years will complete a supervised, 9-month exercise training program
designed to increase bone and muscle mass. The training will include weight lifting and
weight-bearing exercises, such as jumping in place and treadmill walking, up to 5 days per
week. Participants will be randomly assigned to take 1 of 3 study pill combinations before
and after each exercise session. The combinations of study pills will be: placebo
before/placebo after, placebo before/ibuprofen after, or ibuprofen before/placebo after. The
dose of ibuprofen will be 400 mg. Bone density of the hip and spine, body composition (total
body muscle and fat), and markers of bone turnover in the blood will be measured before and
after 4.5 and 9 months of training. Muscle cross-sectional area of the thigh will be
measured by CT before and after 9 months of training. A subset of participants will have
biopsies of the thigh muscle before and after training to measure proteins and genes
associated with muscle build-up and breakdown.

Volunteers who do not use ibuprofen, aspirin, or acetaminophen more than 3 days per month
will be enrolled. People with intolerance to ibuprofen or related drugs, cardiovascular
disease, or orthopedic problems that limit exercise will be excluded from the study.

Inclusion Criteria:

- Aged 60 to 75 years

- Willing to participate in a 9-month supervised exercise program that will start at a
moderate intensity and gradually progress to a vigorous intensity

- Not currently performing regular, moderate-to-vigorous weight-bearing or
weight-lifting exercise

- Average use of NSAIDs (including low-dose aspirin) or acetaminophen less than 3 days
per month

Exclusion Criteria:

- Relative or absolute contraindications to regular use of NSAIDs

- Known allergy or intolerance (heartburn, stomach pain, nausea, vomiting) to NSAIDs;
controlled GERD(Gastroesophageal Reflux Disease), if not related to NSAID use, will
not be an exclusion criterion

- Proton Pump Inhibitor (PPI) use if dose is unstable or if using for less than 6
months prior to study enrollment

- History of peptic ulcer or upper GI bleeding

- Anemia

- Asthma with bronchospasm induced by aspirin or other NSAIDs

- Moderate or severe renal impairment defined as a calculated creatinine clearance

- Chronic hepatobiliary disease, conservatively defined as liver function tests greater
than 1.5 times the upper limit of normal (if such values are obtained on initial
screening and thought to be transient in nature, repeated testing will be allowed)

- Hyperkalemia

- Osteoporosis

- Diabetes mellitus requiring pharmacologic therapy

- Congestive heart failure

- Uncontrolled hypertension; use of thiazide diuretics will be allowed if on a stable
dose for at least 6 months

- Cardiovascular disease

- Thyroid dysfunction

- Orthopedic problems (e.g., chronic back pain, severe osteoarthritis, rheumatoid
arthritis) that limit the ability to perform vigorous exercise and increase the
likelihood that the volunteer will use pain medications other than the study pills

- Certain use of medications, including

- Drugs that are known to alter bone metabolism (e.g., estrogen, SERMs(Selective
estrogen-receptor modulators), testosterone, bisphosphonates, teriparatide,
calcitonin, GnRH(Gonadotropin-releasing hormone) agonists)

- Chronic use of oral corticosteroids or any use in the previous 6 months (use of
inhaled steroids will not be an exclusion criterion based on a meta-analysis
documenting that the effect on bone is not significant)

- Average use of acetaminophen or NSAIDs, including low-dose aspirin, greater than
3 days per month; volunteers using aspirin for primary prevention may enroll in
the study if they discontinue aspirin therapy for the 9-month intervention
period

- Anticoagulants (e.g., warfarin, clopidogrel)

- Narcotics