Starting a Testosterone and Exercise Program After Hip Injury

Hip fractures are common among older women and can have a devastating impact on their ability
to remain independent. A clinically important functional decline and failure to recover
following a hip fracture has been documented as late as a year after the fracture, even among
women who were functioning at high levels before the event. Age-associated androgen
deficiency in women contributes to deficits in muscle mass, strength and power that are
common in this patient population before the fracture, and are exacerbated afterward. A pilot
study of testosterone (T) supplementation in elderly female hip fracture patients has
demonstrated the feasibility of T treatment in this population, and showed gains in lean body
mass (LBM) and muscle strength with active drug, compared to placebo. The benefits of
exercise in restoring muscle strength and physical function after a hip fracture have been
documented. However, it remains unclear whether T treatment can augment the effects of
exercise on mobility and patient-reported function after hip fracture.

The STEP-HI study is a 3-group, multi-center, randomized, placebo-controlled, double-blinded,
parallel group clinical trial in older female hip fracture patients. 300 female hip fracture
patients, age 65 years and older, will be enrolled from 6 clinical sites, using objective
screening criteria for T deficiency (serum total testosterone level < 40 ng/dL) and physical
frailty (Modified Physical Performance Test (PPT) Score of 12-28). The trial will compare the
effects of Enhanced Usual Care with home exercises and no gel treatment (EUC), supervised
exercise training (EX) with inactive (placebo) gel (EX+P), and EX combined with T therapy
(EX+T), to ascertain the incremental impact of adding T to EX in older adult women with a
recent hip fracture. The study team will carefully monitor testosterone levels, adverse
events, biochemical parameters, and factors related to adherence to the interventions.

Information from this study has the potential to alter treatment of hip fracture in older
women, a problem that contributes to significant morbidity and mortality, and has a large
public health impact. The STEP-HI study is highly aligned with NIA's mission of identifying
interventions that target common geriatric conditions and improve treatment options for older
adults with multiple morbidities or risk factors.

Inclusion Criteria:

- Female 65 years and older.

- Surgical repair of a non-pathologic fracture of the proximal femur (Including:
intracapsular, intertrochanteric, and subtrochanteric fractures) with a surgical
repair date that is within 6-14 weeks at screening, and within 16 weeks at
randomization.

- Community-dwelling or in assisted living prior to the hip fracture event.

- Functional impairment at the time of screening, defined as a modified Physical
Performance Score (mPPT) of 12-28.

- Serum total testosterone level <40 ng/dL.

Exclusion Criteria:

- Cognitive impairment or dementia of severity sufficient to interfere with ability to
fully participate in the study or provide one's own informed consent, or a score of 11
or greater on the Short Blessed Test of Orientation, Memory and Concentration.

- Residence too far from research center (specific distance to be determined by each
site) or planned travel greater than 2 weeks within the next 9 months.

- Anticipated to be permanently living in a nursing home at the time of randomization.

- Use of progestin or androgen containing compound within the previous 6 months.

- Treatment with systemic corticosteroids (daily dose > 5 mg prednisone or equivalent)
for at least 90 days within the previous 12 months.

- Visual or hearing impairments that interfere with following directions for research
procedures.

- Active or unstable cardiopulmonary disease (recent MI, unstable angina, class III or
IV CHF) within prior 6 months, which would limit full participation in the study.

- Respiratory disease requiring chronic continuous oxygen therapy, or oxygen therapy
during walking or exercise, which would limit full participation in this study.

- History of thrombotic event requiring treatment.

- Musculoskeletal or neurological conditions that limit participation in this study,
could be made worse by exercise training, or not expected to improve with exercise.

- Lower extremity amputation other than toes.

- Severe lower extremity pain or ulceration that could limit full participation in this
study.

- History of a hormone dependent neoplasia.

- History of HIV or active viral hepatitis.

- End Stage Renal Disease on dialysis or GFR<15 ml/min.

- Allergy to gel components.

- Recent history of alcohol or substance abuse, or current alcohol intake of ≥ 10
drinks/week.

- Planned joint surgery during the intervention period.

- Participation in another research study that in the site investigator's judgement
could interfere or conflict with STEP-HI research assessments or interventions.

- Current use of aldactone, flutamide or leflunomide.

- GDS score ≥ 12 at the screening assessment.

- Uncontrolled hypertention, defined as a systolic BP > 160 mmHg or diastolic BP > 95
mmHg, on at least two occasions.

- Elevated liver transaminase levels ≥ 2.5 times above normal range.

- Erythrocytosis with hematocrit > 51% (all sites except UCD) or ≥ 52% at UCD.

- Severe anemia defined as Hgb < 7gm/dL.

- Uncontrolled diabetes defined as HgbA1C > 10%.

- Untreated or unstable thyroid disease, with serum TSH level ≥ 10 mIU/L or TSH level ≤
0.4 mIU/L.

- Site investigator's judgement that the participant would not be able to complete
research procedures or interventions.