Physical Frailty, Hip Fracture, Elective Hip Replacement, Hypogonadism
Conditions
Keywords
Testosterone Replacement Therapy, Physical Frailty, Hip Fracture
Brief summary
The primary aim of this study is to determine, in hypogonadal older men with physical frailty, whether exercise training combined with testosterone replacement therapy can improve skeletal muscle strength, and lean mass, to a greater degree than exercise training alone.
Detailed description
Decreases in physical abilities, including losses of strength, endurance, balance, and coordination are major causes of disability and loss of independence in older men. Such individuals are at high risk for injurious falls, hospitalization, and use of supportive services. Age-associated testosterone deficiency may contribute to deficits in muscle mass and strength that are common in this patient population. The primary aim of this study is to determine, in hypogonadal older men with physical frailty, whether six months of exercise training combined with testosterone replacement therapy can improve skeletal muscle mass and skeletal muscle strength, to a greater degree than six months of exercise training alone. Secondary study aims are to determine in hypogonadal older men with physical frailty, whether six months of exercise training combined with testosterone replacement therapy can improve physical function, bone mineral density, and quality of life, to a greater degree than six months of exercise training alone. Comparison: Men age 65 years and older who meet criteria for physical frailty and have a serum testosterone level below 350 ng/dl are randomly assigned to one of two groups: 1) transdermal testosterone replacement therapy + supervised exercise training for six months vs. 2) inactive placebo gel + supervised exercise training for six months.
Interventions
DRUGTransdermal Testosterone gel (1%)
Transdermal testosterone replacement therapy with Androgel(TM). Daily application of gel at 5 mg, 7.5 gm, or 10 gm for six months. Target serum total testosterone level between 500-900 ng/dl.
BEHAVIORALSupervised exercise training
Supervised exercise training performed on site at academic medical center exercise facility. Exercise training consisted of 2 months of flexibility, balance, treadmill walking, and physical therapy-type exercises, followed by 4 months of progressive resistance training.
Sponsors
Solvay Pharmaceuticals
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male, age 65 years and older * Total serum testosterone level \< 350 ng/dl * Total Modified Physical Performance Test Score \<28
Exclusion criteria
* Inability to walk 50 feet independently * Current use of estrogen, progestin, or androgen containing compound * Diagnosis of dementia of severity sufficient to interfere with informed consent or compliance with the protocol, or a score of 11 or greater on the Short Blessed Test of Orientation, Memory and Concentration * Visual or hearing impairments that interfere with following directions * Cardiopulmonary disease (recent MI, unstable angina or CHF, etc.), neuromuscular impairments, or unstable medical condition that would contraindicate progressive resistance exercise training * History of prostate cancer or hormone dependent neoplasia * PSA level \> 4 ng/ml * Serum liver transaminase levels of greater than 2 standard deviations above normal * Use of drugs for osteoporosis for less than 1 year * Current participation in a vigorous exercise or weight-training program more than once per week * History of sleep apnea requiring use of CPAP * Uncontrolled thyroid disease * Diagnosis of cancer within the past 5 years other than superficial skin cancer (squamous or basal cell) * hematocrit \> 50% * AUA symptom score \> 16. * History of alcohol or substance abuse * Presence of severe facial acne * Active symptoms of depression with GDS score \> 5 and symptoms severe enough to cause \>5% weight loss in previous 3 months or interfere with research assessments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Total Lean Body Mass | Baseline and Six Months | Total Lean Mass measured by Dual X-ray Absorptiometry (DXA) |
| Change in Skeletal Muscle Strength by 1-RM | Baseline and Six Months | One-repetition maximum strength for leg extension |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Leg Extension Torque at 60 Deg/Sec | Baseline and Six Months | Leg Extension Torque measured with Cybex dynamometry at 60 deg/sec |
| Change in Isokinetic Leg Extension Torque at 0 Deg/Sec | Baseline and Six Months | Leg Extension Torque measured with Cybex dynamometer at 0 deg/sec |
| Change in Total Body Fat Mass | Baseline and Six Months | Total Body Fat Mass as measured by DXA |
| Change in Femoral Bone Mineral Density (BMD) | Baseline and Six Months | Femoral Bone Mineral Density measured with Dual X-ray Absorptiometry (DXA) |
| Change in Total Modified Physical Performance (mPPT) Score | Baseline and Six Months | The Modified Physical Performance Test (mPPT) is a direct observational test that assesses multiple dimensions of physical function (basic and complex activities of daily living \[ADL\]) with different levels of difficulty. The test consists of 9 performance tasks. The total score range is 0-36 (min-max), with higher scores indicating better performance. Sub-scores are assigned for each of 9 item tasks; sub-score range is 0-4 (min-max) with higher scores indicating better performance. The sub-scores are summed to compute the total score. |
| Change in Serum Testosterone Level | Baseline and Six Months | Total Serum Testosterone Level (ng/mL) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum HDL Cholesterol Level | Baseline and Six Months | — |
| Change in Serum LDL Cholesterol Level | Baseline and Six Months | — |
| Change in Hematocrit | Baseline and Six Months | Percentage of the volume of whole blood composed of Red Blood Cells |
| Change in Serum Prostate Specific Antigen (PSA) Level | Baseline and Six Months | — |
| Change in Serum Total Cholesterol Level | Baseline and Six Months | — |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from orthopedic units of local hospitals, rehabilitation facilities (both acute rehabilitation units and SNFs), home care programs, and the community-at-large.
Pre-assignment details
Participants were carefully screened for exclusion criteria prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Exercise + Placebo Participants assigned to this group were prescribed an inactive topical gel for 6 months, and also performed a supervised exercise training program three times per week for 6 months. | 11 |
| Exercise + Testosterone Participants assigned to this group were prescribed transdermal testosterone (Androgel 1%) for six months, and performed a supervised exercise training program three times per week for six months. | 11 |
| Total | 22 |
Baseline characteristics
| Characteristic | Exercise + Testosterone | Exercise + Placebo | Total |
|---|---|---|---|
| Age, Continuous | 77 years STANDARD_DEVIATION 6 | 81 years STANDARD_DEVIATION 4 | 80 years STANDARD_DEVIATION 7 |
| BMI (kg/m2) | 29 kg/m2 STANDARD_DEVIATION 5 | 28 kg/m2 STANDARD_DEVIATION 3 | 29 kg/m2 STANDARD_DEVIATION 4 |
| Body Weight (lbs.) | 195 lbs. STANDARD_DEVIATION 38 | 193 lbs. STANDARD_DEVIATION 30 | 194 lbs. STANDARD_DEVIATION 34 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 11 Participants | 20 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 11 Participants | 11 Participants | 22 Participants |
| Total Modified Physical Performance (mPPT) score | 26 units on a scale STANDARD_DEVIATION 3 | 23 units on a scale STANDARD_DEVIATION 4 | 25 units on a scale STANDARD_DEVIATION 4 |
| Total Testosterone level (ng/dL) | 248 ng/dL STANDARD_DEVIATION 97 | 252 ng/dL STANDARD_DEVIATION 71 | 250 ng/dL STANDARD_DEVIATION 84 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 12 | 1 / 13 |
| serious Total, serious adverse events | 0 / 12 | 1 / 13 |
Outcome results
Primary
Change in Skeletal Muscle Strength by 1-RM
One-repetition maximum strength for leg extension
Time frame: Baseline and Six Months
Population: Only 8 participants in the Exercise+Testosterone group provided Leg Extension 1-RM measurements at baseline and 6-month follow-up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Skeletal Muscle Strength by 1-RM | 59.2 lbs. | Standard Deviation 33.3 |
| Exercise + Testosterone | Change in Skeletal Muscle Strength by 1-RM | 70.3 lbs. | Standard Deviation 37.5 |
p-value: 0.55ANOVA
Primary
Mean Change in Total Lean Body Mass
Total Lean Mass measured by Dual X-ray Absorptiometry (DXA)
Time frame: Baseline and Six Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Mean Change in Total Lean Body Mass | 0.5 kg | Standard Deviation 1.8 |
| Exercise + Testosterone | Mean Change in Total Lean Body Mass | 2.3 kg | Standard Deviation 1 |
p-value: 0.01ANOVA
Secondary
Change in Femoral Bone Mineral Density (BMD)
Femoral Bone Mineral Density measured with Dual X-ray Absorptiometry (DXA)
Time frame: Baseline and Six Months
Population: Only 10 participants in the Exercise+Placebo group, and 10 participants in the Exercise+Testosterone group, provided femoral bone density measurements at baseline and the 6 month follow-up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Femoral Bone Mineral Density (BMD) | -0.008 g/cm2 | Standard Deviation 1.238 |
| Exercise + Testosterone | Change in Femoral Bone Mineral Density (BMD) | 0.084 g/cm2 | Standard Deviation 3.515 |
p-value: 0.93ANOVA
Secondary
Change in Isokinetic Leg Extension Torque at 0 Deg/Sec
Leg Extension Torque measured with Cybex dynamometer at 0 deg/sec
Time frame: Baseline and Six Months
Population: Only 10 participants in Exercise+Placebo group, and 8 participants in Exercise+Testosterone group, provided Leg Extension torque measurements at baseline and 6-month follow-up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Isokinetic Leg Extension Torque at 0 Deg/Sec | 10.4 ft/lb | Standard Deviation 14.2 |
| Exercise + Testosterone | Change in Isokinetic Leg Extension Torque at 0 Deg/Sec | 19.8 ft/lb | Standard Deviation 18.1 |
p-value: 0.23ANOVA
Secondary
Change in Leg Extension Torque at 60 Deg/Sec
Leg Extension Torque measured with Cybex dynamometry at 60 deg/sec
Time frame: Baseline and Six Months
Population: Only 10 participants in the Exercise+Placebo group, and 8 participants in the Exercise+Testosterone group, provided Leg extension torque measurements at baseline and 6 month follow-up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Leg Extension Torque at 60 Deg/Sec | 12.7 ft/lb | Standard Deviation 13.5 |
| Exercise + Testosterone | Change in Leg Extension Torque at 60 Deg/Sec | 19.4 ft/lb | Standard Deviation 21.4 |
p-value: 0.43ANOVA
Secondary
Change in Serum Testosterone Level
Total Serum Testosterone Level (ng/mL)
Time frame: Baseline and Six Months
Population: Only 9 participants in the Exercise+Testosterone group provided serum testosterone levels at baseline and 6-month follow-up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Serum Testosterone Level | -15.3 ng/mL | Standard Deviation 72.6 |
| Exercise + Testosterone | Change in Serum Testosterone Level | 121.2 ng/mL | Standard Deviation 235.5 |
p-value: 0.13ANOVA
Secondary
Change in Total Body Fat Mass
Total Body Fat Mass as measured by DXA
Time frame: Baseline and Six Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Total Body Fat Mass | -0.51 kg | Standard Deviation 0.96 |
| Exercise + Testosterone | Change in Total Body Fat Mass | -1.1 kg | Standard Deviation 1.7 |
p-value: 0.33ANOVA
Secondary
Change in Total Modified Physical Performance (mPPT) Score
The Modified Physical Performance Test (mPPT) is a direct observational test that assesses multiple dimensions of physical function (basic and complex activities of daily living \[ADL\]) with different levels of difficulty. The test consists of 9 performance tasks. The total score range is 0-36 (min-max), with higher scores indicating better performance. Sub-scores are assigned for each of 9 item tasks; sub-score range is 0-4 (min-max) with higher scores indicating better performance. The sub-scores are summed to compute the total score.
Time frame: Baseline and Six Months
Population: Only 10 participants in the Exercise+Placebo group, and 9 participants in the Exercise+Testosterone group, provided baseline and follow-up mPPT measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Total Modified Physical Performance (mPPT) Score | 5.0 units on a scale | Standard Deviation 3.7 |
| Exercise + Testosterone | Change in Total Modified Physical Performance (mPPT) Score | 2.8 units on a scale | Standard Deviation 4.4 |
p-value: 0.24ANOVA
Other Pre-specified
Change in Hematocrit
Percentage of the volume of whole blood composed of Red Blood Cells
Time frame: Baseline and Six Months
Population: Only 10 participants in the Exercise+Placebo group, and 9 participants in the Exercise+Testosterone group, provided hematocrit measurements at baseline and 6-month follow-up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Hematocrit | 0.14 percent | Standard Deviation 2.6 |
| Exercise + Testosterone | Change in Hematocrit | 2.5 percent | Standard Deviation 4.8 |
p-value: 0.19ANOVA
Other Pre-specified
Change in Serum HDL Cholesterol Level
Time frame: Baseline and Six Months
Population: Only 9 participants in the Exercise+Placebo group, and 9 participants in the Exercise+Testosterone group, provided serum for HDL cholesterol measurements at baseline and 6 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Serum HDL Cholesterol Level | -1.4 mg/dL | Standard Deviation 9 |
| Exercise + Testosterone | Change in Serum HDL Cholesterol Level | 1.7 mg/dL | Standard Deviation 7.8 |
p-value: 0.44ANOVA
Other Pre-specified
Change in Serum LDL Cholesterol Level
Time frame: Baseline and Six Months
Population: Only 9 participants in the Exercise+Placebo group, and 9 participants in the Exercise+Testosterone group, provided serum for LDL cholesterol measurements at baseline and 6 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Serum LDL Cholesterol Level | -3.6 mg/dL | Standard Deviation 15.3 |
| Exercise + Testosterone | Change in Serum LDL Cholesterol Level | -1.6 mg/dL | Standard Deviation 39 |
p-value: 0.89ANOVA
Other Pre-specified
Change in Serum Prostate Specific Antigen (PSA) Level
Time frame: Baseline and Six Months
Population: Only 10 participants in the Exercise+Placebo group, and 9 participants in the Exercise+Testosterone group, provided serum PSA level measurements at baseline and 6 month follow-up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Serum Prostate Specific Antigen (PSA) Level | 0.05 ng/mL | Standard Deviation 0.27 |
| Exercise + Testosterone | Change in Serum Prostate Specific Antigen (PSA) Level | 0.21 ng/mL | Standard Deviation 0.63 |
p-value: 0.49ANOVA
Other Pre-specified
Change in Serum Total Cholesterol Level
Time frame: Baseline and Six Months
Population: Only 9 participants in the Exercise+Placebo group, and 9 participants in the Exercise+Testosterone group, provided serum for cholesterol measurements at baseline and 6 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exercise + Placebo | Change in Serum Total Cholesterol Level | -3.2 mg/dL | Standard Deviation 15.4 |
| Exercise + Testosterone | Change in Serum Total Cholesterol Level | -9.0 mg/dL | Standard Deviation 42.9 |
p-value: 0.71ANOVA