The aim of this study is to understand what happens to muscle and bone in spinal cord injured
males after four months of training using stand training, with body weight support (BWS),
with testosterone replacement therapy (TRT), and electrical stimulation (ES). Specifically,
researchers will investigate nerve, muscle, and bone changes in the lower limbs in response
to stand training and ES when combined with TRT compared to i) standing alone with TRT; ii)
stand training alone with placebo; iii) stand training alone and ES with placebo.
To assess the effects of our novel tri combination Activity-Dependent Rehabilitation model
approach on muscle volume of the lower limbs.
i) To better define the mechanisms that contribute to changes in muscle.
Preliminary data from animal studies have shown increased expression of Activin receptor IIB
and increased nuclear localization of Smad2 and Smad3 after SCI and that these adverse
changes are reversed by androgens. Additional studies will examine mRNA levels for myostatin,
its receptor and its inhibitors (e.g., follistatins) and determine nuclear levels of Smad2
and Smad3. We will also measure resting energy expenditure to confirm that changes in muscles
mass correspond to anticipated metabolic effects.
ii) To evaluate the changes in bone and bone structure with Stand Training with TRT and ES.
Individuals with SCI not only lose motor and/or sensory function, they experience dramatic
muscle and bone loss. Locomotor training, an activity-based intervention that engages the
neuromuscular system below the level of lesion for standing and walking enhances EMG activity
and has shown modest improvements in muscle without any attenuation in bone density
[172-177]. Dynamic stand training, an important component of locomotor training, provides
sensory feedback related to standing and bilateral weight bearing, resulting in bilateral
muscle activation via central pathways through the spinal cord [161,178-181]. Thus, the stand
retraining component provides a physiologically relevant multi-muscle activation through
central pathways, dynamic gravity opposed loading of the legs and additional task specific
activation of the muscles [161,162,179]. Functional electrical stimulation is a method of
exercise that has been employed in the SCI population and has demonstrated success in
improving muscle, with less conclusive evidence for its effect on bone albeit there has been
speculation that although slowing or preventing bone loss may be feasible after SCI,
reversing such bone loss (i.e. restoring bone) is not possible, although the evidence is
primarily from applying FES to single muscles [151,171]. TRT has been shown to offer a
logical, efficacious, and cost-effective intervention to, in part, counteract these untoward
body composition, metabolic, and functional sequelae of relative hypogonadism in those with
chronic SCI . In addition, testosterone alone has been shown to increase muscle mass,
muscle strength, and bone in androgen-deficient men and older men with low testosterone
levels [182,183]. The model of compressive loads generated during the combination of stand
retraining and multi muscle ES will be multi-directional and will increase muscle strength
and the forces applied to the hip, femur and tibia bones. We anticipate that the model of
standing plus TRT will increase muscle mass and strength more than standing alone. The
combination of multi muscle TRT+ES while stand training will further increase muscle strength
compared to either arm alone, resulting in an increased synergistic response of benefit which
will surpass the threshold needed to significantly increase bone restoration
[102,184,185].This novel tri-combination synergistic approach of TRT, ES, and Stand Training
is being hypothesized to increase muscle mass and strength to a greater extent than that of
each alone or than that of only two of these interventions. Measurements of muscle torques
will be obtained to demonstrate a quantifiable relationship between muscle strength and bone
1. Must be a male between 18 and 58 years old;
2. Must have a spinal cord injury at a neurological level of injury between the C6-T10
level and an impairment grade A, B, or C, according to the American Spinal Injury
Association (ASIA) Impairment Scale. If a person with quadriplegia their motor level
will be used instead of neurological level. As a quadraplegic the motor level must be
3. Must be able to tolerate electrical stimulation and must show visible muscle
contraction to an electrical stimulus;
4. Must be wheelchair reliant for more than 75% of the time;
5. Must have low testosterone levels (300-325 ng/dL) as determined by a blood test done
at the baseline study visit.
1. Taking spasticity medication (i.e., baclofen). It may be possible that participant can
be weaned off of the spasticity medication prior to starting entry into the study.
This would be under the guidance of the study physician.
2. Less than 6 months or greater than 10 years post injury;
3. A score >3 on the Modified Ashworth Scale as determined by study staff;
4. Bone density measurement for the knee is at or below .5755 gm/cm2 as recorded by study
5. Weigh more than 225 lbs;
6. Taller than 6 feet 3 inches;
7. Presence of a cardiovascular disease;
8. Presence of pulmonary disease;
9. Presence of recent lower limb fractures;
10. Presence of severe contractures;
11. Presence of lower extremity deep vein thrombosis (within the last three months) or
other major medical illness;
12. Taking medications known to influence bone metabolism as determined by study staff
review of medications;
13. A major gastrointestinal problem such as swallowing or gastrointestinal reflux
14. Heart rate or rhythm problems;
15. A pacemaker;
16. Had spinal fusion, must have approval from the referring physician to receive ES -
assisted standing prior to acceptance into the study;
17. As determined by study staff and review of medications, taking medication known to
affect my level of testosterone;
18. A PSA greater than or equal to 4.0 ng/ml as determined by blood tests during screening
19. An elevated PSA or asymmetry or hardening of prostate as determined by blood tests and
digital rectal examination at screening visit.
20. Any known heart or blood vessel problems (cardiovascular disease)
21. An acute illness of any cause;
22. History of anabolic steroid use as determined by study staff review of participant's
23. Have a hematocrit greater than or equal to 55 as measured by the study team.
24. Have an abnormal liver function test from the hepatic panel (greater than 2.5 times
the normal value) as measured by the study team;
25. Have an abnormal digital rectal exam (DRE) at baseline suggestive of malignancy;
26. Currently abuse alcohol or drugs;
27. Have a significant psychological disorder;
28. Have a history of or a current malignancy;
29. Wish to contribute to the conception of a child.
If any of the following occurs in the experimental group following initiation of
testosterone replacement therapy participation will be terminated.
1. Hematocrit greater than or equal to 55;
2. Abnormal liver function test from the hepatic panel (greater than 2.5 times the normal
3. Worsening of any sleep disorder, as determined by the Investigators;
4. A PSA greater than or equal to 4.0 ng/ml;
5. Worsening of mood disorders; i.e. anger and depression as determined by the
6. Planning to contribute to the conception of a child during the study period.
7. Have participated in an electrical stimulation or TRT study in the previous 3 months.