Spinal Cord Injury
Conditions
Keywords
Vitamin D, Electrical Stimulation, Bone Density, Cancellous Bone, Spinal Cord Injury, Rehabilitation, Rowing Exercise
Brief summary
Neurogenic osteoporosis is a common complication of spinal cord injury (SCI) that is associated with low impact bone fractures. It is concerning that more than 46,000 Veterans affected with SCI and are at risk of osteoporosis and possible low impact fractures. About fifty percent of all individuals with SCI will develop low impact fracture in their life time. The management of osteoporosis-related fractures can impose substantial economic burden on the health care system, the individual and the families. Previous studies did not succeed in reversing the process of bone loss after SCI. In the present pilot study, we will evaluate the effect of Neuromuscular Electrical Stimulation Resistance Training in combination with oral Vitamin D supplementation, on bone quality in Veterans with chronic SCI, using a randomized experimental design.
Detailed description
Neurogenic osteoporosis is a devastating problem that is likely to impact 46,000 Veterans with chronic spinal cord injury (SCI). It is typically associated with low impact fractures of long bones and other medical comorbidities. It is estimated that approximately fifty percent of all individuals with SCI will develop low impact fracture during their lifetime. The management of osteoporosis related fractures can impose substantial economic burden on the health care system, individuals with SCI and their families. Advancement in medical research clearly indicated that neurogenic osteoporosis is linked to reduced loading and Vitamin D (Vit D) deficiency. Our pilot work indicated that a simple rehabilitation paradigm targeting towards evoking skeletal muscle hypertrophy may attenuate deterioration in trabecular bone parameters after SCI. Evoked resistance training (RT) using surface neuromuscular electrical stimulation (NMES) has been shown as a successful and feasible home-based approach to load skeletal muscles after SCI. Our earlier results may imply long-term compliance and adherence if successfully applied in conjunction with a telehealth approach. In the present study, we propose a simple home-based approach of using NMES RT in conjunction with oral Vit D supplementation on trabecular bone quality in 20 Veterans with chronic SCI. Data will include measurements of trabecular bone quality as determined by magnetic resonance imaging (MRI) and bone biomarkers associated with the process of bone remodeling. Twenty participants with chronic (\> 1-year post-injury) motor complete (AIS A and B) SCI (18 to 65 years of age) will be randomly assigned into either NMES RT plus 2000IU of Vit D (10 participants) or passive movement plus 2000IU Vit D (10 participants) to participate in a repeated measure design trial for 9 months. The NMES RT plus Vit D will undergo 4.5 months of open kinematic chain resistance training followed by 4.5 months of closed kinematic chain using simple rowing approach. This pilot work will have two main specific aims. Aim 1. To determine the impact of home-based NMES RT protocol plus oral Vit D supplementation compared to passive movement plus oral Vit D on bone microarchitectural properties. Aim 2. To determine the impact of home-based NMES RT protocol plus oral Vit D compared to passive movement and Vit D supplementation on biomarkers of bone formation and bone resorption.
Interventions
DEVICENMES
Subjects will undergo 4.5 months of open kinematic chain resistance training followed by 4.5 months of closed kinematic chain using simple rowing approach
DRUGVitamin D
2000IU oral vitamin D supplementation daily for 9 months
BEHAVIORALPassive movement
Subjects will perform simple passive movement exercise for their legs while sitting in their wheelchairs at their home. The frequency of the training will be twice weekly
Sponsors
VA Office of Research and Development
Virginia Commonwealth University
NYU Langone Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
There are two groups
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
To be included, participants will have to: * Be 18-65 years of age * Have history of traumatic SCI ( 1-year) with NLI of C8-T10 and AIS A or B (confirmed by AIS examination performed by PI or a qualified Provider * Have a caregiver who is available and willing to be trained to apply intervention protocol in the home (placing weights and positioning the Veteran) throughout study duration * Be a wheelchair user for primary mode of mobility * Have Knee extensors that must respond to standard surface electrical stimulation procedures (stimulation frequency procedures, 30 Hz; pulse duration:1 ms and amplitude of the current of less than200 mA) * Be able to receive written clearance from their medical Providers to ensure safety of participants * Be a Veteran (male or female), however, the Department of Veteran Affairs has limited number of female Veterans, especially those with motor complete injury at level C8-T10 (currently, there are only 3 female Veterans with the target NLI in our SCI registry). Hence, inclusion of women Veterans may be challenging due to this disparity in the SCI population. If we fail to recruit 20 Veterans, we may seek an IRB approval to recruit non-Veterans to meet our target sample size * Have normal ECG * Commit to undergo 9 months of trial; 4.5 months of open-kinematic chain resistance training followed by 4.5 months of closed-kinematic chain using simple rowing approach + Vit. D supplementation (Experimental group) or 9 months of passive movement +Vit D supplementation (control group)
Exclusion criteria
Potential participants will be excluded if they exhibit any of the following: * Neurological injury other than SCI * Older than 65 years of age as they may likely have considerable amount of bone loss at that age * Have severe osteoporosis because loading porous/fragile bone by electrical stimulation may result in bone fracture * Those classified as AIS C \& D, as they may already be engaging in weight bearing activities that may confound the results of this trial * Unhealed or unstable fractures in either lower or upper extremities * Severe scoliosis, deformities in the hip, knee, or ankles OR impaired range-of-motion, as these could be a barrier to safe positioning on the rowing machine, and on MRI or DXA tables * No caregiver or family member/significant other, willing to help with placing weights and positioning participants' lower extremities on the rowing machine * Untreated or uncontrolled hypertension (systolic blood pressure (BP) \> 140 mmHg; diastolic BP \> 90 mmHg), and/or sudden hypotension upon transferring from bed to wheelchair, characterized by a drop in BP by 20 mmHg (especially in persons with tetraplegia) or heart rate \> 100 beats per minute * Anti-coagulation or anti-platelet therapy (including aspirin) * Implanted pacemakers, implanted defibrillator devices or any metallic implants including knee or hip implants * Presence of bullets in vertebral column or shrapnel anywhere in the body that may interfere with MRI procedure * Other medical conditions including cardiovascular disease, uncontrolled type II DM, active deep vein thrombosis (DVT), uncontrolled autonomic dysreflexia, use of insulin for DM management, pressures injuries of stage 3 or higher, or active urinary tract infection * Severe hypercalcemia (serum calcium \> 16mg/dl), stage III-V kidney disease, post-menopausal or estrogen dependent female, and men undergoing anti-androgen therapy or are post orchiectomy * DXA total body T-score less than -2.5. Total hip BMD T-scores \< -3.5 and knee BMD scores of less than 0.6 g/cm2 * Untreatable severe spasticity bearing on potential participants' activities of daily living, such as transfers from bed to wheelchair or maintaining position in wheelchair * Any psychiatric illness confounding judgment or cognitive impairment in participant or caregiver who is expected to help participant in the trial * Those with prosthetic lower limbs * Any condition that, in the judgment of the PI or other medical Providers, preclude safe participation in the study and/or has the potential to expose/increase participant's risk of infection * Unable to tolerate increasing either electrical stimulation current or weights to the lower legs for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Trabecular Plate Width (Tb.PW) for Femur and Tibia at 4.5 Months | 4.5 months | The outcome measure was trabecular plate width expressed in μm, as measured by a non-contrast magnetic resonance imaging (MRI) of the femur and tibia. A trained radiology technician performed the MRI using a 3.0T magnet (GE Discovery MR750 software, version: DV24 System 804675VA3T; GE Waukesha, WI). A specific knee coil with a 3D fast-spin gradient echo (10 min) sequence was used to obtain high-resolution images (20-22 FOV). A bilateral phased array coil (USA Instruments) was used to collect 30 contiguous 1-mm slices in the axial plane, starting with the distal end of the femur, and another block of 30 starting with the proximal end of the tibia. The metric used was the median change from baseline to 4.5 months and 9 months, respectively. Higher values indicate improved bone trabeculae. |
| Change in Trabecular Plate Width (Tb.PW) for Femur and Tibia at 9 Months | 9 months | The outcome measure was trabecular spacing expressed in μm, as measured by a non-contrast magnetic resonance imaging (MRI) of the femur and tibia. A trained radiology technician performed the MRI using a 3.0T magnet (GE Discovery MR750 software, version: DV24 System 804675VA3T; GE Waukesha, WI). A specific knee coil with a 3D fast-spin gradient echo (10 min) sequence was used to obtain high-resolution images (20-22 FOV). A bilateral phased array coil (USA Instruments) was used to collect 30 contiguous 1-mm slices in the axial plane, starting with the distal end of the femur, and another set of 30 slices starting with the proximal end of the tibia. The metric used was the median change from baseline to 9 months. Higher values indicate improved Tb. PW. |
| Change in Trabecular Spacing (Tb.Sp) for Femur and Tibia at 4.5 Months | 4.5 months | The outcome measure was trabecular spacing expressed in μm, as measured by a non-contrast magnetic resonance imaging (MRI) of the femur and tibia. The metric used was the median change from baseline to 4.5 months and 9 months, respectively. Higher values indicate poorer bone health. A trained radiology technician performed the MRI using a 3.0T magnet (GE Discovery MR750 software, version: DV24 System 804675VA3T; GE Waukesha, WI). A specific knee coil with a 3D fast-spin gradient echo (10 min) sequence was used to obtain high-resolution images (20-22 FOV). A bilateral phased array coil (USA Instruments) was used to collect 30 contiguous 1-mm slices in the axial plane, starting with the distal end of the femur, and another block of 30 starting with the proximal end of the tibia. |
| Change in Trabecular Spacing (Tb.Sp) for Femur and Tibia at 9 Months | 9 months | The outcome measure was trabecular plate width expressed in μm, as measured by a non-contrast magnetic resonance imaging (MRI) of the femur and tibia. A trained radiology technician performed the MRI using a 3.0T magnet (GE Discovery MR750 software, version: DV24 System 804675VA3T; GE Waukesha, WI). A specific knee coil with a 3D fast-spin gradient echo (10 min) sequence was used to obtain high-resolution images (20-22 FOV). A bilateral phased array coil (USA Instruments) was used to collect 30 contiguous 1-mm slices in the axial plane, starting with the distal end of the femur, and another block of 30 beginning with the proximal end of the tibia. The metric used was the median change from baseline to 4.5 months and 9 months, respectively. Higher values indicate improved bone trabeculae. |
| Change in Trabecular Network Area Density (Tb.NA) Measured in mm^2/mm^3) at 4.5 Months | 4.5 months | The outcome measure was trabecular network area density expressed in mm\^2/mm\^3, as measured by a non-contrast magnetic resonance imaging (MRI) of the femur and tibia. The metric used was the median change from baseline to 4.5 months and 9 months, respectively. Higher values indicate improved bone trabeculae network area density. A trained radiology technician performed the MRI using a 3.0T magnet (GE Discovery MR750 software, version: DV24 System 804675VA3T; GE Waukesha, WI). A specific knee coil with a 3D fast-spin gradient echo (10 min) sequence was used to obtain high-resolution images (20-22 FOV). A bilateral phased array coil (USA Instruments) was used to collect 30 contiguous 1-mm slices in the axial plane, starting with the distal end of the femur, and another block of 30 starting with the proximal end of the tibia. |
| Change in Trabecular Network Area Density (Tb.NA) as Measured by MRI at 9 Months | 9 months | The outcome measure was trabecular network area density expressed in mm\^2/mm\^3, as measured by a non-contrast magnetic resonance imaging (MRI) of the femur and tibia. The metric used was the median change from baseline to 4.5 months and 9 months, respectively. Higher values indicate improved bone trabeculae network area density. A trained radiology technician performed the MRI using a 3.0T magnet (GE Discovery MR750 software, version: DV24 System 804675VA3T; GE Waukesha, WI). A specific knee coil with a 3D fast-spin gradient echo (10 min) sequence was used to obtain high-resolution images (20-22 FOV). A bilateral phased array coil (USA Instruments) was used to collect 30 contiguous 1-mm slices in the axial plane, starting with the distal end of the femur, and another block of 30 starting with the proximal end of the tibia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Bone Mineral Density in Distal Femur as Measured by Dual Energy X-ray Absorptiometry (DXA) Scan | 4.5 months | A dual-energy X-ray absorptiometry scan was performed by a trained technologist using a General Electric iDXA scanner (GE Lunar Inc., Madison, WI) at baseline, 4.5 months, and at 9 months. The scanner was calibrated using a phantom calibration box that mimics human tissues to assess scan precision and reliability. All participants had their jewelry removed before being placed supine on the scanning table with their arms internally rotated and palms facing medially. Participants received scans in the region of interest on both sides (L \& R) of the body (hip, knee), as well as the lumbar spine. |
| Change in Distal Femur Bone Mineral Density | 9 months | A dual-energy X-ray absorptiometry scan was performed by a trained technologist using a General Electric iDXA scanner (GE Lunar Inc., Madison, WI) at baseline, 4.5 months, and at 9 months. The scanner was calibrated using a phantom calibration box that mimics human tissues to assess scan precision and reliability. All participants had their jewelry removed before being placed supine on the scanning table with their arms internally rotated and palms facing medially. Participants received scans in the region of interest on both sides (L \& R) of the body (hip, knee), as well as the lumbar spine. |
| Change in Proximal Tibia Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Scan | 4.5 months | A dual-energy X-ray absorptiometry scan was performed by a trained technologist using a General Electric iDXA scanner (GE Lunar Inc., Madison, WI) at baseline, 4.5 months, and at 9 months. The scanner was calibrated using a phantom calibration box that mimics human tissues to assess scan precision and reliability. All participants had their jewelry removed before being placed supine on the scanning table with their arms internally rotated and palms facing medially. Participants received scans in the region of interest on both sides (L \& R) of the body (hip, knee), as well as the lumbar spine. |
| Change in Proximal Tibia Bone Mineral Density as Measured by a Dual-energy X-ray Absorptiometry (DXA) Scan | 9 months | A dual-energy X-ray absorptiometry scan was performed by a trained technologist using a General Electric iDXA scanner (GE Lunar Inc., Madison, WI) at baseline, 4.5 months, and at 9 months. The scanner was calibrated using a phantom calibration box that mimics human tissues to assess scan precision and reliability. All participants had their jewelry removed before being placed supine on the scanning table with their arms internally rotated and palms facing medially. Participants received scans in the region of interest on both sides (L \& R) of the body (hip, knee), as well as the lumbar spine. |
| Change in Bone Formation Marker - Procollagen Type 1 N-terminal Propeptide (P1NP) in mcg/L | 4.5 months | Fasting blood samples were collected by venipuncture by the same individual at roughly the same time of day and under similar conditions to evaluate P1NP, a marker of bone formation. Samples were analyzed at Quest Diagnostics (Nichols Institute, Chantilly, VA). The reference range for P1NP is 30-110 mcg/L, and an increase indicates poor bone health. |
| Change in Bone Formation Marker - Procollagen Type 1 Intact N-Propeptide (P1NP) Measured in mcg/L | 9 months | Fasting blood samples were collected by venipuncture by the same individual at roughly the same time of day and under similar conditions to evaluate P1NP, a marker of bone formation. Samples were analyzed at Quest Diagnostics (Nichols Institute, Chantilly, VA). The reference range for P1NP is 30-110 mcg/L, and an increase indicates poor bone health. |
| Change in Bone Resorption Marker-C-telopeptide of Type I Collagen (CTX) | 4.5 months | CTX is a biochemical marker of bone resorption. Fasting blood samples were collected from participants via venipuncture by the same person at approximately the same time of day and under similar conditions to measure CTX (pg/mL). The samples were analyzed by Quest Diagnostics (Nichols Institute, Chantilly, VA). Sex and age-related reference ranges for males are: 18-29 years (87-1200), 30-39 years (70-780), 40-49 years (60-700), and 50-68 years (87-345). CTX is released into circulation when osteoclasts break down bone matrix; therefore, higher levels indicate increased osteoclastic activity and faster bone turnover. |
| Change in Serum 25-hydroxyvitamin D [25(OD)D] Level | 4.5 months | 25-hydroxyvitamin D is the major circulating form of vitamin D and the most reliable biochemical indicator of an individual's vitamin D status. It is essential for maintaining bone strength, balance of minerals, and overall bone integrity. Adequate levels of 25(OH)D enhance intestinal calcium absorption for normal bone formation and remodeling. When vitamin D levels are low, calcium absorption decreases, leading to secondary hyperparathyroidism, which in turn increases bone resorption and weakens bone structure. The normal range is 32 to 100 ng/mL. Less than 20ng/mL is considered a deficiency, and 20 to 29 ng/mL is insufficiency. |
| Change in Serum 25-hydroxyvitamin D Level | 9 months | 25-hydroxyvitamin D is the main circulating form of vitamin D and the most reliable biochemical marker of an individual's vitamin D status. Vitamin D is crucial for maintaining bone strength, mineral balance, and overall bone health. Adequate levels of 25(OH)D improve intestinal calcium absorption, which is vital for normal bone formation and remodeling. When vitamin D levels are low, calcium absorption drops, leading to secondary hyperparathyroidism, which then increases bone resorption and weakens bone structure. The normal range is 32 to 100 ng/mL. Less than 20 ng/mL is considered a deficiency, and 20 to 29 ng/mL indicates insufficiency. |
| Change in Quality-of-life Measure: Physical Health (Scored on 1-5 Likert Scale) | 9 months | The secondary outcome measure was the WHO Quality of Life (WHOQOL)-BREF, a 26-item self-administered questionnaire developed by WHO to assess quality of life across four domains, including two general items. Each item is rated on a 5-point Likert scale (1 = negative or low perception, 5 = positive or high perception). The instrument includes four health domains: physical health, psychological health, social relationships, and environmental engagement. Physical health (7 items) evaluates energy, fatigue, sleep, mobility, pain, and activities of daily living. The maximum score for this domain is 100, and a higher score indicates a better quality of life. |
| Change in Quality-of-life Measure- Psychological Health | 9 months | The WHOQOL-BREF instrument was used to assess QOL in four domains of health, including: physical health, psychological health, social relationships, and environmental engagement. The mean scores of items within each domain were used to calculate domain scores, which were then transformed using the WHOQOL-BREF scoring manual to make the domain scores comparable to those used in the WHOQOL-100. Items 3, 4, and 26 were reverse-coded per the instruction manual. Psychological health (6 items) measures self-esteem, body image, negative and positive feelings, and concentration. A higher score denotes higher psychological health. |
| Change in Quality-of-life Measure- Social Relationships Domain | 9 months | The WHOQOL-BREF instrument was used to assess QOL in four domains of health, including: physical health, psychological health, social relationships, and environment. The mean scores of items within each domain were used to calculate domain scores, which were then transformed using the WHOQOL-BREF scoring manual to make the domain scores comparable to those used in the WHOQOL-100. Items 3, 4, and 26 were reverse-coded per the instruction manual. Social relationships (3 items) assess personal relationships, social support, and sexual life. A higher score denotes a higher social relationships. |
| Change in Quality-of-life Measure-environmental Engagement Domain | 9 months | The WHOQOL-BREF instrument was used to assess QOL in four domains of health participants, including: physical health, psychological health, social relationships, and environmental engagement. The mean scores of items within each domain were used to calculate domain scores, which were then transformed using the WHOQOL-BREF scoring manual to make the domain scores comparable to those used in the WHOQOL-100. Items 3, 4, and 26 were reverse-coded per the instruction manual. Environmental engagement (8 items) assesses financial resources, safety, home environment, health care access, and opportunities for recreation and learning. A Higher score denotes better environmental engagement. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDora E Ifon, PhD
Hunter Holmes McGuire VA Medical Center, Richmond, VA
Participant flow
Recruitment details
Participants were recruited from a spinal cord injury outpatient clinic. One participant was referred by another participant.
Pre-assignment details
One participant was excluded prior to the start of the study because he failed to complete baseline screening and did not respond to phone calls.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 53 years |
| Baseline Bone formation marker (Procollagen Type 1 Intact N-Propeptide [P1NP] in mcg/L | 46 mcg/L |
| Baseline Bone resorption marker (C-telopeptide of Type I collagen [CTX]), in pg/mL | 351.5 pg/mL |
| Baseline Distal Femur Bone Mineral Density (BMD) in g/cm2 as measured by DXA Left distal femur BMD | 1.20 g/cm2 |
| Baseline Distal Femur Bone Mineral Density (BMD) in g/cm2 as measured by DXA Right distal femur BMD | 0.96 g/cm2 |
| Baseline environmental engagement domain of Quality of life measure. | 81 units on a scale (0-100) |
| Baseline Physical domain of Quality of life measure | 72 units on a scale (0-100) |
| Baseline Proximal tibia Bone Mineral Density in g/cm2 as measured by DXA. Left proximal tibia BMD | 1.50 g/cm2 |
| Baseline Proximal tibia Bone Mineral Density in g/cm2 as measured by DXA. Right proximal tibia BMD | 1.5 g/cm2 |
| Baseline Psychological health domain of Quality of life measure | 81 units on a scale (0-100) |
| Baseline Serum concentration of 25-hydroxyvitamin D in ng/mL | 23.4 ng/mL |
| Baseline Social relationship domain of Quality of life measure. | 75 units on a scale (0-100) |
| Baseline Trabecular network area density (Tb.NA) (mm^2/mm^3) measured by MRI Tb.NA for left femur and tibia | 0.61 mm^2/mm^3 |
| Baseline Trabecular network area density (Tb.NA) (mm^2/mm^3) measured by MRI Tb.NA for right femur and tibia | 445.60 mm^2/mm^3 |
| Baseline Trabecular plate width (Tb.PW) in μm as measured by MRI Tb.PW for left femur and tibia | 1791.44 μm |
| Baseline Trabecular plate width (Tb.PW) in μm as measured by MRI Tb.PW for right femur and tibia | 1829.0 μm |
| Baseline Trabecular spacing (Tb.Sp) (um) as measured by MRI Tb.Sp for left femur and tibia | 486.66 μm |
| Baseline Trabecular spacing (Tb.Sp) (um) as measured by MRI Tb.Sp for right femur and tibia | 509.55 μm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 2 |
| other Total, other adverse events | 1 / 4 | 0 / 2 |
| serious Total, serious adverse events | 0 / 4 | 0 / 2 |
Outcome results
None listed