Spinal Cord Injury
Conditions
Keywords
spinal cord injury, bone mineral density
Brief summary
Maintenance of bone mass following spinal cord injury (SCI) is essential to fracture prevention and the associated morbidity of bed rest and further secondary complications. Intravenous (IV) zoledronic acid (ZA) is an FDA-approved drug that has been shown to be more effective than other agents in reducing bone mass resorption and leg fractures in post-menopausal women, but has not been studied in patients with acute SCI. This will be a randomized, double-blind, placebo-controlled trial of IV ZA to prevent bone loss early after SCI. Up to 48 subjects will be randomized to receive a one-time dose of 5 mg of IV ZA versus placebo within 21 days of an SCI.
Detailed description
Maintenance of bone mass following spinal cord injury (SCI) is essential to fracture prevention and the associated morbidity of bed rest and further secondary complications. Intravenous (IV) zoledronic acid (ZA) has been shown to be more effective than other agents in reducing bone mass resorption and fracture of the legs in post-menopausal women, but has not been studied in acute spinal cord injury. Two previous studies of ZA in persons with subacute SCI, while promising, were inconclusive. As stated in the long range plan of the National Institute on Disability and Rehabilitation Research (NIDRR), one goal in the area of health and function is to focus on the onset of new conditions…exacerbation of existing conditions, or the development of coexisting conditions. This study is intended to demonstrate reduction in loss of bone mass at the hip and knee regions in acute SCI in a rigorous study of sufficient size to determine effectiveness of our intervention.
Interventions
DRUGZoledronic acid
5 mg zoledronic acid infused intravenously over two hours (2.5mg per hour), given only once, within 21 days of acute traumatic spinal cord injury.
DRUGnormal saline 0.9%
Infusion of equivalent volume of 0.9% normal saline to that of the reconstituted zoledronic acid, given only once over two hours, occurring within 21 days of acute traumatic spinal cord injury
Sponsors
Department of Health and Human Services
Thomas Jefferson University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Ages 18-65, male or female * Traumatic SCI with Neurological level C4-T10, American Spinal Injury Association (ASIA) Impairment Scale (AIS) A, * Serum calcium level \>7.0 mg/dL) at time of study drug administration * Screening baseline serum 25-hydroxy (25-OH) vitamin D of at least 13 ng/ml * No medical contraindication to supplemental vitamin D for participants whose levels are \>13 ng/ml but sub-therapeutic (\<32ng/ml) * No medical contraindication to supplemental calcium * Weight under 300 pounds, which is the maximum permitted on the dual-energy X-ray absorptiometry (DXA) scanner
Exclusion criteria
* Ventilator-dependent individuals * Chronic steroid use (defined as \>6 months) * Rheumatoid disease with use of prior disease modifying anti-rheumatic drugs (DMARDs) affecting bone density * History of osteoporosis or of treatment for osteopenia or osteoporosis with bisphosphonates, or selective reuptake estrogen modifying agents * Current use of medications\* including bisphosphonates to treat osteoporosis (\*note that prior calcium or vitamin D use is not an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Areal Bone Mineral Density at Hip | 4 months | Percent change in areal bone mineral density (aBMD) assessed by dual energy X-ray absorptiometry (DXA) at 4 months compared to baseline. This will compare aBMD at the hip. |
| Change in Areal Bone Mineral Density at Knee | 4 months | Percent change in areal bone mineral density (aBMD) assessed by dual energy X-ray absorptiometry (DXA) at 4 months compared to baseline. This will compare aBMD at the distal femur and proximal tibia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Biomarkers of Bone Resorption (sCTX) | 1 month, 4 months, 12 months | Change in sCTX from baseline to 1- and 4-months post intervention and 12-months post-injury. |
| Change in Biomarkers of Bone Formation (P1NP) | 1 month, 4 months | Change in serum P1NP from baseline to 1- and 4-months post intervention. |
| Safety and Tolerability of Zoledronic Acid | 72-hours and 1 month post intervention. | Assessment of the safety and tolerability of zoledronic acid in the acute spinal cord injury population. This will be done by examination reportable adverse events including fevers, flu-like symptoms, GI upset as measures of safety and report of patient's willingness to have participate in physical therapy in the first week after receiving medication as a measure of tolerability |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from two comprehensive acute inpatient rehabilitation facilities between September 2012 and March 2017.
Pre-assignment details
Prior to day 10 post injury, investigators obtained serum calcium, intact parathyroid hormone and serum 25-hydroxy (25-OH) vitamin D levels to determine further eligibility. Participants with vitamin D deficiency were allowed to receive supplementation to raise their level above 13 ng/mL in order to participate. One participant who was consented was subsequently found to have facial fractures and was withdrawn prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid 5 mg IV Infusion Single infusion of 5 mg intravenous zoledronic acid given within 21 days of acute traumatic spinal cord injury.
Zoledronic acid: 5 mg zoledronic acid infused intravenously over two hours (2.5mg per hour), given only once, within 21 days of acute traumatic spinal cord injury. | 10 |
| Normal Saline 0.9% Infusion of normal saline of equivalent volume to reconstituted zoledronic acid, given only once and run over 2 hours, to occur within 21 days of acute traumatic spinal cord injury.
normal saline 0.9%: Infusion of equivalent volume of 0.9% normal saline to that of the reconstituted zoledronic acid, given only once over two hours, occurring within 21 days of acute traumatic spinal cord injury | 5 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 12-month Follow-up | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Normal Saline 0.9% | Zoledronic Acid 5 mg IV Infusion | Total |
|---|---|---|---|
| Age, Continuous | 30.8 years STANDARD_DEVIATION 9.9 | 35.9 years STANDARD_DEVIATION 12.6 | 34.2 years STANDARD_DEVIATION 11.7 |
| Distal femur aBMD | 1.01 g/cm^2 STANDARD_DEVIATION 0.128 | 0.88 g/cm^2 STANDARD_DEVIATION 0.092 | 0.924 g/cm^2 STANDARD_DEVIATION 0.118 |
| Femoral neck aBMD | 0.98 g/cm^2 STANDARD_DEVIATION 0.178 | 0.86 g/cm^2 STANDARD_DEVIATION 0.078 | 0.90 g/cm^2 STANDARD_DEVIATION 0.127 |
| Intertrochanteric femur aBMD | 1.28 g/cm^2 STANDARD_DEVIATION 0.147 | 1.15 g/cm^2 STANDARD_DEVIATION 0.094 | 1.19 g/cm^2 STANDARD_DEVIATION 0.126 |
| procollagen N-1 terminal propeptide (P1NP) | 52.8 mcg/L STANDARD_DEVIATION 9.5 | 67.9 mcg/L STANDARD_DEVIATION 37.9 | 62.9 mcg/L STANDARD_DEVIATION 31.7 |
| Proximal tibia aBMD | 1.11 g/cm^2 STANDARD_DEVIATION 0.217 | 0.94 g/cm^2 STANDARD_DEVIATION 0.138 | 1.00 g/cm^2 STANDARD_DEVIATION 0.18 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Caucasian | 3 Participants | 6 Participants | 9 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 5 participants | 10 participants | 15 participants |
| serum C-telopeptide (CTX) | 980 pg/ml STANDARD_DEVIATION 439 | 1255 pg/ml STANDARD_DEVIATION 704 | 1163 pg/ml STANDARD_DEVIATION 626 |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 13 Participants |
| Total proximal femur areal bone mineral density (aBMD) | 1.09 g/cm^2 STANDARD_DEVIATION 0.138 | 0.98 g/cm^2 STANDARD_DEVIATION 0.076 | 1.02 g/cm^2 STANDARD_DEVIATION 0.108 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 5 |
| other Total, other adverse events | 7 / 10 | 1 / 5 |
| serious Total, serious adverse events | 2 / 10 | 1 / 5 |
Outcome results
Primary
Change in Areal Bone Mineral Density at Hip
Percent change in areal bone mineral density (aBMD) assessed by dual energy X-ray absorptiometry (DXA) at 12 months post-injury compared to baseline. This will compare aBMD at the hip.
Time frame: one year
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid 5 mg IV Infusion | Change in Areal Bone Mineral Density at Hip | Total proximal femur | -8.2 percentage change | Standard Deviation 3.64 |
| Zoledronic Acid 5 mg IV Infusion | Change in Areal Bone Mineral Density at Hip | Intertrochanteric femur | -8.62 percentage change | Standard Deviation 4.7 |
| Zoledronic Acid 5 mg IV Infusion | Change in Areal Bone Mineral Density at Hip | Femoral neck | -3.93 percentage change | Standard Deviation 5.6 |
| Normal Saline 0.9% | Change in Areal Bone Mineral Density at Hip | Total proximal femur | -21.3 percentage change | Standard Deviation 8.66 |
| Normal Saline 0.9% | Change in Areal Bone Mineral Density at Hip | Intertrochanteric femur | -19.4 percentage change | Standard Deviation 7 |
| Normal Saline 0.9% | Change in Areal Bone Mineral Density at Hip | Femoral neck | -17.0 percentage change | Standard Deviation 11.8 |
Primary
Change in Areal Bone Mineral Density at Hip
Percent change in areal bone mineral density (aBMD) assessed by dual energy X-ray absorptiometry (DXA) at 4 months compared to baseline. This will compare aBMD at the hip.
Time frame: 4 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid 5 mg IV Infusion | Change in Areal Bone Mineral Density at Hip | Total proximal femur | 0.92 percentage change | Standard Deviation 7.14 |
| Zoledronic Acid 5 mg IV Infusion | Change in Areal Bone Mineral Density at Hip | Intertrochanteric femur | 1.19 percentage change | Standard Deviation 7.77 |
| Zoledronic Acid 5 mg IV Infusion | Change in Areal Bone Mineral Density at Hip | Femoral neck | 0.97 percentage change | Standard Deviation 6.12 |
| Normal Saline 0.9% | Change in Areal Bone Mineral Density at Hip | Total proximal femur | -12.0 percentage change | Standard Deviation 7.5 |
| Normal Saline 0.9% | Change in Areal Bone Mineral Density at Hip | Intertrochanteric femur | -12.9 percentage change | Standard Deviation 7.67 |
| Normal Saline 0.9% | Change in Areal Bone Mineral Density at Hip | Femoral neck | -9.37 percentage change | Standard Deviation 6.39 |
Primary
Change in Areal Bone Mineral Density at Knee
Percent change in areal bone mineral density (aBMD) assessed by dual energy X-ray absorptiometry (DXA) at 4 months compared to baseline. This will compare aBMD at the distal femur and proximal tibia.
Time frame: 4 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid 5 mg IV Infusion | Change in Areal Bone Mineral Density at Knee | Distal femur | -0.78 percentage change | Standard Deviation 4.46 |
| Zoledronic Acid 5 mg IV Infusion | Change in Areal Bone Mineral Density at Knee | Proximal tibia | -0.24 percentage change | Standard Deviation 11.7 |
| Normal Saline 0.9% | Change in Areal Bone Mineral Density at Knee | Distal femur | -6.75 percentage change | Standard Deviation 4.04 |
| Normal Saline 0.9% | Change in Areal Bone Mineral Density at Knee | Proximal tibia | -8.56 percentage change | Standard Deviation 14.1 |
Primary
Change in Areal Bone Mineral Density at Knee
Percent change in areal bone mineral density (aBMD) assessed by dual energy X-ray absorptiometry (DXA) at 12 months post-injury compared to baseline. This will compare aBMD at the distal femur and proximal tibia.
Time frame: one year
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid 5 mg IV Infusion | Change in Areal Bone Mineral Density at Knee | Distal femur | -8.07 percentage change | Standard Deviation 5.2 |
| Zoledronic Acid 5 mg IV Infusion | Change in Areal Bone Mineral Density at Knee | Proximal tibia | -4.54 percentage change | Standard Deviation 9.89 |
| Normal Saline 0.9% | Change in Areal Bone Mineral Density at Knee | Distal femur | -10.0 percentage change | Standard Deviation 8.7 |
| Normal Saline 0.9% | Change in Areal Bone Mineral Density at Knee | Proximal tibia | -10.0 percentage change | Standard Deviation 18.3 |
Secondary
Change in Biomarkers of Bone Formation (P1NP)
Change in serum P1NP from baseline to 1- and 4-months post intervention.
Time frame: 1 month, 4 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Zoledronic Acid 5 mg IV Infusion | Change in Biomarkers of Bone Formation (P1NP) | 1 month | 5.66 percentage change |
| Zoledronic Acid 5 mg IV Infusion | Change in Biomarkers of Bone Formation (P1NP) | 4 months | 32.43 percentage change |
| Normal Saline 0.9% | Change in Biomarkers of Bone Formation (P1NP) | 1 month | 65.96 percentage change |
| Normal Saline 0.9% | Change in Biomarkers of Bone Formation (P1NP) | 4 months | 27.45 percentage change |
Secondary
Change in Biomarkers of Bone Resorption (sCTX)
Change in sCTX from baseline to 1- and 4-months post intervention and 12-months post-injury.
Time frame: 1 month, 4 months, 12 months
Population: Ons subject in each group did not return for 12-month labs
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Zoledronic Acid 5 mg IV Infusion | Change in Biomarkers of Bone Resorption (sCTX) | 1 month | -64.1 percentage change |
| Zoledronic Acid 5 mg IV Infusion | Change in Biomarkers of Bone Resorption (sCTX) | 4 months | -45.9 percentage change |
| Zoledronic Acid 5 mg IV Infusion | Change in Biomarkers of Bone Resorption (sCTX) | 12 months | -43.6 percentage change |
| Normal Saline 0.9% | Change in Biomarkers of Bone Resorption (sCTX) | 1 month | 14.4 percentage change |
| Normal Saline 0.9% | Change in Biomarkers of Bone Resorption (sCTX) | 4 months | 23.9 percentage change |
| Normal Saline 0.9% | Change in Biomarkers of Bone Resorption (sCTX) | 12 months | -5.11 percentage change |
Secondary
Safety and Tolerability of Zoledronic Acid
Assessment of the safety and tolerability of zoledronic acid in the acute spinal cord injury population. This will be done by examination reportable adverse events including fevers, flu-like symptoms, GI upset as measures of safety and report of patient's willingness to have participate in physical therapy in the first week after receiving medication as a measure of tolerability
Time frame: 72-hours and 1 month post intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Zoledronic Acid 5 mg IV Infusion | Safety and Tolerability of Zoledronic Acid | Fever > 100.9 within 72 hours of study drug infusion | 7 Participants |
| Zoledronic Acid 5 mg IV Infusion | Safety and Tolerability of Zoledronic Acid | Flu-like symptoms within 72 hours of study drug infusion | 6 Participants |
| Zoledronic Acid 5 mg IV Infusion | Safety and Tolerability of Zoledronic Acid | Acute kidney injury | 1 Participants |
| Normal Saline 0.9% | Safety and Tolerability of Zoledronic Acid | Fever > 100.9 within 72 hours of study drug infusion | 1 Participants |
| Normal Saline 0.9% | Safety and Tolerability of Zoledronic Acid | Flu-like symptoms within 72 hours of study drug infusion | 1 Participants |
| Normal Saline 0.9% | Safety and Tolerability of Zoledronic Acid | Acute kidney injury | 1 Participants |