Zoledronic Acid in Acute Spinal Cord Injury

Study Overview
=================
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.

Official Title
-----------------
Zoledronic Acid to Prevent Bone Loss After Acute Spinal Cord Injury

Conditions
-----------------
Spinal Cord Injury

Intervention / Treatment
-----------------
* Drug: Zoledronic acid
* Drug: normal saline 0.9%


Participation Criteria
=================
Eligibility Criteria
-----------------
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 exclusion criteria) History of more than one lower extremity osteoporosis-related fracture Chronic renal insufficiency, creatinine clearance < 35 ml/min, during screening End stage liver or kidney disease Medical conditions resulting in hypogonadal states that affect bone density Uncontrolled thyroid disease/thyrotoxicosis Hereditary or acquired metabolic bone disorder History of use of unfractionated heparin for >1 year History of selected antiseizure medications, specifically phenobarbital, phenytoin, carbamazepine, sodium valproate >1 year Acute or chronic bilateral lower extremity fractures involving tibia or femur, with placement of surgical hardware in any areas of above locations Severe hypotension requiring use of intravenous blood pressure agents such as dopamine, norepinephrine or phenylephrine. Exception may allow for patients on pressors who arm experiencing hypotension as they acclimate to upright posture. Inability to provide informed consent and understand the consent process Facial fractures requiring oral surgery Dental surgery or oral maxillofacial surgery within 2 weeks of anticipated study drug administration Pregnancy present on admission Vitamin D deficiency on admission testing (serum 25-OH D reported as < 13 ng/mL) Patients with an established reaction to, or history of, anaphylactic shock to aspirin

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zoledronic Acid 5 mg IV infusion<br>Single infusion of 5 mg intravenous zoledronic acid given within 21 days of acute traumatic spinal cord injury. | Drug: Zoledronic acid<br>* 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.<br>* Other names: Reclast;|
| Placebo Comparator: normal saline 0.9%<br>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. | Drug: normal saline 0.9%<br>* 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<br>* Other names: 0.9% saline;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 4 months | 
| 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. | 4 months | 
| 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. | one year | 
| 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. | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Biomarkers of Bone Resorption (sCTX) | Change in sCTX from baseline to 1- and 4-months post intervention and 12-months post-injury. | 1 month, 4 months, 12 months | 
| Change in Biomarkers of Bone Formation (P1NP) | Change in serum P1NP from baseline to 1- and 4-months post intervention. | 1 month, 4 months | 
| 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 | 72-hours and 1 month post intervention. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
spinal cord injury, bone mineral density