Acute Spinal Cord Injury, Bone Loss, Osteoporosis, Spinal Cord Injury
Conditions
Keywords
Osteoporosis, Spinal Cord Injury, Bone Diseases, Metabolic Bone Diseases, Musculoskeletal Diseases, Spinal Cord Diseases, Central Nervous System Diseases, Nervous System Diseases, Nervous System, Wounds and Injuries, Bone Density Conservation Agents, Physiological Effects of Drugs, Pharmacologic Actions, Department of Defense
Brief summary
The overall objective of this study is to define an effective therapeutic approach, using currently available medication, to prevent or mitigate the loss of bone mass and bone strength that occurs after acute spinal cord injury.
Detailed description
This is a randomized, double-blind placebo-controlled study of zoledronic acid to evaluate its efficacy and safety over a 2 year period for the prevention of bone loss and maintenance of bone strength in individuals with recent onset SCI (see diagram below). Subjects will be randomized at the baseline visit to receive either zoledronic acid or placebo. At the end of the first year of the study, each treatment group will be re-randomized to either zoledronic acid or placebo to evaluate the durability of response to zoledronic acid and the utility of serum bone markers to guide therapeutic decision making. DXA imaging, CT imaging and bone markers will be obtained at baseline, 3 months, 6 months, 12 months, 18 months and 24 months.
Interventions
DRUGZoledronic acid
Intravenous infusion of zoledronic acid 5 mg.
DRUGPlacebo
Placebo (saline) infusion to match zoledronic acid
Sponsors
Congressionally Directed Medical Research Programs
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* In-patient at Rehabilitation Institute of Chicago (RIC) or an outpatient who was recently discharged from RIC * Males and females * Age \>/=18 years * Medically stable in the opinion of subject's physiatrist * SCI at within 120 days inclusive at time of screening * SCI with inability to ambulate independently * ASIA Impairment Scale (AIS) A, B, or C, at time of study entry * Capable of positioning to have DXA performed * Able to tolerate acetaminophen * No known endocrinopathies (diabetes type 1 or 2 can be included) * Normal TSH levels * Normal 25-OH vitamin D levels (\>/= 20 ng/ml) at baseline (subjects may be repleted) * Normal calcium levels * Normal renal function (creatinine \<2.0 mg/dl) * Well hydrated with adequate intake of liquids * Able to return for all follow-up visits * Capable of reading and understanding informed consent document * Males and females of childbearing potential must be willing and able to use double barrier method of contraception for 2 months after having received study drug
Exclusion criteria
* Have Paget's disease of the bone * Malignancy as a cause of acute SCI * Have unexplained high levels of alkaline phosphatase in blood * Any active gastrointestinal condition that results in malabsorption * Poor dental hygiene or requirement for invasive dental procedure within two months prior to enrollment * History of bone metastasis and skeletal malignancies * History of alcoholism or drug abuse within the 2 years prior to study screening * Other medical conditions that in the opinion of the investigator would preclude the subject from completing the study * Elevated liver function tests \>2x normal * Currently being prescribed anti-convulsants at a dose or frequency that is determined to interfere with bone metabolism as determined by the investigator * Currently being prescribed glucocorticoids, other than inhaled glucocorticoids * Current or recent use any bone-active agents, including any bisphosphonate, raloxifene, hormone therapy (estrogen and estrogen/progestin), calcitonin or strontium-containing compounds within 60 days of screening. * Pregnant, planning to become pregnant, or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Bone Mass Density (BMD) in the Hip | 0-12 months | Percent change of bone mass density (BMD) in the total hip (as measured by DXA) |
| Percent Change of Bone Mass Density (BMD) in the Femoral Neck | 0-12 months | Percent change of bone mass density (BMD) in the femoral neck (as measured by DXA) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in the Epiphyseal Integral Bone Mass Content (iBMC) of the Femur | 0-12 months | Percent change in the epiphyseal integral bone mass content (iBMC) of the femur, as collected by CT. |
| Percent Change in the Metaphyseal Integral Bone Mass Content (iBMC) of the Femur | 0-12 months | Percent change in the metaphyseal integral bone mass content (iBMC) of the femur, as collected by CT |
Countries
United States
Participant flow
Recruitment details
Patients with acute SCI were recruited from the Shirley Ryan AbilityLab, formerly known as the Rehabilitation Institute of Chicago. Recruitment took place between February 2015 and February 2018.
Pre-assignment details
After meeting eligibility, participants were randomized in a blinded fashion and received study drug at the baseline visit.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid Intravenous infusion of zoledronic acid (Zol) 5 mg at baseline | 30 |
| Placebo Intravenous infusion of placebo (saline) at baseline. | 30 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 5 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Zoledronic Acid | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 28 Participants | 57 Participants |
| Age, Continuous | 37.3 years STANDARD_DEVIATION 15.9 | 38.2 years STANDARD_DEVIATION 15.2 | 37.8 years STANDARD_DEVIATION 15.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 7 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 23 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 6 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 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 | 20 Participants | 21 Participants | 41 Participants |
| Region of Enrollment United States | 30 participants | 30 participants | 60 participants |
| Sex: Female, Male Female | 9 Participants | 3 Participants | 12 Participants |
| Sex: Female, Male Male | 21 Participants | 27 Participants | 48 Participants |
| Time Since Injury (Days) | 68.7 days STANDARD_DEVIATION 28.5 | 62.7 days STANDARD_DEVIATION 23.2 | 65.7 days STANDARD_DEVIATION 25.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 28 / 30 | 22 / 30 |
| serious Total, serious adverse events | 8 / 30 | 9 / 30 |
Outcome results
Primary
Percent Change in Bone Mass Density (BMD) in the Hip
Percent change of bone mass density (BMD) in the total hip (as measured by DXA)
Time frame: 0-12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid | Percent Change in Bone Mass Density (BMD) in the Hip | -2.21 percent change in bone mass density |
| Placebo | Percent Change in Bone Mass Density (BMD) in the Hip | -12.82 percent change in bone mass density |
p-value: 0.05Mixed Models Analysis
Primary
Percent Change of Bone Mass Density (BMD) in the Femoral Neck
Percent change of bone mass density (BMD) in the femoral neck (as measured by DXA)
Time frame: 0-12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid | Percent Change of Bone Mass Density (BMD) in the Femoral Neck | -1.72 percent change in bone mass density |
| Placebo | Percent Change of Bone Mass Density (BMD) in the Femoral Neck | -11.34 percent change in bone mass density |
Secondary
Percent Change in the Epiphyseal Integral Bone Mass Content (iBMC) of the Femur
Percent change in the epiphyseal integral bone mass content (iBMC) of the femur, as collected by CT.
Time frame: 0-12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid | Percent Change in the Epiphyseal Integral Bone Mass Content (iBMC) of the Femur | -9.6 percent change |
| Placebo | Percent Change in the Epiphyseal Integral Bone Mass Content (iBMC) of the Femur | -22.90 percent change |
Secondary
Percent Change in the Metaphyseal Integral Bone Mass Content (iBMC) of the Femur
Percent change in the metaphyseal integral bone mass content (iBMC) of the femur, as collected by CT
Time frame: 0-12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid | Percent Change in the Metaphyseal Integral Bone Mass Content (iBMC) of the Femur | -4.73 percent change |
| Placebo | Percent Change in the Metaphyseal Integral Bone Mass Content (iBMC) of the Femur | -8.88 percent change |