Zoledronic Acid to Prevent Bone Loss After Acute Spinal Cord Injury
Phase: PHASE3
Conditions: Spinal Cord Injury
Sponsor: Thomas Jefferson University

 
 
 
 
 
Official Title: Zoledronic Acid to Prevent Bone Loss After Acute Spinal Cord Injury 
NCT #01642901 
Document date: 02/25/2014 

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 1 of 22 
 
Zoledronic Acid to Prevent Bone Loss after Acute Spinal Cord Injury 
 
 A. 
Project Summary and Timeline 
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” 1.  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.  
Central Hypothesis:  Alteration in levels of osteogenic or osteoclastogenic factors secondary to SCI 
plays a crucial role in bone loss and that this loss can be prevented by a single dose of IV ZA 
administered within three weeks following injury in individuals with complete SCI. This will be a 
randomized, double-blind, placebo-controlled study of ZA enrolling 48 subjects over 4 years, randomized 
to ZA or placebo in a 2:1 ratio.  
Primary Outcome: Change in bone mineral density (BMD) assessed by dual energy X-ray 
absorptiometry (DXA) at baseline, 4 months, and 12 months post-injury.  
This will compare BMD at the hip, distal femur and proximal tibia. 
Secondary Outcome: Collection of blood biomarkers of bone formation and resorption at selected time 
intervals within the first 12 months post-injury.  
This will observe the timing of metabolic indexes of bone formation and resorption, and of pro-
osteoclastogenic factors promoting bone resorption. 
Secondary Outcome: Assessment of the safety and tolerability of ZA in the study population. 
Study Timeline: The timeline for the study is depicted in Table 1 below: 
 
Table 1: Study Timetable 
  
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Quarter 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Set up/confirm DSMB 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Subject Enrollment 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Follow up studies 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Longitudinal follow up 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Reports for DSMB 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Statistical Analysis 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Interpretation of Results  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Progress Reports 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Dissemination of results 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 2 of 22 
 
B. 
Specific Aims 
Specific Aim 1: To determine the short and long term effects of ZA on BMD values of the hip, distal 
femur and proximal tibia in patients with acute SCI relative to patients receiving placebo. 
Primary hypothesis: Subjects treated with ZA will have at least a 50% smaller percentage 
decline in BMD values for the hip, distal femur and proximal tibia at 4 and 12 months post-injury 
than control subjects.  
Secondary hypothesis 1: Subjects treated with ZA will maintain original BMD values for the 
hip, distal femur and proximal tibia at 4 months and lose no more than 5% at12 months post-
injury than control subjects.  
Secondary hypothesis 2 (Exploratory): Incidence of fractures in the hip, distal femur, and 
proximal tibia will be at least 50% lower in subjects treated with ZA compared to controls. This 
final hypothesis is exploratory, since we do not expect to have the numbers to achieve statistical 
significance given the relatively low frequency of sub-lesional fractures in SCI. 
Specific Aim 2: To measure and compare selected blood biomarker levels: 1) pro-osteoclastogenic factor 
IL-1β; 2) bone formation marker P1NP; and 3) bone resorption marker serum C terminal telopeptide of 
type I collagen (s-CTX) in subjects treated with ZA to control subjects.  
Primary hypothesis: Subjects treated with ZA will have lower levels of serum marker of bone 
resorption s-CTX at 4 and 12 months, relative to controls. In terms of absolute marker levels, we 
hypothesize that the ZA subjects will have s-CTX values within the reference range at 4 and 12 
months, in contrast to control subjects whose resorption marker levels will be significantly above 
the reference range at all of the time points.  
Secondary hypothesis:  Levels of serum marker of bone formation P1NP will not be lower than 
control subjects at 4 and 12 months. 
Specific Aim 3: To determine the safety and tolerability of early administration of intravenous ZA in 
persons with acute SCI. We will test the hypotheses that compared to controls, subjects treated with ZA 
will: 1) have an increased incidence of myalgias, fever, gastrointestinal disturbances, and flu-like 
symptoms over the three days after infusion of study drug; 2) be less likely to participate in physical and 
occupational therapy during the first week after infusion, 3) be less likely to want the treatment again.  
C. 
Background and Significance of Bone Loss in SCI 
Increased bone turnover and resultant osteoporosis is a prevalent condition following acute traumatic SCI. 
In the initial weeks following SCI, a process of rapid bone remodeling and bone resorption occurs, with 
resorption exceeding formation, thereby leading to osteoporosis2.  Radiographic evidence suggests that an 
estimated 25% of bone mineral density (BMD) below the level of injury is lost within the first 4 months 
following acute SCI and progresses to a 33% loss by 16 months post injury3,4, leaving patients at or near 
the fracture threshold3. Additional investigations extending the time from injury to 2 years estimate BMD 
reduction of 30-40% at the femoral neck , 37-43% at the distal femur5, and 50-60% at the proximal tibia6, 
with the majority of this loss occurring during the first 12 months. Given that bone loss begins shortly 
after injury with the bulk of loss in BMD occurring within 4-6 months, aggressive steps to prevent bone 
loss should be undertaken shortly after injury. 
Individuals with SCI specifically develop sub-lesional osteoporosis, namely bone loss below the level of 
paralysis5. The regional BMD in the area below the injury, rather than the overall BMD, is among the 
strongest predictors of future “fragility fractures” or ones that occur under conditions of minimal or low 
impact in the absence of trauma7,8. The most significant risk factor for osteoporosis after SCI is the 
completeness of injury9. This association is particularly strong for regions at and below the knee. A higher  
 
 

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 3 of 22 
 
incidence of sub-lesional osteoporosis is also observed with increasing number of years post injury10,11; 
with onset of SCI prior to age 16 when peak bone mass has not yet been achieved5, with increasing 
age9,12, and with female gender13.   
In the patient with SCI, the primary goal of osteoporosis is fracture prevention. Although the annual 
incidence of lower extremity bone fractures has been reported as 2-6% 3,11,14 the above figures may be 
underestimated5,14,15 since many subjects present to local hospitals rather than major spinal cord injury 
centers for evaluation and treatment3. Among those with chronic SCI, 25-49% ultimately experience a 
fragility fracture14,16. The majority of fragility fractures occur in the hip, distal femur and proximal 
tibia5,7,14. Fractures may arise from routine activities such as transfers or low-velocity falls from a 
wheelchair or commode3,7,17. Maintenance of bone mass is essential to fracture prevention given the 
morbidity that can result: hospitalization, increased spasticity, autonomic dysreflexia, heterotopic 
ossification, and in select cases, surgical intervention8. In those fractures treated conservatively, pressure 
ulcers may arise from bracing or splints, temporary casts, or bed rest7. The consequences invariably lead 
to reduced level of independence, increased nursing or attendant care, and greater cost to the patient and 
health care system. With the combined effects of an increased life expectancy after SCI and a greater 
number of new cases among persons above age 55, who may have already developed early osteoporosis, 
the cost physically and emotionally to the patient and financially to the health care system will rise in 
coming years7,18. 
Pathophysiology of Osteoporosis: 
Osteoporosis or “porous bone” is a condition of low bone mass and microarchitectural deterioration of 
bone tissue that together result in increased bone fragility and susceptibility to fracture19. Bone is reduced 
in quantity per area studied but mineralized normally. Bone is comprised of two types of living bone 
cells, the osteoclasts that remove weakened sections of bone and the osteoblasts that initially build and 
continually replace bad bone with new bone throughout the life span. This process leads to thicker and 
stronger bones until approximately the age of 25; after that bone is essentially maintained or slowly lost 
until age 50 when effects of aging and hormone changes occur20. Bone loss can accelerate rapidly in 
certain conditions of high bone turnover such as menopause when estrogen levels fall sharply or medical 
conditions resulting in sudden immobility such as SCI21. The typical pattern of bone loss in an able-
bodied individual beginning around age 25 is illustrated in figure 1 below. 
Figure 1: Mean BMD at the femoral neck by age in the US, data from Looker AC22 
0.5
0.6
0.7
0.8
0.9
1
1.1
20–29
30–39
40–49
50–59
60–69
70–79
>80
Age
BMD gm/cm2
WM
BM
WF
BF
 
 
WM = white males; WF = white females; BM = black males; BF = black females 

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 4 of 22 
 
 
Osteoporosis is traditionally diagnosed with BMD measurements measured by DXA which uses bone 
mineral content in grams by summing pixels in a given region viewed by the scanner and dividing that 
number by the bone area examined in cm2. A patient’s results can be interpreted as a standard deviation 
from the mean of sex-matched peak bone mass (T score).23  The World Health Organization has defined 
osteoporosis as a T score at or below 2.5 standard deviations from the mean BMD of a young normal 
adult of the same gender. It is designed for those who have already reached peak bone mass24 . Another 
measure known as the Z score is defined in standard deviations from the mean of age and sex matched 
bone mass. The Z score is often used for patients below age 25 in which peak bone mass has not been 
achieved, but is a useful measure for all pre-menopausal women and men < 50 years (International 
Society for Clinical Densitometry Official Positions. www.iscd.org. Updated 2007).  A given patient is 
assigned a T or Z score for a given location based on established norms illustrated in Figure 2. 
Figure 2: From ISCD bone densitometry Clinician Course, Lecture 5(2008) accessed at National Osteoporosis 
Foundation website, www.nof.org. 
 
The Z score is an additional means of identifying high risk patients that may not be osteoporotic but are 
below expected bone density for age and thus, should be followed more closely21. While there is no 
specific T score that correlates with fracture threshold, the more negative the T score, the greater the risk. 
In able-bodied post-menopausal females, several prospective studies indicate that half of patients with 
incident fractures had baseline BMD assessed by DXA above the diagnostic threshold of osteoporosis25-27. 
Our study will calculate both T and Z scores for initial and follow up testing so that results can be 
compared to other studies that use these values rather than absolute BMD. 
Causes of Osteoporosis  
In the general population, development of osteoporosis is due to factors such as age, diet, lifestyle (with 
or without weight-bearing exercise, gender, and ethnicity21. However, certain medications, including ones 
given for secondary conditions related to SCI, also contribute to osteoporosis.  Glucocorticoids decrease 
bone formation by downregulating osteoblasts and contribute to further bone loss by prolonging the life 
span of osteoclasts28. Thiazolidinediones given to persons with diabetes mellitus can lead to osteoporosis 
by direct action on bone cell differentiation. The “A Diabetes Outcome Progression Trial” (ADOPT) 
found that patients randomized to rosiglitazone have a higher risk of fractures than those receiving 
metformin or glyburide29,30. Unfractionated heparin given for > 1 year has been associated with decreased 
bone formation and increased resorption, but the effects are notably less with low molecular weight 
heparin31. Proton pump inhibitors moderately inhibit calcium resorption essential to bone formation,  

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 5 of 22 
 
 
while H2 blockers have a smaller adverse effect in some studies and a neutral effect in other reports28. In 
addition, long term use of carbamazepine, phenobarbital, phenytoin and valproic acid have been 
associated with decreased BMD due to elevated vitamin D catabolism; elevated parathyroid hormone or 
increased osteoclastic activity32,33.   
Inadequate stores of serum 25-hydroxy vitamin D contribute to low BMD and increased risk of 
fractures34. Low levels of serum 25-hydroxy vitamin D occur in substantial numbers of persons with acute 
and chronic SCI35,36. The degree of vitamin D deficiency is also important in development of osteoporosis 
due to upregulation of osteoclast cells in proportion to the degree of low vitamin D. Work done by this 
group35 has demonstrated that only 35% of acute SCI patients injured in summer months and 16% in 
winter months actually have therapeutic levels of vitamin D (>32 ng/ml). The remainder required 
supplementation to achieve therapeutic levels. Findings from this study are summarized in Table 2 
below:   
Table 2: Seasonal Vitamin D levels in Acutely Injured SCI Subjects 
Serum 25-OH vitamin D (ng/ml) 
Summer (% total/season) 
Winter (% total/season) 
Therapeutic (≥ 32 ng/ml) 
34.5 
15.4 
Sub-therapeutic (20-31.99) 
31.0 
30.8 
Insufficient (13-19.99) 
27.6 
23.0 
Deficient (0-12.99) 
6.9 
30.8 
Historical patterns of bone loss following SCI:  
Garland3  compared complete, subacute SCI subjects (average 4 months from SCI, with repeat assessment 
at 16 months) to complete chronic subjects 5 years from injury. Results demonstrated 24% lower BMD of 
the distal femur of SCI subjects 4 months after injury and 34% lower BMD 16 months after SCI, relative 
to controls. Mean BMD in the proximal tibia also declined between the 4 month and 16 month 
evaluations. A follow up assessment of the subjects 5 years post-injury showed lower BMD than at 16 
months, but differences were not statistically significant. Roberts illustrated the sudden loss of BMD in 
the immediate post-injury period37  in his longitudinal study where 11 of 30 subjects obtained DXA scans 
at weeks 8 and 24 post-injury. These subjects demonstrated a decline in the total lower limb but not in hip 
BMD between scans. A longitudinal study38 examining BMD at 6 time points during the first year of SCI 
found impressive losses averaging 4% per month for high turnover areas of trabecular bone and 
2%/month for areas of cortical bone. This finding of greater losses in trabecular relative to cortical bone is 
consistent with several previous investigations10,39, particularly in the first 4 months following SCI due to 
its faster turnover rate. The authors found that subjects with motor complete paraplegia lost 40-45% of 
BMD in the pelvis and 25% in the total leg between 5 and 50 weeks post injury.  Moreover, among 
subjects with partial motor recovery, 30% of pelvic bone mineral and 10% of total leg bone mineral 
content was lost between 5 and 50 weeks. In a study of chronic SCI subjects, Biering-Sorenson6  observed 
loss in bone mineral content in the proximal tibia of 40-50% of control subjects and in the femoral neck 
30-40% of controls by 2 years post injury.  Although some evidence suggests a steady state is eventually 
reached with a lower mineral density6,40, others have found a continued, albeit slower decline with years 
post injury41.  
Bone markers: 
In the early weeks following SCI, the rate of bone resorption greatly exceeds that of bone formation due 
primarily to upregulation of the osteoclast42.  Hypercalcemia and hypercalciuria, observed in the weeks 
following paralysis, arise in parallel with elevation of resorption indices such as urine and serum N-
telopeptide, hydroxyproline, and urine pyridinoline42-44 leading to overall bone loss. Trabecular bone is 

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 6 of 22 
 
more commonly affected than cortical bone in the first 4 months following SCI due to its faster turnover 
rate10,39. Roberts37 observed a rapid rise in urinary values of total and free deoxypyridinoline, total 
pyridinoline, and NTX in the immediate period following injury. Elevations in bone resorption markers 
began at one week post injury, peaked at 16-20 weeks post injury, and then gradually declined. At their 
highest value, some markers measured 10 times the upper limit of normal. Following acute SCI, markers 
of bone formation range from mildly depressed to slightly elevated during the first 6 months, depending 
on the study cited6,37,42. Even if markers of formation are slightly increased, this compensatory process is 
not sufficient to counteract the significant bone resorption during this same interval. Since acute SCI 
involves significant edema and inflammation, animal models examining the appearance of pro-
inflammatory mediators in acute SCI have been developed. Interleukin-1β mediates osteoclastogenesis by 
acting upon osteoclast precursors45. Yang46  has observed upregulation of IL-1β six hours after producing 
an SCI in a rat. By 24 hours post trauma, the elevations were no longer detectable in that animal species. 
The timing of comparable elevations of these factors in humans with SCI has not been precisely 
determined but appears to persist longer than in rodents. Based on the work of Davies47, interleukin-1β 
may be one of the earlier factors elevated after SCI 36 but the duration of its presence is unclear. Other 
interleukins, including IL-6 and TNF-α may be chronically elevated in SCI patients with secondary 
conditions including pain and pressure ulcers, but  IL-1β levels are not detectable chronically in these 
patients47. For these reasons, our study will examine levels of Il-1β only to 1 month post injury.  
Non-pharmacologic Interventions for bone loss after SCI 
A number of non-pharmacologic interventions have been explored to prevent and treat bone loss 
secondary to SCI. Effects of gravity, mechanical and electrical stimulation, and other forms of exercise or 
positioning have been undertaken in an effort to improve BMD. The majority of treatments to enhance 
bone density have been initiated after the patient leaves acute care-some during inpatient rehabilitation, 
others during outpatient treatment. Kunkel48  reported a case series on the effect of a standing frame in 6 
SCI patients, all of whom were non-ambulatory and averaged 19 years post injury. After 5 months of 90 
minutes daily standing, measurements in the lumbar spine or proximal femur showed no change. 
Warden49 examined how pulsed therapeutic ultrasound for 6 weeks, 20 minutes daily, was administered in 
a double blind manner to two groups of SCI patients. While similar interventions have been successful in 
post-menopausal osteoporosis, the two groups of SCI patients experienced no benefit. Garland50  
examined use of pulsed electromagnetic field in persons with chronic SCI, with one knee receiving 
treatment and each subject’s contralateral knee serving as a control. After 3 months, DXA results in the 
lower extremity demonstrated a 5% higher value in the treated leg, yet no difference was found in DXA 
scores after 6 months and 12 months.  
 
Results using functional electrical stimulation (FES) have been mixed. Needham-Shropshire found no 
improvement in a study of complete paraplegics after 3 months therapy with a microprocessor-controlled 
FES unit known as a “Parastep”51. Leeds and colleagues also found no BMD change using an FES bicycle 
ergometry in seven tetraplegic patients 2-7 years after original injury52.  
However, a similar study of FES-
induced lower extremity exercise found BMD reductions that were smaller than expected and less than 
control subjects53. Belanger et al. had greater benefits in their use of FES, with 30% recovery seen in 
BMD of the distal femur and proximal tibia relative to pre-treatment values54.  But, final BMD values 
remained significantly lower than in able-bodied controls. 
Early investigations of oral and IV bisphosphonates 
Several groups have explored the use of various bisphosphonates for prevention of bone loss in acute and 
chronic SCI.  Two studies examined the use of oral alendronate plus calcium.  Zehnder55 studied 
alendronate plus calcium in 55 motor complete males (AIS A or B) with chronic SCI over a 24 month 
period and compared them to control subjects who received only calcium supplementation.  Vitamin D 
400 IU was given only to those with severe deficiency of serum 25-OH vitamin D <6 ng/ml. The mean 

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 7 of 22 
 
time from injury was 9.8 years, when significant amounts of BMD had already been lost. The group that 
received oral alendronate 10 mg daily plus 500 mg daily calcium was able to maintain their lower pre-
treatment level of BMD at the total hip, tibial diaphysis and tibial epiphysis, but BMD continued to 
decline steadily in the calcium only group serving as a control.  The baseline z scores were already in the 
osteopenic range for the hip (-1.83) and tibial diaphysis (-1.75) and in the osteoporotic range (-3.39) and 
the tibial epiphysis.  In order to prevent the baseline osteoporosis seen in this study, an earlier intervention 
would be needed.  
A double blind, placebo controlled study by Gilchrist56  examined 31 subjects with neurological levels of 
injury C4-L2 and AIS grades A-D, 10 days from injury. All were between ages 18-55.  Subjects were 
divided equally into an experimental group given alendronate 70 mg weekly for 12 months and a control 
group given placebo. Subjects were not given supplemental calcium. Oral vitamin D of unlisted amount 
was given only to those in the deficient range (<12.5 ng/ml), rather than to all subjects for prevention. 
Alendronate-treated subjects had a decline in BMD of 5.6% in the total leg and 3.3% in the total hip, but 
this degree of bone loss was notably less than the decline observed in the placebo group, who lost 12.7% 
in the total leg and 20.7% in the hip.  However, many of these subjects were incomplete injuries, and 
several patients had regained ambulation, possibly reducing the amount of bone loss in both groups.  
Challenges exist to giving oral alendronate in the setting immediately following SCI. Limitations to 
upright posture include post-operative spinal stability precautions, delay in brace fitting needed to 
maintain stability in sitting position, autonomic effects of orthostasis, and pain. Erosive esophagitis may 
occur following consumption of oral bisphosphonates, unless patients are able to sit fully upright after 
administration of medications. In the previously described study by Gilchrist56, authors specifically 
reported no difficulties encountered with GI symptoms. This may have been due to the number of 
subjects with AIS Grades B-D or with thoracolumbar neurological levels of injury. Severe orthostatic 
hypotension is less common in these groups, permitting earlier functional mobility and facilitating upright 
positioning sooner after injury. Because IV formulations can be administered in the supine position, 
investigators have explored the use of IV bisphosphonates in the setting of acute SCI. An early 
investigation by Nance57 examined the use of IV pamidronate, a relatively weak bisphosphonate, within 6 
weeks of injury in 24 subjects with traumatic SCI. This non-randomized trial divided the sample into 14 
subjects receiving 30 mg of IV pamidronate monthly for 6 consecutive months and 10 controls with 
comparable degrees of SCI given standard rehabilitation therapy but no drug. Interpretation of results was 
limited by the heterogeneity of subjects: some had sensory and motor complete injuries (AIS A), while 
others were AIS D, a subset of whom were ambulatory. Outcomes at 12 months evaluated BMD at the 
hip, distal femur and proximal tibia by percent change from baseline. Only the pamidronate-treated AIS D 
subjects demonstrated an increase in BMD and this rise was observed only in the distal femur. The 
proximal tibia and hip were largely unchanged from subjects’ baseline BMD, but control subjects 
demonstrated BMD losses of .5%, 13.4% and 10.5% respectively. In this study, control subjects with AIS 
grade A injury lost 14.6% of original BMD, while pamidronate-treated subjects lost only 6.5% of their 
original BMD. Neither group was able to maintain their pre-injury bone density. A second investigation 
by Bauman58 examined the effect of IV pamidronate on sublesional osteoporosis in 11 subjects with acute 
SCI 22-65 days post injury.  Although early mild reduction in the degree of BMD loss was observed, by 
the end of 12 months both placebo and pamidronate-treated subjects lost statistically similar amounts of 
BMD below the level of injury: 18 vs. 15% in the pelvis; 28 vs. 17% in the distal femur, and 42 vs. 36% 
in the proximal tibia.   
Zoledronic Acid: Initial trial data and clinical pharmacology  
Zoledronic acid demonstrates superior pharmacodynamic properties for suppression of the primary bone 
resorbing cell, the osteoclast, in comparison to actions of earlier generation oral and IV 
bisphosphonates59. Zoledronic acid has a particularly high affinity for binding to the calcium phosphate 
bone mineral, hydroxyapatite. Binding localizes to regions of high bone turnover, specifically trabecular 

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 8 of 22 
 
bone. Within the osteoclast, zoledronic acid inhibits a key regulatory enzyme known as farnesyl 
diphosphate synthetase which is 17 times more effectively than alendronate and 67 times more than 
pamidronate59,60.  Zoledronic acid in the 5 mg dose is now an option for treatment of post-menopausal 
osteoporosis in patients with advanced disease who may have failed less aggressive therapies, including 
treatment with other bisphosphonate drugs. This medication is administered IV once annually and has the 
advantage of single time administration. 
Side Effects of Zoledronic Acid 
Due to the potency of IV ZA, adverse effects of the agent may occur.  The most common side effects of 
ZA are an acute phase reaction involving fever (15%), myalgias (8%), flu-like illness (7%), headache 
(6%) and arthralgias (5%)61,62. In rare cases, patients may experience noncardiac chest pain (1/3%). 
Because infusion of IV ZA can cause  an increase in serum creatinine up to 30 days post treatment, the 
drug should be avoided in persons  with creatinine clearance <35 mL/min. An association between atrial 
fibrillation and IV ZA use was observed in a large study of over 7000 patients62. The FDA subsequently 
conducted an investigation, comparing results of the prior trial to other studies of IV ZA, and concluded 
that no clear relationship could be identified between bisphosphonate use and atrial fibrillation63. Both 
oral and IV bisphosphonates have been associated with osteonecrosis of the jaw (ONJ), but further review 
of the data by the American Dental Association found that incidence of ONJ is rare in post-menopausal 
women with osteoporosis but more common in those with monthly infusions for cancer treatment64. This 
group recommended no special treatment beyond routine dental care for those using IV ZA for 
osteoporosis. Finally, several reports of low trauma fractures of the femur have been observed among 
patients primarily over age 60 who are prescribed chronic bisphosphonate treatment (2.5-8 years)61,65.   A 
recent cohort study of over 1.1 million patients by Dell at el. found that while duration of use of 
bisphosphonates was correlated with incidence of atypical femur fractures, (particularly beyond 5 years of 
use), no correlation with age and duration of use was found.66 Because our study will involve only a 
single dose of ZA, we do not anticipate observing the above effect from the drug alone.  Based on these 
new findings, we also believe that individuals ages 61-65 should not be excluded by age alone. 
Previous Clinical Trials of Zoledronic Acid 
Zoledronic acid has been used in several studies of able-bodied individuals, most commonly in post-
menopausal females. The HORIZON Pivotal Fracture Trial62 examined 7765 subjects with established 
clinical osteoporosis over 3 years. Findings demonstrated 70% and 41% reductions in vertebral and hip 
fractures respectively. Reduction of markers of bone resorption and bone formation were also observed, 
with levels reduced from baseline by 59% for β-CTX, 58% for PINP, and 30% for bone specific alkaline 
phosphatase (ALP) at 12 months without progressive decline in subsequent years. A direct comparison of 
a single 5 mg IV ZA dose and 70 mg weekly oral alendronate in post-menopausal females67 found more 
striking and rapid declines in markers of bone resorption at weeks 1, 12, and 24 of the study in the ZA 
group as well as greater reduction in bone formation markers at 12 weeks. The nadir in all bone resorption 
markers was reached at 1 week for the ZA group but took at least 12 weeks to be achieved in the 
alendronic acid group, demonstrating a more rapid impact of ZA in suppressing bone resorption.   
Two small investigations have explored the use of ZA in subacute SCI. In a double-blind placebo-
controlled trial, Shapiro et al68. examined the effect of IV ZA in 17 patients with AIS grade A or B SCI 
given at 10-12 weeks post injury.  Four subjects received 4 mg IV ZA, four received 5 mg ZA, and the 
remaining nine received placebo. Both the intertrochanteric region and the cortical shaft in the ZA treated 
group maintained BMD near baseline values up to 12 months, while BMD declined in the control group. 
In contrast, the femoral neck had shown an increased BMD from baseline at 6 months, but fell back to 
baseline by 12 months in the ZA group. At 12 months, the BMD at the femoral neck did not differ 
significantly between groups. Bubbear69  completed a randomized, open-label study of 14 patients with 
acute SCI, all of whom received either 4 mg IV ZA or standard medical treatment within 3 months (mean 
of 58 days of injury). Neurological levels of participants ranged from C4 to L3 and included 11 complete 

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 9 of 22 
 
(5 experimental, 6 control) and 3 incomplete subjects (2 experimental, 1 control). Differences between 
ZA-treated subjects and controls were 3% for the lumbar spine (p<.05); 12% for the total hip (p<.05), 5% 
for the femoral neck (NS), and 11% (p<.05) at the greater trochanter 12 months after study drug 
administration.  In the ZA group, BMD at the total hip and greater trochanter were maintained from 
baseline, but the area of the femoral neck still lost 10% of the original BMD. In both of the above studies, 
pharmacologic intervention did not occur until 2-3 months post injury, when a notable amount of bone 
mass is already lost.  Furthermore, neither study evaluated BMD at the distal femur and proximal tibia, 
two high risk areas for sublesional fractures after SCI. 
Areal Bone Mineral Density 
Since marked sub-lesional bone loss after SCI is found consistently5,6, our study will provide new 
information on the effectiveness of ZA in preventing bone loss after SCI because it differs from prior 
studies in the following important aspects: 
1. We will administer ZA within 21 days of SCI, when bone resorption is just beginning. This is 
sooner than the prior studies on ZA in SCI. 
2. We will limit enrollment to patients with complete injuries, minimizing potential 
confounding between ambulatory and non-ambulatory subjects. 
3. We will monitor calcium and vitamin D levels periodically throughout the study, with 
aggressive supplementation of all patients noted to be low, and we will supply supplemental 
calcium and vitamin D to all subjects to prevent anticipated losses in the initial year of 
injury35.  
4. We will evaluate the effect of ZA on BMD at the hip, the distal femur, and proximal tibia. 
D. 
Study Design 
This will be a prospective, double-blind, randomized, placebo-controlled trial with a 2:1 ratio of ZA to 
placebo in 48 persons with complete traumatic SCI.  
Study Location and SCI Population 
This study will be conducted at the Regional Spinal Cord Injury Center of the Delaware Valley 
(RSCICDV), located at Thomas Jefferson University and Hospital (TJU/H) in Philadelphia, PA.  
TJUH, in affiliation with the Magee Rehabilitation Hospital, is designated as one of the United 
States’ 16 Model Spinal Cord Injury Centers, by the National Institute on Disability and 
Rehabilitation Research, Department of Education's Office of Special Education and 
Rehabilitative Services. It is the only such facility in the Delaware Valley. The RSCIC has 
treated more than 3,000 persons with spinal cord injury and provides for multidisciplinary 
coordination of emergency and acute medical/surgical care, rehabilitation at the onset of acute 
care, with vocational evaluation and training, and lifetime follow-up care for persons with SCI. 
Over 50 percent of the SCI patient population is admitted to the RSCIC within three days of 
injury and the RSCIC has demonstrated a mortality rate of 5 percent. Over the past 5 years the 
RSCIC has annually admitted an average of 28-30 patients with complete SCI within 7 days of injury. 
D.1. 
Subjects 
Forty-eight subjects evaluated to have ASIA impairment scale Grade A injuries (motor and sensory 
complete) will be identified, screened, and approached to participate in the study. Persons who have 
recently experienced traumatic complete SCI and are within 21 days of injury are eligible to participate. 
The sample size calculation allows for reduced enrollment rates and drop outs. The ASIA impairment 
scale is detailed in Table 3 below. 
 
 
 

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 10 of 22 
 
Table 3: ASIA Impairment Scale (ISNCSCI, 2011) 
SCI Injury Grade 
Description 
A = Complete 
No motor or sensory function is preserved in the sacral segments S4-S5. 
B = Incomplete 
Sensory but not motor function is preserved below the neurological level and includes 
the sacral segments S4-S5. 
C = Incomplete 
Motor function is preserved below the neurological level, and more than half of key 
muscles below the neurological level have a muscle grade less than 3. 
D = Incomplete: 
Motor function is preserved below the neurological level, and at least half of key 
muscles below the neurological level have a muscle grade of 3 or more. 
E = Normal 
Motor and sensory functions are normal. 
D.2. 
Inclusion/Exclusion Criteria 
Inclusion criteria: 
 
Ages 18- 65, male or female 
 
Traumatic SCI with Neurological level C4-T10, AIS A, Serum calcium level >7.0 mg/dL) at time 
of study drug administration  
 
Screening baseline serum 25OH 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 DXA scanner 
Exclusion criteria: 
 
Ventilator dependent individuals who are not in weaning phase and are unable to provide consent 
through alternative communication 
 
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 IV blood pressure agents such as dopamine, norepinephrine, 
or phenylephrine. Exception may allow for patients on pressors who are experiencing 
hypotension as they acclimate to upright posture 
 
Inability to provide informed consent and understand the consent process 
 
Facial fractures requiring oral surgery  

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 11 of 22 
 
 
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 
D.3. 
Methods 
1. Sample Size Calculations 
The sample size calculation is based on the primary outcome of BMD loss at the proximal tibia at 12 
months. A set target of at least 50% reduction in percent BMD loss between treatment and control groups 
is projected. Expected BMD loss is taken from the placebo group of Bauman(58). 
Subjects in this study lost 8% +/- 3% BMD at 3 months and 29% +/- 13% at 12 months in the proximal 
tibia. The effect size (difference in mean percent reduction divided by standard deviation) for a 50% 
reduction in BMD loss is 1.3 at 3 months and 1.1 at 12 months. Assuming 2:1 randomization, two-sample 
t-test, 80% power and two-sided type-I error rate of 5%, we would need a total sample size of 24 for an 
effect size of 1.3, 33 for an effect size of 1.1, and 39 for an effect size of 1.0. We plan to enroll 48 
subjects to allow for potential attrition. With a dropout rate of 18% we would reach a final sample of 39; a 
dropout rate of 30% would result in a final sample of 33. The enrollment of 10 subjects/year (total = 40) 
would still allow an 18% drop out to achieve a final sample of 33. 
2. Randomization Method  
The randomization schedule will be generated by the TJU Division of Biostatistics. Randomization will 
use the method of random permuted blocks. The block size will not be disclosed to the investigators. The 
TJU Division of Biostatistics will prepare a randomization scheme document to be kept by the TJUH 
Investigational Drug Service (IDS).  Once a subject is confirmed to be eligible and the informed consent 
is completed, the IDS will be alerted to assign a randomization and prepare for the subsequent medication 
preparation and delivery. A completed randomization assignment log will be returned to Biostatistics so 
they can monitor randomization and accrual.  
3. Management of Study Drug Infusion  
The TJUH Investigational Drug Service is a well-established service within the Pharmacy Department 
that participates in numerous inpatient and outpatient research protocols. The IDS reviews all inpatient 
investigational drug protocols and assists with patient enrollment (randomization), staff education and 
maintenance of study records, including protocol budgets. The IDS maintains all investigational drug 
records in accordance with FDA regulations as well as with the policies and procedures of the 
Institutional Review Board.  The IDS provides the procurement, storage, dispensing and maintenance of 
records for all investigational drugs.  
4. Study Activities and Assessments 
A. 
Screening: Post injury days 0-17 
 
Subjects admitted to the RSCIC with suspected complete SCI will be approached for participation 
shortly after admission.  After providing informed consent, subjects will be screened between 0 
and 17 days post injury. The screening  will review of the medical record medical/surgical history 
and physical/neurological examination performed according to ISNCSCI guidelines to ensure an 
AIS Grade A SCI is present, or post-menopausal) and social or lifestyle factors that could alter 
ability to participate. 
 
A serum pregnancy test (for females of child bearing age). 
 
Standard of Care laboratory tests of kidney (TJUH Basic Metabolic Panel) and liver function 
(TJUH Hepatic Panel) will be reviewed to ensure the patient does not have a history of chronic 
liver or kidney failure, unknown to family or subject or not revealed on subject history interview.   

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 12 of 22 
 
 
Serum calcium measurement.  If initial serum calcium is <7.0 mg/dl, the subject will be given 
correctional calcium doses in accordance with standard hospital treatment protocol for subjects 
with critically low calcium levels. The subject may still be able to participate if the calcium level 
is corrected by the day prior to study drug infusion.   
 
Serum Vitamin D measurement.  Subjects with initial vitamin D levels in the deficient range 
(<13ng/ml) will not be eligible for participation.  If subject’s 25-OH vitamin D is between 13 and 
20, the subject will be supplemented with high potency oral ergocalciferol 50,000 International 
Units (IU) per week until retesting occurs at 4 weeks.  At the time the screening value is returned, 
subjects with 25-OH vitamin D levels between 20 and 32 will be started on 2000 IU vitamin D 
daily and those will levels 32 and higher will be initiated on 1000 IU daily.  Supplemental oral 
calcium of 1200 mg daily will be started on the same day as the vitamin D, except in cases of low 
values as described above.    
 
Intact Parathyroid Hormone (iPTH) measurement. 
B. 
Baseline Assessments: Post-injury days 8-21  
A Baseline Assessment will be completed between 8 and 21 days post-injury, and include the following: 
 
Completion of the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX)73. 
The FRAX asks for information about age, date of birth, sex, weight, height, previous fracture 
history, parental fracture history, smoking, steroid use, history of rheumatoid arthritis, presence of 
a medical condition related to osteoporosis, alcohol use, and current hip bone mineral density (see 
data collection forms in Appendix B). All data are then entered into the FRAX website (available 
through the WHO) to obtain the 10 year probability of a fracture. No personal identifiers are used 
and no data is saved on the website. 
 
Collection of blood sample for pre-treatment levels of PINP as measures of bone formation, s-
CTX as marker of bone resorption, IL-1β as a pro-osteoclastogenic factor, CPK (Creatinine 
Phosphokinase) as a marker of muscle tissue and kidney function, and serum calcium.  
DXA scan, to be obtained as soon as the subject is medically stable for testing off the 
intensive/acute care floor (may be done up to 7 days after the infusion of study drug). 
C. 
Study drug infusion: Post injury day 21 
Within day 21 post injury, subjects will be administered study drug and assessed as follows: 
 
Measurement of serum calcium level to ensure therapeutic levels. 
 
A single IV infusion of ZA 5 mg or a placebo drug with the same dilution and duration of 
administration (prepared and dispensed by the TJUH IDS).  
 
The single IV infusion will be administered over a 2 hour period (2.5 mg per hour) 
 
Supplemental hydration as needed to keep urine output > 2000 cc per day from the day prior to 
study drug administration until 3 days post-infusion. 
 
Acetaminophen 650 mg every 4 hours for the 24 hour period following drug administration. This 
is intended to reduce the frequency and severity of fever or myalgias associated with ZA 
administration61.  
D.  
Days 1-7, Post Drug Infusion 
 
After the first day, acetaminophen will continue to be offered as needed every 4 hours through 
day 3 post-infusion. 
 
Supplemental hydration will be continued as needed to keep urine output > 2000 cc per day until 
3 days post-infusion 
 
Subjects will be assessed daily for 3 days, then weekly for one month after study drug 
administration for known side effects of the drugs, including myalgias, fever, gastrointestinal 
disturbances, and flu-like symptoms. 

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 13 of 22 
 
 
Subjects will be assessed for participation in physical therapy and occupational therapy since 
receiving the study drug, as well as willingness to get study drug again via interview held 7 days 
following infusion.  
E.  
Days 1, 3, 7, 14, Post-Drug Infusion 
 
Subjects will be assessed weekly for one month after study drug administration for known side 
effects of the drugs, including myalgias, fever, gastrointestinal disturbances, and flu-like 
symptoms. 
 
Laboratory values will be drawn for serum calcium, phosphate, and magnesium. 
F.  
Month 1 Post Injury (+/-4 days)  
 
Subjects will be assessed weekly for one month after study drug administration for known side 
effects of the drugs, including myalgias, fever, gastrointestinal disturbances, and  flu-like 
symptoms. 
 
Blood samples* for laboratory values will be drawn for s-CTX, IL-1β, 25-OH vitamin D, serum 
calcium, intact parathyroid hormone, and Serum P1NP. *The total amount of blood drawn for all 
laboratory tests will be < 25 ml at each data collection session.  
G.  
Month 2, 6 & 10 Post Injury  
A patient questionnaire will be administered either in-person or by telephone. The questions cover: 
 Any evidence or knowledge of bone fractures since the previous contact.  
 Information about exercises and standing, including use of functional electrical stimulation 
(FES), such as how often and average daily duration.  
 Supply of vitamin D and calcium tablets with reminder to bring pill bottles with them to clinic for 
follow up assessments and study sponsored refill of medications. At these follow up visits, pill 
counts will be done to assess their compliance with medication use. 
H.  
Months 4 & 12 Post Injury 
 
Blood sample will be drawn for s-CTX, 25-OH vitamin D, serum calcium, intact parathyroid 
hormone.  Serum P1NP will also be drawn at 4 months. The total amount of blood drawn for all 
laboratory tests will be < 25 ml at each data collection session. 
 
Complete neurological exam (at 12 months only)  
 
A patient questionnaire will be administered. 
 
DXA scan 
I.  
Month 8 Post Injury 
 
Blood sample will be drawn for 25-OH vitamin D and serum calcium. The total amount of blood 
drawn for all laboratory tests will be < 25 ml at each data collection session.  
J.  
Serum 25-OH Vitamin D Monitoring and Supplements 
Since serum 25OH vitamin D represents a storage level of vitamin D accumulated over the preceding 
months, subjects with therapeutic values immediately after injury may have normal vitamin D stores 
which decline in subsequent months. For this reason, vitamin D levels in all subjects will be monitored 
not only at baseline but also at months 1, 4, 8 and 12.  Subjects will be supplemented with 50,000 IU oral 
ergocalciferol weekly, if insufficient (serum level 13-20 ng/ml); 2000 IU cholecalciferol or ergocalciferol 
daily, if sub-therapeutic (serum vitamin D level 21-31ng/ml). Those subjects in the therapeutic range for 
serum 25-OH vitamin D will be given a maintenance dose of 1000 IU oral vitamin D daily.  
 
 
 

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 14 of 22 
 
Table 4: Study Events and Visit Schedule 
 
Screening 
(Day 0 -17) 
Baseline  
(Day 8-21) 
Study Drug and 
Acetaminophen 
Administration 
(within 21 days 
of injury) 
1 month 
+ / - 4 days 
 
4 months 
+ / - 7 days 
8 months 
+ / - 14 days 
 
1 year 
+ / - 14 days 
 
Medical History 
Standard Care 
X 
 
 
 
 
 
 
Physical Exam 
Standard Care 
X 
 
 
 
 
 
 
Basic Metabolic 
and Hepatic Panel) 
Standard Care 
 
X 
 
 
 
 
 
 
FRAX Score 
 
X 
 
 
 
 
 
Study Drug 
Infusion 
 
 
 
X 
 
 
 
 
Acetaminophen 
Administration 
 
 
X a X b 
 
 
 
 
Serum calcium, 
magnesium, phos 
Standard Care 
X 
X 
 
X 
X 
X 
X 
Serum 25OH-D 
Standard Care 
X 
 
 
X 
X 
X 
X 
Serum iPTHd 
Study Specific 
X 
 
 
X 
X 
 
X 
P1NPe 
Study Specific 
 
X 
 
X 
X 
 
 
IL-1 betaf 
Study Specific 
 
X 
 
X 
 
 
 
Serum CTXg 
Study Specific 
 
X 
 
X 
X 
 
X 
CPKh 
Study Specific 
 
X 
 
 
 
 
 
DXA** 
Study Specific 
 
         X c 
 
 
 
         X 
 
 
           X 
a) Administered every 4 hours for the first 24 hours following study drug infusion 
b) Administered every 4 hours PRN through day 3 following study drug infusion 
c) To be obtained as soon as medically stable to undergo DXA testing  
d) iPTH 
 
Blood Test Intact parathyroid hormone  
 
 
e) P1NP   
Blood Test N-terminal propeptide of Type I collagen   
f) 
IL-1 beta  
Blood Test Interleukin 1 beta 
g) S-CTX    
Blood Test Serum carboxy-terminal telopeptide of type I collagen 
h) CPK 
 
Blood Test Creatinine Phosphokinase 
 
Table 5 Schedule of follow up contacts for Years 2 through 4 of the study. 
 
Year 1 
Every 2 Months 
Year 2 
Month 6 
Year 2 
Month 12 
Year 3 
Month 6 
Year 3 
Month 12 
Year 4 
Month 6 
Year 4 
Month 12 
Questions about 
fractures 
X 
X 
X 
X 
X 
X 
X 
Questions about 
Vitamin D/calcium 
supplements 
X 
X 
X 
X 
X 
X 
X 
Questions about 
exercise and other 
treatments 
X 
X 
X 
X 
X 
X 
X 

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Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 16 of 22 
 
The DSMB will be recruited from Jefferson Medical College (JMC) faculty members and charged with 
monitoring study compliance. They will review screening and enrollment procedures, data collection and 
analysis, reporting of adverse events, and subject safety.  The DSMB members will meet every 6 months 
or more frequently as needed. The study investigators will meet with the DSMB chair every 6 months to 
review recommendations or concerns.  
The DSMB will be composed of the following members: 
John F. Ditunno Jr, MD (Chair)  
Professor of Rehabilitation Medicine 
Edward B. Ruby, MD  
 
Assistant Professor of Medicine, Division of Endocrinology 
Edward J. Filippone, MD 
 
Clinical Assistant Professor of Medicine, Division of Nephrology 
E. 
Data Analysis  
1. Evaluation of Baseline Characteristics 
We will compare the treatment and control groups for baseline characteristics using t-tests and Chi-square 
tests as appropriate. Specifically, we will compare age at injury, baseline FRAX fracture risk, sex and 
injury level (tetraplegia/paraplegia) distribution. The level of significance for all analyses will be 0.05. 
2. Evaluation of Hypotheses 
Specific Aim 1: To determine the short and long term effects of zoledronic acid on BMD values of the 
hip, distal femur, and proximal tibia in patients with acute SCI relative to patients receiving placebo.  
The primary hypothesis is that subjects treated with zoledronic acid will have at least a 50% smaller 
percentage decline in BMD values for the hip, distal femur and proximal tibia at 4 and 12 months post-
injury than control subjects.    
Analysis: For each of the bone sites to be evaluated, a percent change from baseline ([baseline BMD – 
follow-up BMD]/baseline BMD) will be modeled using mixed effects linear regression. Fixed effects will 
be included for treatment assignment, time, treatment by time interaction, and baseline BMD level. A 
random intercept term will be included to account for correlation among repeated measurements from the 
same subject.  Within this regression model, we will estimate the difference between treatment groups at 
4 and 12 months and test for significance of this difference. If the outcome of percent change is not 
normally distributed, we will apply an appropriate transformation (e.g., log, logit). If the necessary 
transformation is too complex for interpretation, we will consider using rank-based methods.   
Secondary hypothesis 1 is that subjects treated with zoledronic acid will maintain original BMD values 
for the hip, distal femur and proximal tibia at 4 months and lose no more than 5% at12 months post-
injury.   
Analysis: We will estimate the mean percent change at 4 and 12 months for the active treatment group 
along with associated 95% confidence intervals from the results of the mixed effects regression.  BMD 
values at 4 months will be considered equivalent to those at baseline if the bounds of the confidence 
interval are within +/-2%. At 12 months, we will test the one-sided null hypothesis that the percentage 
decline is greater than 5% vs. the alternative that it is less than or equal to 5%.   
Secondary hypothesis 2 is that fractures in the hip, distal femur, and proximal tibia will be at least 50% 
lower in the ZA group relative to controls over the course of the grant cycle. This final hypothesis is 
exploratory, since we do not expect to have the numbers to achieve statistical significance given the 
relatively low frequency of sublesional fractures in SCI.   
Analysis: The relative risks of all fractures and site-specific fractures will be calculated along with exact 
95% confidence intervals.  Statistical significance will be evaluated using Fisher’s exact test.   
Specific Aim 2: To measure and compare levels of pro-osteoclastogenic factor IL-1β, bone formation 
marker P1NP, and bone resorption marker serum C terminal telopeptide of type I collagen (s-CTX) in 

 
 
 
Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
Page 17 of 22 
 
acute traumatic motor complete SCI subjects who receive intravenous zoledronic acid in the first 21 days 
post injury to the same markers in a similar group of spinal cord injury subjects receiving placebo.   
The primary hypothesis is that subjects treated with zoledronic acid will have lower levels of serum 
marker of bone resorption s-CTX at 4 and 12 months, relative to controls.  In terms of absolute marker 
levels, we hypothesize that the ZA subjects will have s-CTX values within the reference range at 4 and 12 
months, in contrast to control subjects whose resorption marker levels will be significantly above the 
reference range at all of the time points.   
The secondary hypothesis is that levels of serum marker of bone formation P1NP will not be lower than 
controls at 4 and 12 months. 
Analysis: We will again use mixed effects linear regression to model each marker at 1, 4 and 12 months 
with fixed effects for time, treatment, time by treatment interaction, and baseline biomarker level and a 
random subject-specific intercept. At months 4 and 12, we will estimate mean group-specific biomarker 
levels and associated 95% confidence intervals and test for treatment group differences. Since IL-1β will 
only be measured at baseline and one month, we will use analysis of covariance to compare group 
averages at one month adjusted for baseline measures.   
Specific Aim 3: To determine the safety and tolerability of early administration of intravenous zoledronic 
acid in persons with acute SCI. We expect to see only minor, transient side effects from zoledronic acid.  
To evaluate this we will test the hypotheses that compared to controls, subjects treated with zoledronic 
acid will have (3a) an increased incidence of myalgias, fever, gastrointestinal disturbances, and flu-like 
symptoms over the three days after infusion of study drug; (3b) be less likely to participate in physical 
and occupational therapy during the first week after infusion, and (3c) be less likely to want the treatment 
again.    
Analysis: For each outcome, we will estimate group-specific rates (proportions) along with exact 
binomial confidence intervals. Comparisons between groups will be performed using Fisher’s exact test.   
 
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IRB Control #11F.612 
February 25, 2014 
 
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IRB Control #11F.612 
February 25, 2014 
 
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February 25, 2014 
 
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Christina V. Oleson, MD 
Zoledronic Acid in acute spinal cord injury 
IRB Control #11F.612 
February 25, 2014 
 
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