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Zoledronic Acid Treatment After Acute Spinal Cord Injury: Results of a Randomized, Placebo-Controlled Pilot Trial
PM R XXX (2016) 1-10
www.pmrjournal.org
Original Research
Zoledronic Acid Treatment After Acute Spinal Cord Injury: Results of a Randomized, Placebo-Controlled Pilot Trial Thomas J. Schnitzer, MD, PhD, Ki Kim, MD, Julia Marks, BS, Renita Yeasted, BS, Narina Simonian, BS, David Chen, MD
Abstract Objective: To determine the effect of intravenous zoledronic acid 5 mg on the extent and course of bone loss after spinal cord injury (SCI). Design: Double-blind, randomized, placebo-controlled parallel-group trial. Setting: Acute in-patient, tertiary-care rehabilitation hospital. Participants: Convenience sample of 17 in-patients with SCI <12 weeks before randomization; American Spinal Injury Association Impairment scale A, B, or C and medically stable. Twelve patients were evaluated at the primary endpoint at 6 months. Methods: Patients meeting study criteria were randomly assigned to zoledronic acid 5 mg or matching placebo. Dual x-ray absorptiometry scan and serum for bone markers (type 1 procollagen amino-terminal propeptide, bone-specific alkaline phosphatase, collagen type 1 cross-linked C-telopeptide) were obtained at baseline and after 3 months, 6 months, and the every 6 months for up to 2 years. Main Outcome Measures: The primary endpoint was change in bone mineral density (BMD) at the total hip after 6 months; secondary endpoints were changes in BMD at other skeletal sites and changes in levels of serum bone markers. Results: The group treated with zoledronic acid had a smaller decrease in BMD at 6 months at the total hip than the placebo group (right: 2.2 3.4% versus 8.6 3.5%, respectively, P ¼ .03; left: 3.7 1.0% versus 12.3 6.9%, P ¼ .03). Differences in BMD at the femoral neck were similar (right: 5.1 6.5% versus 20.0 6.4%, P ¼ .01; left: 1.1 3.5% versus 11.1 7.4%, P ¼ .02) with larger bone loss and smaller between group differences at the knee. Zoledronic acid resulted in a decrease in serum levels of both formation and resorption markers. Conclusions: Zoledronic acid is effective at mitigating bone loss after SCI. Duration of efficacy and activity at different skeletal sites may differ from that observed in able-bodied individuals and needs further study.
Introduction Traumatic spinal cord injury (SCI) occurs in approximately 12,000 people each year in the United States [1]. Bone loss is an almost universal sequela of SCI and is attributed to the response of bone to loss of normal weight-bearing as well as possibly to the disruption of normal neurologic and hormonal factors [2]. Bone resorption is markedly enhanced and bone formation depressed in the skeletal areas below the neurologic level of the injury, resulting in rapid and extensive loss of bone mass and alteration of normal bone architecture [3,4]. The consequences of these changes are reflected in the marked increase in the incidence of fracture
experienced by people with SCI, affecting primarily their lower extremities, particularly the skeletal sites around the knee [5,6]. These fractures result in both an increase in cost of care as well as adversely impacting the mobility, functioning, and quality of life of those affected [7]. Bone loss is most marked during the first 2 years after SCI, after which there is a return to a new steady state of bone turnover in the affected skeletal sites [8-10]. The degree of the bone loss is greatest in individuals with tetraplegia and those with complete motor injuries, with greater maintenance of bone in people with incomplete motor loss and those able to regain some degree of weight-bearing. Attempts to
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Zoledronic Acid Treatment After Acute SCI
prevent bone loss via the use of standard nonpharmacologic rehabilitative modalities (physical therapy, supported weight-bearing, standing) have not been successful, although increasing load by the use of electrical stimulation has shown efficacy in research settings [11,12]. Previous pharmacologic approaches to prevent bone loss have attempted to inhibit bone resorption with either oral or intravenous bisphosphonates. Although early studies with these agents yielded negative or equivocal results [13,14], recent studies that use more potent bisphosphonates have documented a slowing of bone loss in the lower extremities. Gilchrist et al [15] undertook at 12-month randomized trial of oral alendronate 70 mg weekly compared with placebo and demonstrated a marked reduction of bone loss at all hip skeletal sites in the alendronate group. Shapiro et al [16] and Bubbear et al [17] evaluated the effects of a single infusion of zoledronic acid 4 mg or 5 mg compared with placebo-treated participants with acute SCI. Both studies reported a reduction in bone loss at hip skeletal sites in the zoledronic acidetreated group, with greater efficacy after 6 months compared with 12 months. In each of these trials, bone resorption markers were suppressed successfully by bisphosphonate use. Longer term follow-up beyond 18 months was not reported. A recent observational cohort study provided further support for zoledronic acid efficacy at reducing bone loss at hip skeletal sites after SCI but reported an increase in bone loss at the distal femur and proximal tibia in treated individuals [18]. The current placebo-controlled randomized trial was undertaken to evaluate the effect of a single infusion of zoledronic acid 5 mg, a dosage used to treat osteoporosis, on bone changes after acute SCI. In contrast to previous studies, participants were followed for up to 2 years after treatment to evaluate durability of response, and bone changes were evaluated at skeletal sites around the knee in addition to the standard skeletal sites. Methods Study Design and Participants Between January 2010 and December 2012, 17 patients recently admitted to the Rehabilitation Institute of Chicago, Chicago, IL, age 18 years or older, with acute SCI participated in a prospective, parallel-group, double-blind, placebo-controlled study to determine the efficacy and safety of zoledronic acid. Participants had to be classified by the American Spinal Injury Association Impairment scale (AIS) [19] as A or B at the time of study entry, or AIS C if not weight-bearing, with an SCI that occurred within 6 months of study entry. Participants were excluded if they were pregnant or lactating, mentally unstable, had significant renal
impairment (estimated creatinine clearance <30 mL/ min), or evidence of hypocalcemia, vitamin D deficiency, or abnormal thyroid hormone status. Female participants of child-bearing potential had to be willing to use the double-barrier method of contraception for 2 months after having received the study drug to participate. All participants who were currently or recently (within 12 months) taking drugs that affect bone metabolism (bisphosphonates, teriparatide, selective estrogen modulators) were excluded. Participants who had osteoporosis at the hip or spine at the baseline visit after imaging by dual x-ray absorptiometry (DXA) were excluded. Participants with a history of malignancy or poor dental hygiene (that required invasive dental procedure within 2 months of enrollment) were excluded. All participants gave written consent to take part in the study before any procedures being performed. This study was approved by the Northwestern University Institutional Review Board and registered at clinicaltrials.gov (NCT00844480). Participants were assigned in computer-generated blocks of 4 to be randomized to receive either 5 mg intravenous zoledronic acid (Zometa, Novartis Pharmaceuticals, Basel Switzerland; active treatment group) or an infusion of placebo (diluent alone) in a blinded fashion and a 1:1 allocation. Study medication was assigned by the hospital research pharmacist; all other study staff were blinded to treatment allocation. Both active and identical matching placebo treatments were provided by Novartis Pharmaceuticals. A complete medical history, including surgical history, family history, medications, smoking, alcohol, diet/exercise information, and bone-specific information regarding previous fractures and falls, was collected at the initial screening visit. Laboratory evaluations for hepatic and renal function, vitamin D levels, and thyroid status were performed at this time. Weight, height, and AIS classification were obtained from clinical records at admission. After screening, participants who qualified for the study had a baseline DXA examination and serum obtained for bone metabolic markers and hormone levels, followed within 1 week by infusion of study medication. Participants with low serum 25-OH vitamin D levels (<20 ng/mL) were repleted with oral vitamin D and had levels 20 ng/mL at time of infusion. For prophylaxis against the postinfusion febrile response that can occur after zoledronic acid infusion, all participants were given acetaminophen 1000 mg 1-2 hours before the infusion and continued as needed if they developed fever, myalgias, or malaise after infusion up to 4 g/day [20] or less if they were taking other acetaminophen-containing medications. Study visits were scheduled at 3, 6, and 12 months after the initial infusion. At each study visit, bone mineral density (BMD) was determined by DXA, serum samples were obtained for measurement of bone markers, and adverse events noted at each visit and
T.J. Schnitzer et al. / PM R XXX (2016) 1-10
graded according to severity, duration, and suspected causal relationship. All participants received supplemental vitamin D (1000 IU cholecalciferol) and calcium 500 mg bid for the duration of the study. Participants demonstrating excessive bone loss (defined as >10% decrease in BMD compared with baseline) at any skeletal site at month 6 were offered study treatment in a blinded fashion such that if they had received placebo at baseline they would receive an intravenous infusion of zoledronic acid 5 mg and if they had received active treatment at baseline they would be offered an infusion of placebo. All participants were scheduled to be followed for a minimum of 1 year after their last infusion. To determine the duration of efficacy of zoledronic acid therapy, participants were offered the opportunity to return for continued BMD and bone marker monitoring every 6 months for up to 12 months after the initial one-year study period. Measurements DXA Acquisition and Analysis The DXA scans were performed with the Hologic QDR 4500A (Hologic, Waltham, MA); standard acquisition and analysis protocols were used to quantify areal BMD of spine, femoral neck, and total proximal femur regions bilaterally [21]. For areal BMD acquisition of the knee, a modified forearm algorithm was elected for scan acquisition, with the imaging field comprising the distal two-thirds of the femur and the proximal onethird of the tibia. The distal femur was divided into 2 regions for analysis, the femoral epiphysis (R1) and the metaphysis (R2) with a separate region of interest for the proximal tibia (R3) as described in a previous publication [22]. During the scans, participants were placed in a supine position and the lower limb was stabilized in full extension. When possible, duplicate scans were obtained. We performed calibrations of the machine before each subject visit by using a spine phantom, air scans, and tissue bar scans. The day-to-day coefficient of variation of the spine phantom over the testing period was 0.387% (n ¼ 315). The precision of the DXA measurements at the distal femur epiphysis, distal femur metaphysic, and the proximal tibia has been published previously, with the root-mean-square coefficient of variation being 3.12%, 4.70%, and 3.40%, respectively [23]. If heterotopic ossification was visualized within the region of interest, data from that skeletal site were not used. Similarly, regions of interest containing metallic objects also were excluded. Bone Markers Serum was obtained at baseline and each subsequent visit and frozen at 70 C until assessed for type 1 procollagen amino-terminal propeptide (P1NP), collagen
3
type 1 cross-linked C-telopeptide (CTX), and bonespecific alkaline phosphatase by Maine Medical Research Institute (Scarborough, ME) via the use of the iSYS Analyzer (chemiluminescence) system (Immunodiagnostic Systems, Inc, Gaithersburg, MD). Statistical Analysis and Sample Size Power calculations based on Nance et al [14] indicated that a sample size of 15 in each group would give sufficient statistical power (>80%) to show a difference in bone loss of 7% per year or more between treatments as statistically significant (2-tailed ¼ .05). Subsequent studies with oral alendronate [15] demonstrated a difference in bone loss between alendronate and placebo of 10% at 6 months, which would permit a smaller sample size. Because of many of the participants having had bone loss of >10% at 6 months and the difficulty of enrollment (as the result of many patients living too far to easily return for further visits as well as others concerned about the possibility of receiving placebo treatment), it was decided to discontinue further enrollment after 17 participants had been randomized. The original statistical analysis plan was to evaluate changes in BMD at 12 months between the active and placebo groups. Because many participants experienced >10% loss of BMD at 6 months and elected to undergo retreatment or discontinued from the study, the analysis plan was changed before unblinding to use the 6-month time point for evaluation and to use changes in BMD at the total hip as the primary outcome. Change in BMD from baseline to the 6-month visit was compared within and between the zoledronic acid and placebo groups by means of paired and unpaired Student t-test despite the small sample size [24]. Baseline comparisons between groups were evaluated by either Student t-test or c2 methodology. Results Study Conduct Seventeen patients initially were screened and signed informed consent. Nine participants were assigned to treatment with placebo and 7 to treatment with zoledronic acid; 1 participant withdrew consent before being infused (Figure 1). Of the 9 assigned to placebo, 3 did not wish to return for their 6-month visit; the remaining 6 participants all demonstrated >10% change in BMD at 1 or more skeletal sites after 6 months and were offered the opportunity to be retreated. Three participants elected for retreatment; the remaining 3 refused retreatment as well as further participation in the study. All felt that the potential benefit was not worth the inconvenience of having to return for study visits. Of the 7 participants assigned to zoledronic acid, 6 were available for evaluation at
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Zoledronic Acid Treatment After Acute SCI
Enrollment
Screened/Signed Consent (n = 17)
Excluded (n = 0)
Follow up
Allocation
Randomized (n = 17)
Allocated to zoledronic acid (n =8)
Allocated to placebo (n = 9)
Received allocated intervention (n =7)
Received allocated intervention (n = 9)
Withdrew consent (n =1)
Withdrew consent (n = 3)
6 months Analyzed (n = 6)
6 months Analyzed (n = 6)
Analysis
Follow up Analysis
Lost to follow up (n =1)
Withdrew consent (n = 3) Retreated with zoledronate
12 months Analyzed (n = 5)
18 months Analyzed (n = 3)
Lost to follow up (n =1)
24 months Analyzed (n=4) Figure 1. Consort flow chart.
6 months and 5 at 12 months. Four of the original members of zoledronic acidetreated group contributed data up to 24 months after initial infusion. The 3 placebo-treated participants who were retreated at 6 months were all followed for an additional 12 months.
Participant Demographics and Clinical Descriptors The demographics and clinical descriptors of the participants in each group are shown in Table 1. All but
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Table 1 Baseline characteristics Characteristic
Control Group (n ¼ 9)
Zoledronic Acid Group (n ¼ 7)
Age, y Gender, male/female Ethnicity, AA/Hispanic or Latino/white Level of lesion (cervical/thoracic) ASIA classification, A/B/C Days to enrollment Baseline 25-hydroxyvitamin D, nmol/L Baseline BMD lumbar spine, g/cm2 Baseline BMD total hip, g/cm2 Baseline BMD femoral neck, g/cm2 Height, inches Weight, lbs BMI Walking regained during study Alcohol, units/wk Smoking, units/d
34.1 ( 15.5) 8:1 2:1:6 6:3 3:4:2 95.3 ( 50.0) 32.4 ( 16.0) 1.086 ( 0.118) 1.000 ( 0.138) 0.899 ( 0.160) 70.1 ( 3.0) 156.3 ( 29.2) 22.2 ( 3.0) 1 1.7 ( 2.5) 0.0 ( 0.0)
44.3 ( 16.3) 7:0 0:3:4 2:5 3:1:1 35.1 ( 15.4)* 30.6 ( 10.7) 1.116 ( 0.222) 1.084 ( 0.107) 0.944 ( 0.126) 68.9 ( 1.7) 187.6 ( 35.0) 27.8 ( 5.0)* 1 0.3 ( 0.5) 0.3 ( 0.7)
Values are mean SD unless stated otherwise. AA ¼ African American; ASIA ¼ American Spinal Injury Association; BMD ¼ bone mineral density; BMI ¼ body mass index. * P < .05; all other categories P > .05.
1 of the participants was male, with the only female participant in the placebo group. The overall mean age was 38.6 16.6 years, and the average BMI of participants was 25.0 4.9. Ethnicity, injury level and AIS classification are all shown in Table 1. Participants were an average of 69.0 days 49.0 days post-SCI at enrollment. During the trial 2 participants became ambulatory; both were classified as being AIS C at study entry, and one was assigned to the treatment group, whereas the other was originally assigned to the placebo group and then retreated with zoledronic acid after 6 months. The control and treatment groups were well matched for most baseline clinical characteristics. The treatment group participants had a greater BMI and were enrolled closer to the date of their injury on average. At study entry, the BMD at the spine, total hip, femoral neck, and distal femur did not differ significantly between the placebo and zoledronic acid groups (P > .05 for comparisons at each site).
Change in BMD at the Spine Participants receiving zoledronic acid had a significant increase from baseline in spine BMD at 6 months of 2.4 1.8% (P ¼ .02). Those participants who received placebo had a significant decrease of 2.5 2.2% (P ¼ .02) in spine BMD compared with study entry at that time point (Figure 2). The difference in spine BMD between the 2 groups at the 6-month time point was statistically significant (P < .01). Participants treated with zoledronic acid continued to have a further increase in spine BMD over the ensuing 18 months, with an increase in spine BMD of 5.0 0.8% over the 2-year period since infusion.
Change in BMD at the Hip and Femoral Neck Participants receiving placebo demonstrated significant bone loss at both the total hip and femoral neck over the 6 months that they were followed. At the total hip, participants receiving placebo had a change from baseline in BMD at the right hip of 8.6 3.5% at 6 months and a similar change in BMD of 12.3 6.9% in the left hip at that time point (Figure 2). In the group receiving zoledronic acid, there was a change in BMD of 2.2 3.4% in the right hip and 3.7 1.0% in the left hip at the same time point. The differences between the changes in BMD in the 2 groups was significant at both the right and left total hip (P ¼ .03 for both). Changes in BMD at the femoral neck were greater in magnitude, with the placebo group demonstrating significant changes of 20.0 6.4% and 11.1 7.4% at the right and left femoral neck, respectively, whereas the group receiving zoledronic acid had nonsignificant changes from baseline of 5.1 6.5% and 1.1 3.5%, at the right and left femoral neck, respectively (Figure 2). The difference in change in BMD from baseline between the 2 treatment groups was statistically significant for both the right (P ¼ .01) and left (P ¼ .02) femoral neck. Over the additional period of observation of the zoledronic acid-treated group, bone loss continued, with a change from baseline in BMD at 12 months of 3.1 2.7% and 4.8 1.1% at the right and left hip and a further decrease by 18 months to 13.1 2.4% and 6.2 2.6% change from baseline. At the 24-month time point, change from baseline for the left hip was 12.4 0.8%; right hip imaging was not possible for some participants, and there were therefore insufficient data to report right hip changes at this time point. Changes in BMD from baseline at the femoral neck, right
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Zoledronic Acid Treatment After Acute SCI
Figure 2. Mean percent change in bone mineral density (BMD) SE from mean baseline values over time in the placebo and zoledronic acide treated groups at the (A) spine, (B) total hip, (C) femoral neck, and (D) distal femur/proximal tibia skeletal sites. †Significant change from baseline within a treatment group. *Significant change from baseline between zoledronic acid and placebo treatment groups.
and left, respectively, were: at 12 months, 2.6 4.1% and 0.7 4.2%; at 18 months, 7.8 7.5% and 1.5 2.5%; and at 24 months, 4.1 2.7% on the left and 15.5% on the right in a single individual.
Change in BMD at the Distal Femur and Proximal Tibia DXA imaging was performed at skeletal sites about the knee to determine how changes in BMD at those skeletal sites would compare with skeletal sites at the hip. Only data from the left distal femur are reported, as too few images were obtained from the right side because of the presence of hardware and/or technical difficulties in imaging. Changes from baseline in both treatment groups are shown over time in Figure 2 for the distal femur with complete data over time for each skeletal site in the zoledronic acid group included in Table 2. There were no placebo participants who continued beyond 6 months.
Change in Serum Markers of Bone Metabolism At baseline, serum levels of CTX, a marker of bone resorption, was elevated in both treatment groups: 1.11 ng/mL (0.74, 1.44; first, third quartile) and 1.13 ng/mL (0.99, 1.66), zoledronic acid and placebo groups, respectively. After infusion of zoledronic acid, there was a reduction in the median serum CTX level to 0.25 ng/mL (0.24, 0.31) at the 3-month visit, and levels remained in this range for the duration of the 24 months of the study (Figure 3). The group receiving placebo likewise had a reduction in median serum levels of CTX, but less marked, to 0.97 ng/mL (0.68, 1.18) after 3 months with a further reduction at 6 months to 0.68 ng/mL (0.63, 0.80). Baseline serum levels of P1NP, a marker of bone formation, also were elevated in both treatment groups (130.97 ng/mL [114.73, 151.79] in the zoledronic acid group and 139.52 [76.81, 217.80] in the placebo group) with a steep reduction at 3 months after zoledronic acid infusion to 58.48 ng/mL (54.11, 62.93), these levels being maintained for the duration of the
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Table 2 Percent change from baseline over time in BMD at knee skeletal sites Zoledronic Acid
Placebo
Months
R1
R2
R3
R1
R2
R3
6 12 24
8.2 7.7 17.7 7.8 27.5 10.7
11.0 8.2 13.8 11.7 26.2 19.1
3.3 2.9 11.8 7.7 21.9 7.3
9.1 7.1 ND ND
16.4 12.2 ND ND
13.8 10.5 ND ND
BMD ¼ bone mineral density; ND ¼ not determined.
study. In contrast, those receiving placebo had a small, nonsignificant reduction in their baseline levels of P1NP at the 3-month visit but then had a significant reduction to 87.00 ng/mL (82.13, 145.13) at the 6-month time point.
infusions that lasted 24-36 hours despite pretreatment with acetaminophen. No other adverse effects were associated with zoledronic acid treatment.
Delayed Treatment With Zoledronic Acid
A single infusion of zoledronic acid 5 mg was effective at slowing, although not preventing, bone loss that occurs after acute SCI. Bone loss after SCI is a consequence of markedly enhanced bone resorption, driven by the lack of normal loading with possible contributions from changes in nervous system and hormonal inputs [2]. Therefore, intervention with an agent that will prevent bone resorption would be expected to blunt the altered pathophysiologic state. Zoledronic acid is a third-generation amino-bisphosphonate with features that make it particularly attractive for use in the SCI population, and it have been approved for use to treat osteoporosis in a once-yearly parenteral form [25]. Thus, unlike oral bisphosphonates, there are no issues with people having to maintain upright postures or wait to take their morning medications or breakfast. The prolonged efficacy may be partially attributable to the enhanced potency of zoledronic acid and also to the fact that parenteral administration allows much larger amounts of drug to be delivered to bone, as oral
Three participants who had received placebo at baseline received an infusion of zoledronic acid after their 6-month visit demonstrated a loss of >10% BMD at either the hip or femoral neck. Subsequent changes in their BMD, when their 6-month values were used as baseline, are shown in Figure 4. At all skeletal sites about the hip, there was no further bone loss and BMD increased from 1% to 5% after 6 months with a gradual decline over the ensuing 12 months. At the knee, there continued to be loss of BMD at 6 months and over the following period of follow-up, suggesting a differential effect of the infusion at the skeletal sites. Safety Three participants receiving zoledronic acid experienced temperature elevations greater than 102 F, myalgias and general discomfort shortly after their
Discussion
Figure 3. Change in mean serum levels of collagen type 1 cross-linked C-telopeptide (CTX-1; ng/mL) and type 1 procollagen amino-terminal propeptide (P1NP; ng/mL) over time in the placebo and zoledronic acidetreated groups.
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Zoledronic Acid Treatment After Acute SCI
Figure 4. Mean percent change in bone mineral density (BMD) at the spine, total hip, femoral neck, and distal femur from values at month 6 in those individuals in the placebo group who underwent reinfusion, receiving zoledronic acid.
bisphosphonates are extremely poorly absorbed [26]. Regardless, adherence to treatment is assured once an infusion is complete and there are no interferences with other medical management. In this study, the participants receiving placebo had a significant decrease in mean BMD at the total hip and femoral neck as early as 3 months after study entry. By 6 months, every participant in the study who had received a placebo infusion had a 10% decrease in BMD from their baseline values at either the total hip or femoral neck skeletal sites. The mean decrease in BMD at the total hip at 6 months was almost 10% and greater yet at the femoral neck, in the range of 11%-20%. The actual bone loss since the actual injury was no doubt even greater, because the initial DXA imaging was only done at a mean time of 3 months after SCI. Although we do not have data on the extent of bone loss at 1 year after SCI from this study, we and others [15,17,27] have found changes in BMD at the hip and femoral neck in the range of 20%. Treatment with zoledronic acid was shown in this study to be able to mitigate much of this bone loss. At the total hip, the mean decrease in BMD was less than 5% for the initial 12 months after infusion, with similar data observed at the femoral neck. At times beyond 12 months after infusion, BMD did decrease at an accelerated pace at the total hip but less rapid bone loss was seen at the femoral neck. Retreatment of those receiving zoledronic acid was not included in this study to evaluate duration of effect. From the data obtained, it would appear that efficacy in terms of BMD response at the hip was fairly well maintained through 12 months, but by 18 months BMD values at both the total hip and femoral neck had declined to the range seen in the placebo group at the 6 month time point. Hence, a single infusion was able to delay bone loss by approximately 12 months at these skeletal sites about the hip.
BMD at the knee was of particular interest as this skeletal area is most commonly involved in fracture in individuals after SCI [28,29]. Our results demonstrate what appears to be a quantitatively different bone response at the knee compared with the hip. The effect of zoledronic acid at the knee is significantly less marked compared with the hip, and differences between the zoledronic acid and placebo groups were small and did not reach statistical significance. It should be noted that because of the limited sample size of the study and the large variability in bone changes at the knee, the study was not adequately powered to be able to reliably detect even moderately large differences that may have clinical significance. The basis for the apparent difference in response at the knee compared with the hip is not known. The degree and rate of bone loss in the placebo group at both the hip and knee is approximately the same, making it unlikely that a possible differential loading effect (greater in the pelvic area than the knee) is a likely explanation. The effect seen at the proximal femur is more similar to that seen at the hip, but of shorter duration, supporting the possibility of more rapid turnover in the distal lower extremities. In contrast to effects at the hip and knee, zoledronic acid infusion resulted in an increase in BMD at the spine in patients after acute SCI. The spine is normally loaded and not denervated after SCI, and this BMD response observed at the spine is in the range of that reported after zoledronic acid treatment of osteoporotic men and women [30,31]. Baseline bone marker levels of both CTX and P1NP were elevated, markedly so in some individuals. Zoledronic acid infusion resulted in a marked decrease in both of these biomarkers to within the normal range at the 3-month time point. These results are consistent with effects on these biomarkers in previous studies of zoledronic acid [32], although it should be noted that levels did not decrease to below the normal range. Thus, some degree of both bone resorption and bone formation was still occurring. Previous studies in which the authors examined the effects of bisphosphonates on bone after SCI have also observed inhibition of the expected bone loss. The earliest and largest of these studies, reported by Gilchrist et al [15], was a randomized, placebo-controlled clinical trial that involved 31 SCI patients treated with oral weekly alendronate for 12 months. This study was remarkable for the early onset of treatment (within 10 days of SCI) and the marked benefit observed. Mean loss of BMD at all skeletal regions of interest at the hip was less than 5% after 1 year of treatment, compared with BMD loss in the range of 20% or more observed in the placebo-treated group. The results in the zoledronic acid-treated group are similar to those reported in the current study, as was the magnitude of the bone loss seen at 6 months in the placebo group. Zoledronic acid
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treatment after SCI has been evaluated in 2 previous studies. The study by Shapiro et al [16] enrolled 17 patients after SCI in a placebo-controlled randomized trial and reported an increase from baseline in BMD at 6 months at all hip skeletal sites in participants treated with zoledronic acid; however, at the 12-month time point, there was a subsequent decline in BMD, suggesting that the effect of zoledronic acid was not sustained for the entire study period. A subsequent study of zoledronic acid by Bubbear et al [17] in 14 participants after SCI reported sustained efficacy of zoledronic acid on BMD measured at the total hip and trochanter skeletal sites with a statistically significant difference compared with the placebo-treated group, but no significant difference was seen at the femoral neck. In all studies, spine BMD increased after zoledronic acid treatment and serum markers of bone resorption were reduced. The study by Bauman et al [18] evaluated 6 individuals after motor-complete SCI who received zoledronic acid and compared them to a control cohort of 7 nontreated individuals, finding a slowing of bone loss at the hip but an apparent increase in bone loss at skeletal sites around the knee in the zoledronic acid group. Because of the small number of participants and the nonrandomized design, further studies are needed before any definitive conclusions can be made about the responses observed at the knee skeletal sites. However, the data in this study are consistent with a lesser effect of zoledronic acid at these distal skeletal sites in the lower extremity compared with the hip. In those participants in the current study who initially received placebo infusion, subsequent treatment with zoledronic acid at a time more than 6 months after acute SCI resulted in an abrupt cessation of bone loss at skeletal sites at the hip but again was apparently less effective at skeletal sites at the knee. The reason for this difference is not clear, as serum levels of CTX were effectively reduced by zoledronic acid treatment. The study was limited by a relatively small sample size and a number of technical difficulties associated with the DXA imaging procedure. Several of our participants, evenly divided between the treatment groups, developed heterotopic ossification around the hip during the course of the study which prevented obtaining valid BMD values at those skeletal areas. Positioning for DXA on repeated visits was consistently challenging and resulted in larger variances in BMD, particularly at skeletal sites around the knee. All of these factors reduced the ability to distinguish small-to-moderate differences that may have existed between treatment groups. Results of this pilot study suggest that the use of zoledronic acid after SCI may be effective in slowing bone loss, certainly at skeletal sites around the hip and possibly at the knee as well. These data need to be confirmed and extended by studies with larger populations and for longer treatment and follow-up times.
9
Although bisphosphonate use for a period of many years in people with SCI may not be warranted because of safety concerns [33], it should be noted that currently the majority of people with SCI injuries retain some degree of motor function below the level of the injury, and an increasing proportion of people do become weight-bearing or ambulatory, either as part of their physical therapy regime or independently [34], after which further bone loss is slowed or may even be prevented. Therefore, particularly for these individuals, prevention of bone loss during the first 6 months after SCI would result in greater BMD as they age and will have a large impact on their future risk of fracture. Prevention of acute bone loss, which can be in the range of 20% or more in their lower extremities during the immediate months after SCI, should be a high priority, particularly because this study and others have demonstrated that such an outcome is feasible, safe, inexpensive, and does not interfere with other medical management or with rehabilitation. Conclusion In individuals after acute SCI, a single infusion of zoledronic acid 5 mg compared with placebo resulted in a slowing of bone loss at lower extremity skeletal sites, more so at the hip than the knee. Whether these beneficial effects can be sustained is not known and will require longer follow-up with larger populations. Acknowledgments Zoledronic acid and placebo were provided by Novartis. We thank the individuals with spinal cord injury who graciously and generously gave of their time to be involved. References 1. University of Alabama at Birmingham Spinal cord injury facts and figures at a glance. Available at https://www.nscisc.uab.edu/ PublicDocuments/fact_figures_docs/Facts%202013.pdf. Accessed January 28, 2016. 2. Jiang SD, Jiang LS, Dai LY. Mechanisms of osteoporosis in spinal cord injury. Clin Endocrinol (Oxf) 2006;65:555-565. 3. Maimoun L, Fattal C, Micallef JP, Peruchon E, Rabischong P. Bone loss in spinal cord-injured patients: From physiopathology to therapy. Spinal Cord 2006;44:203-210. 4. Jiang SD, Dai LY, Jiang LS. Osteoporosis after spinal cord injury. Osteoporos Int 2006;17:180-192. 5. Logan WC Jr, Sloane R, Lyles KW, Goldstein B, Hoenig HM. Incidence of fractures in a cohort of veterans with chronic multiple sclerosis or traumatic spinal cord injury. Arch Phys Med Rehabil 2008;89:237-243. 6. Lazo MG, Shirazi P, Sam M, Giobbie-Hurder A, Blacconiere MJ, Muppidi M. Osteoporosis and risk of fracture in men with spinal cord injury. Spinal Cord 2001;39:208-214. 7. Morse LR, Battaglino RA, Stolzmann KL, et al. Osteoporotic fractures and hospitalization risk in chronic spinal cord injury. Osteoporos Int 2009;20:385-392.
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8. Reiter AL, Volk A, Vollmar J, Fromm B, Gerner HJ. Changes of basic bone turnover parameters in short-term and long-term patients with spinal cord injury. Eur Spine J 2007;16:771-776. 9. Roberts D, Lee W, Cuneo RC, et al. Longitudinal study of bone turnover after acute spinal cord injury. J Clin Endocrinol Metab 1998;83:415-422. 10. Frotzler A, Berger M, Knecht H, Eser P. Bone steady-state is established at reduced bone strength after spinal cord injury: A longitudinal study using peripheral quantitative computed tomography (pQCT). Bone 2008;43:549-555. 11. Frotzler A, Coupaud S, Perret C, et al. High-volume FES-cycling partially reverses bone loss in people with chronic spinal cord injury. Bone 2008;43:169-176. 12. Dudley-Javoroski S, Saha PK, Liang G, Li C, Gao Z, Shields RK. High dose compressive loads attenuate bone mineral loss in humans with spinal cord injury. Osteoporos Int 2012;23:2335-2346. 13. Bauman WA, Wecht JM, Kirshblum S, et al. Effect of pamidronate administration on bone in patients with acute spinal cord injury. J Rehabil Res Dev 2005;42:305-313. 14. Nance PW, Schryvers O, Leslie W, Ludwig S, Krahn J, Uebelhart D. Intravenous pamidronate attenuates bone density loss after acute spinal cord injury. Arch Phys Med Rehabil 1999;80:243-251. 15. Gilchrist NL, Frampton CM, Acland RH, et al. Alendronate prevents bone loss in patients with acute spinal cord injury: A randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2007;92:1385-1390. 16. Shapiro J, Smith B, Beck T, et al. Treatment with zoledronic acid ameliorates negative geometric changes in the proximal femur following acute spinal cord injury. Calcif Tissue Int 2007;80: 316-322. 17. Bubbear JS, Gall A, Middleton FR, Ferguson-Pell M, Swaminathan R, Keen RW. Early treatment with zoledronic acid prevents bone loss at the hip following acute spinal cord injury. Osteoporos Int 2011;22:271-279. 18. Bauman WA, Cirnigliaro CM, La Fountaine MF, Martinez L, Kirshblum SC, Spungen AM. Zoledronic acid administration failed to prevent bone loss at the knee in persons with acute spinal cord injury: an observational cohort study. J Bone Miner Metab 2015;33: 410-421. 19. Marino RJ, Barros T, Biering-Sorensen F, et al. International standards for neurological classification of spinal cord injury. J Spinal Cord Med 2003;26(suppl 1):S50-S56. 20. Wark JD, Bensen W, Recknor C, et al. Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Osteoporos Int 2012;23:503-512. 21. Gordon KE, Wald MJ, Schnitzer TJ. Effect of parathyroid hormone combined with gait training on bone density and bone
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architecture in people with chronic spinal cord injury. PM R 2013; 5:663-671. Edwards WB, Schnitzer TJ, Troy KL. Bone mineral and stiffness loss at the distal femur and proximal tibia in acute spinal cord injury. Osteoporos Int 2014;25:1005-1015. McPherson JG, Edwards WB, Prasad A, Troy KL, Griffith JW, Schnitzer TJ. Dual energy X-ray absorptiometry of the knee in spinal cord injury: Methodology and correlation with quantitative computed tomography. Spinal Cord 2014;52:821-825. de Winter JCF. Using the Student’s t-test with extremely small sample sizes. Pract Assess Res Eval 2013;18:1-12. Russell RG, Xia Z, Dunford JE, et al. Bisphosphonates: An update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 2007;1117:209-257. Russell RG. Bisphosphonates: Mode of action and pharmacology. Pediatrics 2007;119(suppl 2):S150-S162. Biering-Sorensen F, Bohr HH, Schaadt OP. Longitudinal study of bone mineral content in the lumbar spine, the forearm and the lower extremities after spinal cord injury. Eur J Clin Invest 1990; 20:330-335. Zehnder Y, Luthi M, Michel D, et al. Long-term changes in bone metabolism, bone mineral density, quantitative ultrasound parameters, and fracture incidence after spinal cord injury: A crosssectional observational study in 100 paraplegic men. Osteoporos Int 2004;15:180-189. Garland DE, Adkins RH, Kushwaha V, Stewart C. Risk factors for osteoporosis at the knee in the spinal cord injury population. J Spinal Cord Med 2004;27:202-206. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356:1809-1822. Orwoll ES, Miller PD, Adachi JD, et al. Efficacy and safety of a once-yearly i.v. Infusion of zoledronic acid 5 mg versus a onceweekly 70-mg oral alendronate in the treatment of male osteoporosis: A randomized, multicenter, double-blind, activecontrolled study. J Bone Miner Res 2010;25:2239-2250. Delmas PD, Munoz F, Black DM, et al. Effects of yearly zoledronic acid 5 mg on bone turnover markers and relation of PINP with fracture reduction in postmenopausal women with osteoporosis. J Bone Miner Res 2009;24:1544-1551. Suresh E, Pazianas M, Abrahamsen B. Safety issues with bisphosphonate therapy for osteoporosis. Rheumatology 2014;53: 19-31. National Spinal Cord Injury Statistical Center. 2014 Annual Statistical Report for the Spinal Cord Injury Model Systems, Complete Public Version. University of Alabama at Birmingham. Available at https://www.nscisc.uab.edu/reports.aspx. Accessed February 12, 2016.
Disclosure T.J.S. Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611. Address correspondence to: T.J.S.; e-mail: tjs@ northwestern.edu Disclosures related to this publication: provision of writing assistance, medicine, equipment, or administrative support; Novartis provided only study drugs and placebo (no money) K.K. Northwestern University Feinberg School of Medicine, Chicago, IL; and Rehabilitation Institute of Chicago, Chicago, IL Disclosure: nothing to disclose J.M. Northwestern University Feinberg School of Medicine, Chicago, IL Disclosure: nothing to disclose
R.Y. Northwestern University Feinberg School of Medicine, Chicago, IL Disclosure: nothing to disclose N.S. Northwestern University Feinberg School of Medicine, Chicago, IL Disclosure: nothing to disclose D.C. Northwestern University Feinberg School of Medicine, Chicago, IL; and Rehabilitation Institute of Chicago, Chicago, IL Disclosure: nothing to disclose Funding source: Zoledronic acid and placebo provided by Novartis. Submitted for publication September 16, 2015; accepted January 23, 2016.
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Original Research
Zoledronic Acid Treatment After Acute Spinal Cord Injury: Results of a Randomized, Placebo-Controlled Pilot Trial Thomas J. Schnitzer, MD, PhD, Ki Kim, MD, Julia Marks, BS, Renita Yeasted, BS, Narina Simonian, BS, David Chen, MD
Abstract Objective: To determine the effect of intravenous zoledronic acid 5 mg on the extent and course of bone loss after spinal cord injury (SCI). Design: Double-blind, randomized, placebo-controlled parallel-group trial. Setting: Acute in-patient, tertiary-care rehabilitation hospital. Participants: Convenience sample of 17 in-patients with SCI <12 weeks before randomization; American Spinal Injury Association Impairment scale A, B, or C and medically stable. Twelve patients were evaluated at the primary endpoint at 6 months. Methods: Patients meeting study criteria were randomly assigned to zoledronic acid 5 mg or matching placebo. Dual x-ray absorptiometry scan and serum for bone markers (type 1 procollagen amino-terminal propeptide, bone-specific alkaline phosphatase, collagen type 1 cross-linked C-telopeptide) were obtained at baseline and after 3 months, 6 months, and the every 6 months for up to 2 years. Main Outcome Measures: The primary endpoint was change in bone mineral density (BMD) at the total hip after 6 months; secondary endpoints were changes in BMD at other skeletal sites and changes in levels of serum bone markers. Results: The group treated with zoledronic acid had a smaller decrease in BMD at 6 months at the total hip than the placebo group (right: 2.2 3.4% versus 8.6 3.5%, respectively, P ¼ .03; left: 3.7 1.0% versus 12.3 6.9%, P ¼ .03). Differences in BMD at the femoral neck were similar (right: 5.1 6.5% versus 20.0 6.4%, P ¼ .01; left: 1.1 3.5% versus 11.1 7.4%, P ¼ .02) with larger bone loss and smaller between group differences at the knee. Zoledronic acid resulted in a decrease in serum levels of both formation and resorption markers. Conclusions: Zoledronic acid is effective at mitigating bone loss after SCI. Duration of efficacy and activity at different skeletal sites may differ from that observed in able-bodied individuals and needs further study.
Introduction Traumatic spinal cord injury (SCI) occurs in approximately 12,000 people each year in the United States [1]. Bone loss is an almost universal sequela of SCI and is attributed to the response of bone to loss of normal weight-bearing as well as possibly to the disruption of normal neurologic and hormonal factors [2]. Bone resorption is markedly enhanced and bone formation depressed in the skeletal areas below the neurologic level of the injury, resulting in rapid and extensive loss of bone mass and alteration of normal bone architecture [3,4]. The consequences of these changes are reflected in the marked increase in the incidence of fracture
experienced by people with SCI, affecting primarily their lower extremities, particularly the skeletal sites around the knee [5,6]. These fractures result in both an increase in cost of care as well as adversely impacting the mobility, functioning, and quality of life of those affected [7]. Bone loss is most marked during the first 2 years after SCI, after which there is a return to a new steady state of bone turnover in the affected skeletal sites [8-10]. The degree of the bone loss is greatest in individuals with tetraplegia and those with complete motor injuries, with greater maintenance of bone in people with incomplete motor loss and those able to regain some degree of weight-bearing. Attempts to
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Zoledronic Acid Treatment After Acute SCI
prevent bone loss via the use of standard nonpharmacologic rehabilitative modalities (physical therapy, supported weight-bearing, standing) have not been successful, although increasing load by the use of electrical stimulation has shown efficacy in research settings [11,12]. Previous pharmacologic approaches to prevent bone loss have attempted to inhibit bone resorption with either oral or intravenous bisphosphonates. Although early studies with these agents yielded negative or equivocal results [13,14], recent studies that use more potent bisphosphonates have documented a slowing of bone loss in the lower extremities. Gilchrist et al [15] undertook at 12-month randomized trial of oral alendronate 70 mg weekly compared with placebo and demonstrated a marked reduction of bone loss at all hip skeletal sites in the alendronate group. Shapiro et al [16] and Bubbear et al [17] evaluated the effects of a single infusion of zoledronic acid 4 mg or 5 mg compared with placebo-treated participants with acute SCI. Both studies reported a reduction in bone loss at hip skeletal sites in the zoledronic acidetreated group, with greater efficacy after 6 months compared with 12 months. In each of these trials, bone resorption markers were suppressed successfully by bisphosphonate use. Longer term follow-up beyond 18 months was not reported. A recent observational cohort study provided further support for zoledronic acid efficacy at reducing bone loss at hip skeletal sites after SCI but reported an increase in bone loss at the distal femur and proximal tibia in treated individuals [18]. The current placebo-controlled randomized trial was undertaken to evaluate the effect of a single infusion of zoledronic acid 5 mg, a dosage used to treat osteoporosis, on bone changes after acute SCI. In contrast to previous studies, participants were followed for up to 2 years after treatment to evaluate durability of response, and bone changes were evaluated at skeletal sites around the knee in addition to the standard skeletal sites. Methods Study Design and Participants Between January 2010 and December 2012, 17 patients recently admitted to the Rehabilitation Institute of Chicago, Chicago, IL, age 18 years or older, with acute SCI participated in a prospective, parallel-group, double-blind, placebo-controlled study to determine the efficacy and safety of zoledronic acid. Participants had to be classified by the American Spinal Injury Association Impairment scale (AIS) [19] as A or B at the time of study entry, or AIS C if not weight-bearing, with an SCI that occurred within 6 months of study entry. Participants were excluded if they were pregnant or lactating, mentally unstable, had significant renal
impairment (estimated creatinine clearance <30 mL/ min), or evidence of hypocalcemia, vitamin D deficiency, or abnormal thyroid hormone status. Female participants of child-bearing potential had to be willing to use the double-barrier method of contraception for 2 months after having received the study drug to participate. All participants who were currently or recently (within 12 months) taking drugs that affect bone metabolism (bisphosphonates, teriparatide, selective estrogen modulators) were excluded. Participants who had osteoporosis at the hip or spine at the baseline visit after imaging by dual x-ray absorptiometry (DXA) were excluded. Participants with a history of malignancy or poor dental hygiene (that required invasive dental procedure within 2 months of enrollment) were excluded. All participants gave written consent to take part in the study before any procedures being performed. This study was approved by the Northwestern University Institutional Review Board and registered at clinicaltrials.gov (NCT00844480). Participants were assigned in computer-generated blocks of 4 to be randomized to receive either 5 mg intravenous zoledronic acid (Zometa, Novartis Pharmaceuticals, Basel Switzerland; active treatment group) or an infusion of placebo (diluent alone) in a blinded fashion and a 1:1 allocation. Study medication was assigned by the hospital research pharmacist; all other study staff were blinded to treatment allocation. Both active and identical matching placebo treatments were provided by Novartis Pharmaceuticals. A complete medical history, including surgical history, family history, medications, smoking, alcohol, diet/exercise information, and bone-specific information regarding previous fractures and falls, was collected at the initial screening visit. Laboratory evaluations for hepatic and renal function, vitamin D levels, and thyroid status were performed at this time. Weight, height, and AIS classification were obtained from clinical records at admission. After screening, participants who qualified for the study had a baseline DXA examination and serum obtained for bone metabolic markers and hormone levels, followed within 1 week by infusion of study medication. Participants with low serum 25-OH vitamin D levels (<20 ng/mL) were repleted with oral vitamin D and had levels 20 ng/mL at time of infusion. For prophylaxis against the postinfusion febrile response that can occur after zoledronic acid infusion, all participants were given acetaminophen 1000 mg 1-2 hours before the infusion and continued as needed if they developed fever, myalgias, or malaise after infusion up to 4 g/day [20] or less if they were taking other acetaminophen-containing medications. Study visits were scheduled at 3, 6, and 12 months after the initial infusion. At each study visit, bone mineral density (BMD) was determined by DXA, serum samples were obtained for measurement of bone markers, and adverse events noted at each visit and
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graded according to severity, duration, and suspected causal relationship. All participants received supplemental vitamin D (1000 IU cholecalciferol) and calcium 500 mg bid for the duration of the study. Participants demonstrating excessive bone loss (defined as >10% decrease in BMD compared with baseline) at any skeletal site at month 6 were offered study treatment in a blinded fashion such that if they had received placebo at baseline they would receive an intravenous infusion of zoledronic acid 5 mg and if they had received active treatment at baseline they would be offered an infusion of placebo. All participants were scheduled to be followed for a minimum of 1 year after their last infusion. To determine the duration of efficacy of zoledronic acid therapy, participants were offered the opportunity to return for continued BMD and bone marker monitoring every 6 months for up to 12 months after the initial one-year study period. Measurements DXA Acquisition and Analysis The DXA scans were performed with the Hologic QDR 4500A (Hologic, Waltham, MA); standard acquisition and analysis protocols were used to quantify areal BMD of spine, femoral neck, and total proximal femur regions bilaterally [21]. For areal BMD acquisition of the knee, a modified forearm algorithm was elected for scan acquisition, with the imaging field comprising the distal two-thirds of the femur and the proximal onethird of the tibia. The distal femur was divided into 2 regions for analysis, the femoral epiphysis (R1) and the metaphysis (R2) with a separate region of interest for the proximal tibia (R3) as described in a previous publication [22]. During the scans, participants were placed in a supine position and the lower limb was stabilized in full extension. When possible, duplicate scans were obtained. We performed calibrations of the machine before each subject visit by using a spine phantom, air scans, and tissue bar scans. The day-to-day coefficient of variation of the spine phantom over the testing period was 0.387% (n ¼ 315). The precision of the DXA measurements at the distal femur epiphysis, distal femur metaphysic, and the proximal tibia has been published previously, with the root-mean-square coefficient of variation being 3.12%, 4.70%, and 3.40%, respectively [23]. If heterotopic ossification was visualized within the region of interest, data from that skeletal site were not used. Similarly, regions of interest containing metallic objects also were excluded. Bone Markers Serum was obtained at baseline and each subsequent visit and frozen at 70 C until assessed for type 1 procollagen amino-terminal propeptide (P1NP), collagen
3
type 1 cross-linked C-telopeptide (CTX), and bonespecific alkaline phosphatase by Maine Medical Research Institute (Scarborough, ME) via the use of the iSYS Analyzer (chemiluminescence) system (Immunodiagnostic Systems, Inc, Gaithersburg, MD). Statistical Analysis and Sample Size Power calculations based on Nance et al [14] indicated that a sample size of 15 in each group would give sufficient statistical power (>80%) to show a difference in bone loss of 7% per year or more between treatments as statistically significant (2-tailed ¼ .05). Subsequent studies with oral alendronate [15] demonstrated a difference in bone loss between alendronate and placebo of 10% at 6 months, which would permit a smaller sample size. Because of many of the participants having had bone loss of >10% at 6 months and the difficulty of enrollment (as the result of many patients living too far to easily return for further visits as well as others concerned about the possibility of receiving placebo treatment), it was decided to discontinue further enrollment after 17 participants had been randomized. The original statistical analysis plan was to evaluate changes in BMD at 12 months between the active and placebo groups. Because many participants experienced >10% loss of BMD at 6 months and elected to undergo retreatment or discontinued from the study, the analysis plan was changed before unblinding to use the 6-month time point for evaluation and to use changes in BMD at the total hip as the primary outcome. Change in BMD from baseline to the 6-month visit was compared within and between the zoledronic acid and placebo groups by means of paired and unpaired Student t-test despite the small sample size [24]. Baseline comparisons between groups were evaluated by either Student t-test or c2 methodology. Results Study Conduct Seventeen patients initially were screened and signed informed consent. Nine participants were assigned to treatment with placebo and 7 to treatment with zoledronic acid; 1 participant withdrew consent before being infused (Figure 1). Of the 9 assigned to placebo, 3 did not wish to return for their 6-month visit; the remaining 6 participants all demonstrated >10% change in BMD at 1 or more skeletal sites after 6 months and were offered the opportunity to be retreated. Three participants elected for retreatment; the remaining 3 refused retreatment as well as further participation in the study. All felt that the potential benefit was not worth the inconvenience of having to return for study visits. Of the 7 participants assigned to zoledronic acid, 6 were available for evaluation at
4
Zoledronic Acid Treatment After Acute SCI
Enrollment
Screened/Signed Consent (n = 17)
Excluded (n = 0)
Follow up
Allocation
Randomized (n = 17)
Allocated to zoledronic acid (n =8)
Allocated to placebo (n = 9)
Received allocated intervention (n =7)
Received allocated intervention (n = 9)
Withdrew consent (n =1)
Withdrew consent (n = 3)
6 months Analyzed (n = 6)
6 months Analyzed (n = 6)
Analysis
Follow up Analysis
Lost to follow up (n =1)
Withdrew consent (n = 3) Retreated with zoledronate
12 months Analyzed (n = 5)
18 months Analyzed (n = 3)
Lost to follow up (n =1)
24 months Analyzed (n=4) Figure 1. Consort flow chart.
6 months and 5 at 12 months. Four of the original members of zoledronic acidetreated group contributed data up to 24 months after initial infusion. The 3 placebo-treated participants who were retreated at 6 months were all followed for an additional 12 months.
Participant Demographics and Clinical Descriptors The demographics and clinical descriptors of the participants in each group are shown in Table 1. All but
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5
Table 1 Baseline characteristics Characteristic
Control Group (n ¼ 9)
Zoledronic Acid Group (n ¼ 7)
Age, y Gender, male/female Ethnicity, AA/Hispanic or Latino/white Level of lesion (cervical/thoracic) ASIA classification, A/B/C Days to enrollment Baseline 25-hydroxyvitamin D, nmol/L Baseline BMD lumbar spine, g/cm2 Baseline BMD total hip, g/cm2 Baseline BMD femoral neck, g/cm2 Height, inches Weight, lbs BMI Walking regained during study Alcohol, units/wk Smoking, units/d
34.1 ( 15.5) 8:1 2:1:6 6:3 3:4:2 95.3 ( 50.0) 32.4 ( 16.0) 1.086 ( 0.118) 1.000 ( 0.138) 0.899 ( 0.160) 70.1 ( 3.0) 156.3 ( 29.2) 22.2 ( 3.0) 1 1.7 ( 2.5) 0.0 ( 0.0)
44.3 ( 16.3) 7:0 0:3:4 2:5 3:1:1 35.1 ( 15.4)* 30.6 ( 10.7) 1.116 ( 0.222) 1.084 ( 0.107) 0.944 ( 0.126) 68.9 ( 1.7) 187.6 ( 35.0) 27.8 ( 5.0)* 1 0.3 ( 0.5) 0.3 ( 0.7)
Values are mean SD unless stated otherwise. AA ¼ African American; ASIA ¼ American Spinal Injury Association; BMD ¼ bone mineral density; BMI ¼ body mass index. * P < .05; all other categories P > .05.
1 of the participants was male, with the only female participant in the placebo group. The overall mean age was 38.6 16.6 years, and the average BMI of participants was 25.0 4.9. Ethnicity, injury level and AIS classification are all shown in Table 1. Participants were an average of 69.0 days 49.0 days post-SCI at enrollment. During the trial 2 participants became ambulatory; both were classified as being AIS C at study entry, and one was assigned to the treatment group, whereas the other was originally assigned to the placebo group and then retreated with zoledronic acid after 6 months. The control and treatment groups were well matched for most baseline clinical characteristics. The treatment group participants had a greater BMI and were enrolled closer to the date of their injury on average. At study entry, the BMD at the spine, total hip, femoral neck, and distal femur did not differ significantly between the placebo and zoledronic acid groups (P > .05 for comparisons at each site).
Change in BMD at the Spine Participants receiving zoledronic acid had a significant increase from baseline in spine BMD at 6 months of 2.4 1.8% (P ¼ .02). Those participants who received placebo had a significant decrease of 2.5 2.2% (P ¼ .02) in spine BMD compared with study entry at that time point (Figure 2). The difference in spine BMD between the 2 groups at the 6-month time point was statistically significant (P < .01). Participants treated with zoledronic acid continued to have a further increase in spine BMD over the ensuing 18 months, with an increase in spine BMD of 5.0 0.8% over the 2-year period since infusion.
Change in BMD at the Hip and Femoral Neck Participants receiving placebo demonstrated significant bone loss at both the total hip and femoral neck over the 6 months that they were followed. At the total hip, participants receiving placebo had a change from baseline in BMD at the right hip of 8.6 3.5% at 6 months and a similar change in BMD of 12.3 6.9% in the left hip at that time point (Figure 2). In the group receiving zoledronic acid, there was a change in BMD of 2.2 3.4% in the right hip and 3.7 1.0% in the left hip at the same time point. The differences between the changes in BMD in the 2 groups was significant at both the right and left total hip (P ¼ .03 for both). Changes in BMD at the femoral neck were greater in magnitude, with the placebo group demonstrating significant changes of 20.0 6.4% and 11.1 7.4% at the right and left femoral neck, respectively, whereas the group receiving zoledronic acid had nonsignificant changes from baseline of 5.1 6.5% and 1.1 3.5%, at the right and left femoral neck, respectively (Figure 2). The difference in change in BMD from baseline between the 2 treatment groups was statistically significant for both the right (P ¼ .01) and left (P ¼ .02) femoral neck. Over the additional period of observation of the zoledronic acid-treated group, bone loss continued, with a change from baseline in BMD at 12 months of 3.1 2.7% and 4.8 1.1% at the right and left hip and a further decrease by 18 months to 13.1 2.4% and 6.2 2.6% change from baseline. At the 24-month time point, change from baseline for the left hip was 12.4 0.8%; right hip imaging was not possible for some participants, and there were therefore insufficient data to report right hip changes at this time point. Changes in BMD from baseline at the femoral neck, right
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Zoledronic Acid Treatment After Acute SCI
Figure 2. Mean percent change in bone mineral density (BMD) SE from mean baseline values over time in the placebo and zoledronic acide treated groups at the (A) spine, (B) total hip, (C) femoral neck, and (D) distal femur/proximal tibia skeletal sites. †Significant change from baseline within a treatment group. *Significant change from baseline between zoledronic acid and placebo treatment groups.
and left, respectively, were: at 12 months, 2.6 4.1% and 0.7 4.2%; at 18 months, 7.8 7.5% and 1.5 2.5%; and at 24 months, 4.1 2.7% on the left and 15.5% on the right in a single individual.
Change in BMD at the Distal Femur and Proximal Tibia DXA imaging was performed at skeletal sites about the knee to determine how changes in BMD at those skeletal sites would compare with skeletal sites at the hip. Only data from the left distal femur are reported, as too few images were obtained from the right side because of the presence of hardware and/or technical difficulties in imaging. Changes from baseline in both treatment groups are shown over time in Figure 2 for the distal femur with complete data over time for each skeletal site in the zoledronic acid group included in Table 2. There were no placebo participants who continued beyond 6 months.
Change in Serum Markers of Bone Metabolism At baseline, serum levels of CTX, a marker of bone resorption, was elevated in both treatment groups: 1.11 ng/mL (0.74, 1.44; first, third quartile) and 1.13 ng/mL (0.99, 1.66), zoledronic acid and placebo groups, respectively. After infusion of zoledronic acid, there was a reduction in the median serum CTX level to 0.25 ng/mL (0.24, 0.31) at the 3-month visit, and levels remained in this range for the duration of the 24 months of the study (Figure 3). The group receiving placebo likewise had a reduction in median serum levels of CTX, but less marked, to 0.97 ng/mL (0.68, 1.18) after 3 months with a further reduction at 6 months to 0.68 ng/mL (0.63, 0.80). Baseline serum levels of P1NP, a marker of bone formation, also were elevated in both treatment groups (130.97 ng/mL [114.73, 151.79] in the zoledronic acid group and 139.52 [76.81, 217.80] in the placebo group) with a steep reduction at 3 months after zoledronic acid infusion to 58.48 ng/mL (54.11, 62.93), these levels being maintained for the duration of the
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7
Table 2 Percent change from baseline over time in BMD at knee skeletal sites Zoledronic Acid
Placebo
Months
R1
R2
R3
R1
R2
R3
6 12 24
8.2 7.7 17.7 7.8 27.5 10.7
11.0 8.2 13.8 11.7 26.2 19.1
3.3 2.9 11.8 7.7 21.9 7.3
9.1 7.1 ND ND
16.4 12.2 ND ND
13.8 10.5 ND ND
BMD ¼ bone mineral density; ND ¼ not determined.
study. In contrast, those receiving placebo had a small, nonsignificant reduction in their baseline levels of P1NP at the 3-month visit but then had a significant reduction to 87.00 ng/mL (82.13, 145.13) at the 6-month time point.
infusions that lasted 24-36 hours despite pretreatment with acetaminophen. No other adverse effects were associated with zoledronic acid treatment.
Delayed Treatment With Zoledronic Acid
A single infusion of zoledronic acid 5 mg was effective at slowing, although not preventing, bone loss that occurs after acute SCI. Bone loss after SCI is a consequence of markedly enhanced bone resorption, driven by the lack of normal loading with possible contributions from changes in nervous system and hormonal inputs [2]. Therefore, intervention with an agent that will prevent bone resorption would be expected to blunt the altered pathophysiologic state. Zoledronic acid is a third-generation amino-bisphosphonate with features that make it particularly attractive for use in the SCI population, and it have been approved for use to treat osteoporosis in a once-yearly parenteral form [25]. Thus, unlike oral bisphosphonates, there are no issues with people having to maintain upright postures or wait to take their morning medications or breakfast. The prolonged efficacy may be partially attributable to the enhanced potency of zoledronic acid and also to the fact that parenteral administration allows much larger amounts of drug to be delivered to bone, as oral
Three participants who had received placebo at baseline received an infusion of zoledronic acid after their 6-month visit demonstrated a loss of >10% BMD at either the hip or femoral neck. Subsequent changes in their BMD, when their 6-month values were used as baseline, are shown in Figure 4. At all skeletal sites about the hip, there was no further bone loss and BMD increased from 1% to 5% after 6 months with a gradual decline over the ensuing 12 months. At the knee, there continued to be loss of BMD at 6 months and over the following period of follow-up, suggesting a differential effect of the infusion at the skeletal sites. Safety Three participants receiving zoledronic acid experienced temperature elevations greater than 102 F, myalgias and general discomfort shortly after their
Discussion
Figure 3. Change in mean serum levels of collagen type 1 cross-linked C-telopeptide (CTX-1; ng/mL) and type 1 procollagen amino-terminal propeptide (P1NP; ng/mL) over time in the placebo and zoledronic acidetreated groups.
8
Zoledronic Acid Treatment After Acute SCI
Figure 4. Mean percent change in bone mineral density (BMD) at the spine, total hip, femoral neck, and distal femur from values at month 6 in those individuals in the placebo group who underwent reinfusion, receiving zoledronic acid.
bisphosphonates are extremely poorly absorbed [26]. Regardless, adherence to treatment is assured once an infusion is complete and there are no interferences with other medical management. In this study, the participants receiving placebo had a significant decrease in mean BMD at the total hip and femoral neck as early as 3 months after study entry. By 6 months, every participant in the study who had received a placebo infusion had a 10% decrease in BMD from their baseline values at either the total hip or femoral neck skeletal sites. The mean decrease in BMD at the total hip at 6 months was almost 10% and greater yet at the femoral neck, in the range of 11%-20%. The actual bone loss since the actual injury was no doubt even greater, because the initial DXA imaging was only done at a mean time of 3 months after SCI. Although we do not have data on the extent of bone loss at 1 year after SCI from this study, we and others [15,17,27] have found changes in BMD at the hip and femoral neck in the range of 20%. Treatment with zoledronic acid was shown in this study to be able to mitigate much of this bone loss. At the total hip, the mean decrease in BMD was less than 5% for the initial 12 months after infusion, with similar data observed at the femoral neck. At times beyond 12 months after infusion, BMD did decrease at an accelerated pace at the total hip but less rapid bone loss was seen at the femoral neck. Retreatment of those receiving zoledronic acid was not included in this study to evaluate duration of effect. From the data obtained, it would appear that efficacy in terms of BMD response at the hip was fairly well maintained through 12 months, but by 18 months BMD values at both the total hip and femoral neck had declined to the range seen in the placebo group at the 6 month time point. Hence, a single infusion was able to delay bone loss by approximately 12 months at these skeletal sites about the hip.
BMD at the knee was of particular interest as this skeletal area is most commonly involved in fracture in individuals after SCI [28,29]. Our results demonstrate what appears to be a quantitatively different bone response at the knee compared with the hip. The effect of zoledronic acid at the knee is significantly less marked compared with the hip, and differences between the zoledronic acid and placebo groups were small and did not reach statistical significance. It should be noted that because of the limited sample size of the study and the large variability in bone changes at the knee, the study was not adequately powered to be able to reliably detect even moderately large differences that may have clinical significance. The basis for the apparent difference in response at the knee compared with the hip is not known. The degree and rate of bone loss in the placebo group at both the hip and knee is approximately the same, making it unlikely that a possible differential loading effect (greater in the pelvic area than the knee) is a likely explanation. The effect seen at the proximal femur is more similar to that seen at the hip, but of shorter duration, supporting the possibility of more rapid turnover in the distal lower extremities. In contrast to effects at the hip and knee, zoledronic acid infusion resulted in an increase in BMD at the spine in patients after acute SCI. The spine is normally loaded and not denervated after SCI, and this BMD response observed at the spine is in the range of that reported after zoledronic acid treatment of osteoporotic men and women [30,31]. Baseline bone marker levels of both CTX and P1NP were elevated, markedly so in some individuals. Zoledronic acid infusion resulted in a marked decrease in both of these biomarkers to within the normal range at the 3-month time point. These results are consistent with effects on these biomarkers in previous studies of zoledronic acid [32], although it should be noted that levels did not decrease to below the normal range. Thus, some degree of both bone resorption and bone formation was still occurring. Previous studies in which the authors examined the effects of bisphosphonates on bone after SCI have also observed inhibition of the expected bone loss. The earliest and largest of these studies, reported by Gilchrist et al [15], was a randomized, placebo-controlled clinical trial that involved 31 SCI patients treated with oral weekly alendronate for 12 months. This study was remarkable for the early onset of treatment (within 10 days of SCI) and the marked benefit observed. Mean loss of BMD at all skeletal regions of interest at the hip was less than 5% after 1 year of treatment, compared with BMD loss in the range of 20% or more observed in the placebo-treated group. The results in the zoledronic acid-treated group are similar to those reported in the current study, as was the magnitude of the bone loss seen at 6 months in the placebo group. Zoledronic acid
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treatment after SCI has been evaluated in 2 previous studies. The study by Shapiro et al [16] enrolled 17 patients after SCI in a placebo-controlled randomized trial and reported an increase from baseline in BMD at 6 months at all hip skeletal sites in participants treated with zoledronic acid; however, at the 12-month time point, there was a subsequent decline in BMD, suggesting that the effect of zoledronic acid was not sustained for the entire study period. A subsequent study of zoledronic acid by Bubbear et al [17] in 14 participants after SCI reported sustained efficacy of zoledronic acid on BMD measured at the total hip and trochanter skeletal sites with a statistically significant difference compared with the placebo-treated group, but no significant difference was seen at the femoral neck. In all studies, spine BMD increased after zoledronic acid treatment and serum markers of bone resorption were reduced. The study by Bauman et al [18] evaluated 6 individuals after motor-complete SCI who received zoledronic acid and compared them to a control cohort of 7 nontreated individuals, finding a slowing of bone loss at the hip but an apparent increase in bone loss at skeletal sites around the knee in the zoledronic acid group. Because of the small number of participants and the nonrandomized design, further studies are needed before any definitive conclusions can be made about the responses observed at the knee skeletal sites. However, the data in this study are consistent with a lesser effect of zoledronic acid at these distal skeletal sites in the lower extremity compared with the hip. In those participants in the current study who initially received placebo infusion, subsequent treatment with zoledronic acid at a time more than 6 months after acute SCI resulted in an abrupt cessation of bone loss at skeletal sites at the hip but again was apparently less effective at skeletal sites at the knee. The reason for this difference is not clear, as serum levels of CTX were effectively reduced by zoledronic acid treatment. The study was limited by a relatively small sample size and a number of technical difficulties associated with the DXA imaging procedure. Several of our participants, evenly divided between the treatment groups, developed heterotopic ossification around the hip during the course of the study which prevented obtaining valid BMD values at those skeletal areas. Positioning for DXA on repeated visits was consistently challenging and resulted in larger variances in BMD, particularly at skeletal sites around the knee. All of these factors reduced the ability to distinguish small-to-moderate differences that may have existed between treatment groups. Results of this pilot study suggest that the use of zoledronic acid after SCI may be effective in slowing bone loss, certainly at skeletal sites around the hip and possibly at the knee as well. These data need to be confirmed and extended by studies with larger populations and for longer treatment and follow-up times.
9
Although bisphosphonate use for a period of many years in people with SCI may not be warranted because of safety concerns [33], it should be noted that currently the majority of people with SCI injuries retain some degree of motor function below the level of the injury, and an increasing proportion of people do become weight-bearing or ambulatory, either as part of their physical therapy regime or independently [34], after which further bone loss is slowed or may even be prevented. Therefore, particularly for these individuals, prevention of bone loss during the first 6 months after SCI would result in greater BMD as they age and will have a large impact on their future risk of fracture. Prevention of acute bone loss, which can be in the range of 20% or more in their lower extremities during the immediate months after SCI, should be a high priority, particularly because this study and others have demonstrated that such an outcome is feasible, safe, inexpensive, and does not interfere with other medical management or with rehabilitation. Conclusion In individuals after acute SCI, a single infusion of zoledronic acid 5 mg compared with placebo resulted in a slowing of bone loss at lower extremity skeletal sites, more so at the hip than the knee. Whether these beneficial effects can be sustained is not known and will require longer follow-up with larger populations. Acknowledgments Zoledronic acid and placebo were provided by Novartis. We thank the individuals with spinal cord injury who graciously and generously gave of their time to be involved. References 1. University of Alabama at Birmingham Spinal cord injury facts and figures at a glance. Available at https://www.nscisc.uab.edu/ PublicDocuments/fact_figures_docs/Facts%202013.pdf. Accessed January 28, 2016. 2. Jiang SD, Jiang LS, Dai LY. Mechanisms of osteoporosis in spinal cord injury. Clin Endocrinol (Oxf) 2006;65:555-565. 3. Maimoun L, Fattal C, Micallef JP, Peruchon E, Rabischong P. Bone loss in spinal cord-injured patients: From physiopathology to therapy. Spinal Cord 2006;44:203-210. 4. Jiang SD, Dai LY, Jiang LS. Osteoporosis after spinal cord injury. Osteoporos Int 2006;17:180-192. 5. Logan WC Jr, Sloane R, Lyles KW, Goldstein B, Hoenig HM. Incidence of fractures in a cohort of veterans with chronic multiple sclerosis or traumatic spinal cord injury. Arch Phys Med Rehabil 2008;89:237-243. 6. Lazo MG, Shirazi P, Sam M, Giobbie-Hurder A, Blacconiere MJ, Muppidi M. Osteoporosis and risk of fracture in men with spinal cord injury. Spinal Cord 2001;39:208-214. 7. Morse LR, Battaglino RA, Stolzmann KL, et al. Osteoporotic fractures and hospitalization risk in chronic spinal cord injury. Osteoporos Int 2009;20:385-392.
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Disclosure T.J.S. Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611. Address correspondence to: T.J.S.; e-mail: tjs@ northwestern.edu Disclosures related to this publication: provision of writing assistance, medicine, equipment, or administrative support; Novartis provided only study drugs and placebo (no money) K.K. Northwestern University Feinberg School of Medicine, Chicago, IL; and Rehabilitation Institute of Chicago, Chicago, IL Disclosure: nothing to disclose J.M. Northwestern University Feinberg School of Medicine, Chicago, IL Disclosure: nothing to disclose
R.Y. Northwestern University Feinberg School of Medicine, Chicago, IL Disclosure: nothing to disclose N.S. Northwestern University Feinberg School of Medicine, Chicago, IL Disclosure: nothing to disclose D.C. Northwestern University Feinberg School of Medicine, Chicago, IL; and Rehabilitation Institute of Chicago, Chicago, IL Disclosure: nothing to disclose Funding source: Zoledronic acid and placebo provided by Novartis. Submitted for publication September 16, 2015; accepted January 23, 2016.