Calcif Tissue Int (2007) 80:316–322 DOI: 10.1007/s00223-007-9012-6
Treatment with Zoledronic Acid Ameliorates Negative Geometric Changes in the Proximal Femur following Acute Spinal Cord Injury J. Shapiro,1 B. Smith,2 T. Beck,3 P. Ballard,2 M. Dapthary,3 K. BrintzenhofeSzoc,4 J. Caminis5 1
Department of Physical Medicine and Rehabilitation, Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205, USA National Rehabilitation Hospital, 102 Irving Street NW, Washington, DC 20010, USA 3 Department of Radiology, Johns Hopkins University Outpatient Center, 601 North Caroline Street, Suite 4233, Baltimore, MD 21287, USA 4 Catholic University of America, 2344 Nebraska Avenue NW, Washington, DC 20016, USA 5 Novartis Pharmaceuticals, Inc., One Health Plaza, Building 122, East Hanover, NJ 07936, USA 2
Received: 27 February 2006 / Accepted: 6 December 2006 / Online publication: 7 April 2007
Abstract. Acute spinal cord injury is associated with rapid bone loss and an increased risk of fracture. In this double-blind, randomized, placebo-controlled trial, 17 patients were followed for 1 year after administration of either 4 or 5 mg of zoledronic acid or placebo. Bone mineral density (BMD) and structural analyses of the proximal femur were performed using the hip structural analysis program at entry, 6 months, and 12 months. The 17 subjects completed 12 months of observation, nine receiving placebo and eight zoledronic acid. The placebo group showed a decrease in BMD, cross-sectional area, and section modulus and an increase in buckling ratio at each proximal femur site at 6 and 12 months. Six months after zoledronic acid, BMD, crosssectional area, and section modulus increased at the femoral neck and intertrochanteric regions and buckling ratio decreased consistent with improved bone stability. However, at 12 months, the femoral narrow-neck values declined to baseline. In contrast to placebo, the intertrochanteric region and femur shaft were maintained at or near baseline through 12 months in the zoledronic acid-treated group. Urine N-telopeptide excretion was increased at baseline and declined in both the placebo and treatment groups during the 12 months of observation. We conclude that a single administration of zoledronic acid will ameliorate bone loss and maintain parameters of bone strength at the three proximal femur sites for 6 months and at the femur intertrochanteric and shaft sites for 12 months. Key words: Bone loss — Spinal cord injury — Zoledronic acid — Dual-energy X-ray absorptiometry — Hip structural analysis
According to the 1988 National Health Interview Surveys, approximately 10,000 individuals suffer acute spinal cord injury (SCI) in the United States each year [1]. Their average age at injury is 32 years, indicating that many will experience the musculoskeletal effects of
Correspondence to: J. Shapiro; E-mail:
[email protected]
non-weight-bearing throughout their lives [2]. We propose that prevention of bone loss following acute injury may lessen the fracture risk in later years. Bone loss in the pelvis and lower extremities is greater than that in the spine due to the loss of mechanical strain caused by the absence of effective load bearing on the lower extremities [3, 4]. The distal femur and tibia are frequent sites of minimal trauma fractures that occur in SCI. Also, increased mobilization of mineral from bone increases the risk of renal calculi [5]. Our objective was to evaluate the effect of zoledronic acid, a potent, longacting, nitrogen-containing bisphosphonate, as a countermeasure to bone loss following acute SCI. Bisphosphonates are widely used in the treatment of different forms of osteoporosis. Etidronate, clondronate, tiludronate, pamidronate, and alendronate have been administered to individuals following both acute and chronic SCI in order to prevent bone loss. However, the results have varied with the specific bisphosphonate as well as the characteristics of the patients treated [6 10]. For example, intravenous pamidronate is more effective at preventing bone loss in SCI subjects able to partially ambulate compared to those who are completely non-weight-bearing [11]. This report describes results of a double-blind, placebo-controlled trial to evaluate the effects of zoledronic acid (Novartis Pharmaceuticals, East Hanover, NJ) administered intravenously as a single dose on the bone mineral density (BMD) and structural geometry of the proximal femur in acute SCI subjects followed for 12 months after their injury. Patients and Methods Patient Population This is a randomized, double-blind, placebo-controlled trial to evaluate the effects of a single dose of zoledronic acid on patients with acute traumatic C2 to T12 SCI. Subjects were tet-
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Table 1. Baseline demographics of placebo and zoledronic acid groups
Characteristics Age (years) Height (cm) Weight (kg) BMI (kg/m2) Serum calcium (mg/dL) Serum 25OHD (ng/mL) Serum osteocalcin (ng/mL) Urine NTx/Cr (nmolBCE/mmol Cr)a Bone-specific alkaline phosphatase (lg/L) Serum intact PTH (pg/mL) Serum Cr (mg/dL) a
Reference ranges
8.0 10.5 8.0 38.0 Male 11.3 35.4 ng/mL, female 7.2 27.9 ng/mL 21 66 male, 19 63 female 0 20 9.0 78.0 0.6 1 2
Placebo group gender-grouped (n = 10)
Treatment group gender-grouped (n = 8)
P
28.4 ± 9.4 178 ± 8.8 78.4 24.5 9.02 ± 1.7 16.8 ± 8.8 16.9 ± 8.6
30.1 ± 14.2 175.8 ± 6.7 78.1 25.5 9.49 ± 0.59 14.4 ± 6.2 21 ± 11.9
0.72 0.85 0.93 0.1 0.27 0.51 0.43
181.5 ± 71.8 16.2 ± 4.4 8.4 ± 4.1 0.6 ± 0.08
224.4 ± 103.2 13.7 ± 5.0 19.6 ± 16.2 0.6 ± 0.2
0.34 0.55 0.10 0.23
Non-SCI values are not available
raplegic or paraplegic, American Spinal Injury Association (ASIA) classification A (n = 14) with no motor or sensory function preserved in sacral segments, or ASIA B (n = 4) with sensory but no motor function below the lesion level [12]. Eighteen participants were initially enrolled, and 17 completed 1 year of observation, eight in the zoledronic acid group and nine receiving a placebo. The protocol and consent procedure were approved by the Institutional Review Board of the Medstar Research Institute (Hyattsville, MD). Sixteen subjects were enrolled within 10 weeks of injury and two were enrolled at 12 weeks. This interval from injury was required because of the time to heal related to the trauma and the psychological difficulty these subjects experience in adapting to their injuries. Study subjects included 14 males, aged 18 60 years, and four females, aged 18 45 years. The average age was 28.4 ± 9.4 years for the placebo group and 30.1 ± 14.2 years for the zoledronic acid group (Table 1). Baseline heights and weights were not significantly different. In the initial group, seven patients were of European ancestry, nine were of African ancestry, there was one Indian national, and one was from the Philippines. At entry, five patients were tetraplegic and 13 were paraplegic. At baseline, body mass index (BMI) and various biochemical parameters were not statistically different between the placebo and treatment groups (Table 1). Females had normal menses prior to injury and when enrolled. Subjects were ambulatory and in good health prior to their injury, defined as the absence of major cardiac, renal, or liver disease. Subjects with active medical complications, such as large decubitus ulcers or tracheostomy, were excluded. Major exclusions included prior use of bisphosphonates or other bone-active agents, an Ashworth muscle spasticity scale score >3, a serum creatinine level >1.8 mg/dL, and chronic use of corticosteroids during the 6 months prior to injury or following injury, with the exception of the acute single postinjury dose which is standard care [13]. Treatment Regimens Following injury, patients were transferred to the National Rehabilitation Hospital, Washington, DC, where they were inpatients for 4 8 weeks. They were subsequently followed as outpatients at 3-month intervals. During that time, each received customary rehabilitation therapy consistent with their injury. Of the 17 individuals who finished 12 months, 15 remained in ASIA A or B class for the 12-month period following randomization to zoledronate or placebo. Two individuals, discussed below, had progressed to ASIA C class with limited static weight-bearing. There were no dropouts due to adverse drug reactions.
Subjects were assigned to receive zoledronic acid or placebo by a random number table in 50 mL of normal saline solution infused over 15 min. Eight patients were treated with zoledronic acid: four received 4 mg and four received 5 mg. Although this modification was requested by the manufacturer to test the higher dose, having instituted an Food and Drug Administration (FDA)-approved 5 mg trial for osteoporosis and PagetÕs disease, the limited number of subjects prevented independent evaluation of the two doses. The dose approved by the FDA for the treatment of cancer-related hypercalcemia and bone malignancy remains 4 mg [13a]. Both patients and investigators were blinded to the medication. Diets were reviewed to assure minimum daily calcium and vitamin D intake of 800 mg and 800 IU, respectively. Subjects found to have serum 25-hydroxyvitamin D (25OHD) levels
