Randomized double blind, placebo-controlled trial.
To examine the effect of early intravenous zoledronic acid (ZA) on bone markers and areal bone mineral density (aBMD) in persons with acute ASIA Impairment Scale (AIS) A traumatic spinal cord injury (SCI).
Two inpatient rehabilitation units.
Thirteen men, 2 women, aged 19–65, C4-T10 AIS A SCI, received 5 mg intravenous ZA vs. placebo 12–21 days post injury. Markers of bone formation (procollagen N-1 terminal propeptide [P1NP]), bone resorption (serum C-telopeptide [CTX]), and aBMD by dual-energy X-ray absorptiometry (DXA) for hip (femur—proximal, intertrochanteric, neck), and knee (distal femur, proximal tibia) were obtained at baseline, 2 weeks post infusion (P1NP, CTX only), 4 and 12 months post injury.
P1NP remained unchanged, while CTX decreased in ZA but increased in controls at 2 weeks (mean difference = −97%, p < 0.01), 4 months (mean difference = −54%, p < 0.05), but not 12 months (mean difference = 3%, p = 0.23). Changes in aBMD at the hip favored ZA at 4 months (mean difference 10.3–14.1%, p < 0.01) and 12 months (mean difference 10.8–13.1%, p < 0.02). At 4 months, changes in aBMD favored ZA at the distal femur (mean difference 6.0%, 95% CI: 0.7–11.2, p < 0.03) but not proximal tibia (mean difference 8.3%, 95% CI: −6.9 to 23.6, p < 0.23). Both groups declined in aBMD at 12 months, with no between group differences.
ZA administered ≤21 days of complete traumatic SCI maintains aBMD at the hip and distal femur at 4 months post injury. This effect is partially maintained at 12 months.
Subscribe to Journal
Get full journal access for 1 year
only $30.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
All data generated or analyzed during this study are included in this published article and its supplementary information files. Data of individual participants were kept in locked files within the Spinal Cord Injury Center of Thomas Jefferson University. The University retains ownership of these records following study completion
Garland DE, Stewart CA, Adkins RH, Hu SS, Rosen C, Liotta FJ, et al. Osteoporosis after spinal cord injury. J Orthop Res. 1992;10:371–8.
Frey-Rindova P, de Bruin ED, Stüssi E, Dambacher MA, Dietz V. Bone mineral density in upper and lower extremities during 12 months after spinal cord injury measured by peripheral quantitative computed tomography. Spinal Cord. 2000;38:26–32.
Chantraine A, Heynen G, Franchimont P. Bone metabolism, parathyroid hormone, and calcitonin in paraplegia. Calcif Tissue Int. 1979;27:199–204.
Minaire P, Neunier P, Edouard C, Bernard J, Courpron P, Bourret J. Quantitative histological data on disuse osteoporosis: comparison with biological data. Calcif Tissue Res. 1974;17:57–73.
Craven BC, Robertson LA, McGillivray CF, Adachi JD. Detection and treatment of sublesional osteoporosis among patients with chronic spinal cord injury: proposed paradigms. Top Spinal Cord Inj Rehabil. 2009;14:1–22.
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 Investig. 1990;20:330–5.
Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharm Exp Ther. 2001;296:235–42.
Coxon FP, Helfrich MH, Van’t Hof R, Sebti S, Ralston SH, Hamilton A, et al. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Min Res. 2000;15:1467–76.
Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Peiper CP, Mautalen C, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N. Engl J Med. 2007;357:1799–809.
Saag K, Lindsay R, Kriegman A, Beamer E, Zhou W. A single zoledronic acid infusion reduces bone resorption markers more rapidly than weekly oral alendronate in postmenopausal women with low bone mineral density. Bone. 2007;40:1238–43.
Shapiro J, Smith B, Beck T, Ballard P, Dapthary M, BrintzenhofeSzoc K, et al. Treatment with zoledronic acid ameliorates negative geometric changes in the proximal femur following acute spinal cord injury. Calcif Tissue Int. 2007;80:316–22.
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 spinal cord injury. Osteoporos Int. 2011;22:271–9.
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 person with acute spinal cord injury an observational cohort study. J Bone Min Metab. 2015;33:410–21.
Eser P, Frotzler A, Zehnder Y, Denoth J. Fracture threshold in the femur and tibia of people with spinal cord injury as determined by peripheral quantitative computed tomography. Arch Phys Med Rehabil. 2005;86:498–504.
Goenka S, Sethi S, Panday N, Joshi M, Jindal R. Effect of early treatment with zoledronic acid on prevention of bone loss in patients with acute spinal cord injury: a randomized controlled trial. Spinal Cord. 2018;56:1207–11.
Schnitzer TJ, Kim K, Marks J, Yeasted R, Simonian N, Chen D. Zoledronic acid treatment after acute spinal cord injury: results of a randomized, placebo-controlled pilot trial. Phys Med Rehabil. 2016;8:833–43.
Shields RK, Schlechte J, Dudley-Javoroski S, Zwart BD, Clark SD, Grant SA, et al. Bone mineral density after spinal cord injury: a reliable method for knee measurement. Arch Phys Med Rehabil. 2005;86:1969–73.
Ikebuchi Y, Aoki S, Honma M, Hayashi M, Sugamori Y, Khan M, et al. Coupling of bone resorption and formation by RANKL reverse signaling. Nature. 2018;561:195–200.
Kirshblum KC, Botticello AL, Dyston-Hudson TA, Byrne R, Marino RJ, Lammertse DP. Patterns of sacral sparing components on neurologic recovery in newly injured persons with traumatic spinal cord injury. Arch Phys Med Rehabil. 2016;97:1647–55.
Aimetti AA, Kirshblum S, Curt A, Mobley J, Grossman RG, Guest JD. Natural history of neurological improvement following complete (AIS A) thoracic spinal cord injury across three registries to guide acute clinical trial design and interpretation. Spinal Cord. 2019;57:753–62.
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;16:771–6.
Bauman WA, Spungen AM. Metabolic changes in persons after spinal cord injury. Phys Med Rehabil Clin N Am. 2000;11:109–40.
Frisbie JH. Fractures after myelopathy: the risk quantified. J Spinal Cord Med. 1997;20:66–69.
Roberts D, Lee W, Cuneo RC, Wittmann J, Ward G, Flatman R, et al. Longitudinal study of bone turnover after acute spinal cord injury. J Clin Endocrinol Metab. 1998;83:415–22.
Davies AL, Hayes KC, Dekaban GA. Clinical correlates of elevated serum concentrations of cytokines and autoantibodies in patients with spinal cord injury. Arch Phys Med Rehabil. 2007;88:1384–93.
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;27:202–6.
Pietschmann P, Pils P, Woloszczik W, Maerk R, Lessan D, Stipicic J. Increased serum osteocalcin levels in patients with paraplegia. Paraplegia. 1992;30:204–9.
Dauty M, Perrouin VB, Maugars Y, Dubois C, Mathe JF. Supralesional and sublesional bone mineral density in spinal cord injured patients. Bone. 2000;27:305–9.
Edwards WB, Schnitzer TJ, Troy KL. Bone mineral stiffness loss at the distal femur and proximal tibia in acute spinal cord injury. Osteoporos Int. 2014;25:1005–15.
The authors wish to thank the following individuals for their contribution to this work: Annie S. Kim, BS, Thomas Jefferson University, for assistance with manuscript preparation, table and figure construction. Justin A. Smith, MD, Case Western Reserve University, for assistance with table and figure creation. Marilyn P. Owens, RN, Thomas Jefferson University, for assistance with recruitment, obtaining signed consent forms, blood draws, and follow-up phone calls. Brittany Hayes, BSN, Thomas Jefferson University, for assistance with recruitment, obtaining signed consent forms, data archiving in secured patient files, and follow-up phone calls. Amanda B. Morina, PT, DPT, Thomas Jefferson University, for performing leg length measurements for DXA readings and performing ISNCSCI examinations. Chuan Zhang, Ph.D., University of Georgia, for assistance with image construction and reformatting of supplementary figures.
This research was supported by the U.S. Department of Health & Human Services | ACL | National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) (90SI5012). Cost of brand name Zoledronic acid and all supplies were funded by the grant and purchased through Jefferson pharmacy. Investigators did not shift to generic drugs mid-study, although they became available on study year 3.
Conflict of interest
The authors declare that they have no conflict of interest.
We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during the course of this research.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Oleson, C.V., Marino, R.J., Formal, C.S. et al. The effect of zoledronic acid on attenuation of bone loss at the hip and knee following acute traumatic spinal cord injury: a randomized-controlled study. Spinal Cord (2020). https://doi.org/10.1038/s41393-020-0431-9