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Local effect of zoledronic acid on new bone formation in posterolateral spinal fusion with demineralized bone matrix in a murine model

  • Orthopaedic Surgery
  • Published:
Archives of Orthopaedic and Trauma Surgery Aims and scope Submit manuscript

Abstract

Background

Posterolateral spinal fusion is a common orthopaedic surgery performed to treat degenerative and traumatic deformities of the spinal column. In posteriolateral spinal fusion, different osteoinductive demineralized bone matrix products have been previously investigated. We evaluated the effect of locally applied zoledronic acid in combination with commercially available demineralized bone matrix putty on new bone formation in posterolateral spinal fusion in a murine in vivo model.

Methods

A posterolateral sacral spine fusion in murine model was used to evaluate the new bone formation. We used the sacral spine fusion model to model the clinical situation in which a bone graft or demineralized bone matrix is applied after dorsal instrumentation of the spine. In our study, group 1 received decortications only (n = 10), group 2 received decortication, and absorbable collagen sponge carrier, group 3 received decortication and absorbable collagen sponge carrier with zoledronic acid in dose 10 µg, group 4 received demineralized bone matrix putty (DBM putty) plus decortication (n = 10), and group 5 received DBM putty, decortication and locally applied zoledronic acid in dose 10 µg. Imaging was performed using MicroCT for new bone formation assessment. Also, murine spines were harvested for histopathological analysis 10 weeks after surgery.

Results

The surgery performed through midline posterior approach was reproducible. In group with decortication alone there was no new bone formation. Application of demineralized bone matrix putty alone produced new bone formation which bridged the S1–S4 laminae. Local application of zoledronic acid to demineralized bone matrix putty resulted in significant increase of new bone formation as compared to demineralized bone matrix putty group alone.

Conclusions

A single local application of zoledronic acid with DBM putty during posterolateral fusion in sacral murine spine model increased significantly new bone formation in situ in our model. Therefore, our results justify further investigations to potentially use local application of zoledronic acid in future clinical studies.

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References

  1. Omidi-Kashani F, Hasankhani EG, Rahimi MD, Khanzadeh R (2014) Comparison of functional outcomes following surgical decompression and posterolateral instrumented fusion in single level low grade lumbar degenerative versus isthmic spondylolisthesis. Clin Orthop Surg 6:185–189

    Article  PubMed  PubMed Central  Google Scholar 

  2. Choi KC, Shim HK, Kim JS, Lee SH (2015) Does pre-existing L5–S1 degeneration affect outcomes after isolated L4–5 fusion for spondylolisthesis? J Orthop Surg Res 10:39

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ajiboye RM, Hamamoto JT, Eckardt MA, Wang JC (2015) Clinical and radiographic outcomes of concentrated bone marrow aspirate with allograft and demineralized bone matrix for posterolateral and interbody lumbar fusion in elderly patients. Eur Spine J 24:2567–2572

    Article  PubMed  Google Scholar 

  4. Fu TS, Wang IC, Lu ML, Hsieh MK, Chen LH, Chen WJ (2016) The fusion rate of demineralized bone matrix compared with autogenous iliac bone graft for long multi-segment posterolateral spinal fusion. BMC Musculoskelet Disord 17:3

    Article  PubMed  PubMed Central  Google Scholar 

  5. Feiertag MA, Boden SD, Schimandle JH, Norman JT (1996) A rabbit model for nonunion of lumbar intertransverse process spine arthrodesis. Spine (Phila Pa 1976) 21:27–31

    Article  CAS  Google Scholar 

  6. McAfee PC, Farey ID, Sutterlin CE, Gurr KR, Warden KE, Cunningham BW (1991) The effect of spinal implant rigidity on vertebral bone density. A canine model. Spine (Phila Pa 1976) 16(6 Suppl):190–197

    Article  Google Scholar 

  7. Wing KJ, Fisher CG, O’Connell JX, Wing PC (2000) Stopping nicotine exposure before surgery. The effect on spinal fusion in a rabbit model. Spine (Phila Pa 1976) 25:30–34

    Article  CAS  Google Scholar 

  8. Kodera R, Miyazaki M, Yoshiiwa T, Kawano M, Kaku N, Tsumura H (2014) Manipulation of anabolic and catabolic responses with bone morphogenetic protein and zoledronic acid in a rat spinal fusion model. Bone 58:26–32

    Article  CAS  PubMed  Google Scholar 

  9. Bransford R, Goergens E, Briody J, Amanat N, Cree A, Little D (2007) Effect of zoledronic acid in an L6–L7 rabbit spine fusion model. Eur Spine J 16:557–562

    Article  PubMed  Google Scholar 

  10. Deyo RA, Nachemson A, Mirza SK (2004) Spinal-fusion surgery—the case for restraint. N Engl J Med 350:722–726

    Article  CAS  PubMed  Google Scholar 

  11. Aghdasi B, Montgomery SR, Daubs MD, Wang JC (2013) A review of demineralized bone matrices for spinal fusion: the evidence for efficacy. Surgeon 11:39–48

    Article  CAS  PubMed  Google Scholar 

  12. Hoffmann MF, Jones CB, Sietsema DL (2012) Adjuncts in posterior lumbar spine fusion: comparison of complications and efficacy. Arch Orthop Trauma Surg 132:1105–1110

    Article  PubMed  Google Scholar 

  13. Kang J, An H, Hilibrand A, Yoon ST, Kavanagh E, Boden S (2012) Grafton and local bone have comparable outcomes to iliac crest bone in instrumented single-level lumbar fusions. Spine (Phila Pa 1976) 37:1083–1091

    Article  Google Scholar 

  14. Tilkeridis K, Touzopoulos P, Ververidis A, Christodoulou S, Kazakos K, Drosos GI (2014) Use of demineralized bone matrix in spinal fusion. World J Orthop 5:30–37

    Article  PubMed  PubMed Central  Google Scholar 

  15. Benford HL, McGowan NW, Helfrich MH, Nuttall ME, Rogers MJ (2001) Visualization of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro. Bone 28:465–473

    Article  CAS  PubMed  Google Scholar 

  16. Russell RG, Xia Z, Dunford JE, Oppermann U, Kwaasi A, Hulley PA, Kavanagh KL, Triffitt JT, Lundy MW, Phipps RJ, Barnett BL, Coxon FP, Rogers MJ, Watts NB, Ebetino FH (2007) Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 1117:209–257

    Article  CAS  PubMed  Google Scholar 

  17. Jobke B, Milovanovic P, Amling M, Busse B (2014) Bisphosphonate-osteoclasts: changes in osteoclast morphology and function induced by antiresorptive nitrogen-containing bisphosphonate treatment in osteoporosis patients. Bone 59:37–43

    Article  CAS  PubMed  Google Scholar 

  18. Zwolak P, Dudek AZ (2013) Antineoplastic activity of zoledronic acid and denosumab. Anticancer Res 33:2981–2988

    CAS  PubMed  Google Scholar 

  19. Kang CN, Kim CW, Moon JK (2016) The outcomes of instrumented posterolateral lumbar fusion in patients with rheumatoid arthritis. Bone Jt J 98-B:102–108

    Article  Google Scholar 

  20. Martin GJ Jr, Boden SD, Titus L, Scarborough NL (1999) New formulations of demineralized bone matrix as a more effective graft alternative in experimental posterolateral lumbar spine arthrodesis. Spine (Phila Pa 1976) 24:637–645

    Article  Google Scholar 

  21. Kim MK, Lee SH, Kim ES, Eoh W, Chung SS, Lee CS (2011) The impact of sagittal balance on clinical results after posterior interbody fusion for patients with degenerative spondylolisthesis: a pilot study. BMC Musculoskelet Disord 12:69

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bobyn J, Rasch A, Little DG, Schindeler A (2013) Posterolateral inter-transverse lumbar fusion in a mouse model. J Orthop Surg Res 8:2

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kiely PD, Brecevich AT, Taher F, Nguyen JT, Cammisa FP, Abjornson C (2014) Evaluation of a new formulation of demineralized bone matrix putty in a rabbit posterolateral spinal fusion model. Spine J 14:2155–2163

    Article  PubMed  Google Scholar 

  24. Faucheux C, Verron E, Soueidan A, Josse S, Arshad MD, Janvier P, Pilet P, Bouler JM, Bujoli B, Guicheux J (2009) Controlled release of bisphosphonate from a calcium phosphate biomaterial inhibits osteoclastic resorption in vitro. J Biomed Mater Res Part A 89:46–56

    Article  CAS  Google Scholar 

  25. Mundy GR, Yoneda T, Hiraga T (2001) Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. Semin Oncol 28(2 Suppl 6):35–44

    Article  CAS  PubMed  Google Scholar 

  26. Peng H, Sohara Y, Moats RA, Nelson MD Jr, Groshen SG, Ye W, Reynolds CP, DeClerck YA (2007) The activity of zoledronic Acid on neuroblastoma bone metastasis involves inhibition of osteoclasts and tumor cell survival and proliferation. Cancer Res 67:9346–9355

    Article  CAS  PubMed  Google Scholar 

  27. Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C, Holen I, Monkkonen H, Boccadoro M, Forni G, Musiani P, Bosia A, Cavallo F, Massaia M (2010) Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J Cell Mol Med 14:2803–2815

    Article  CAS  PubMed  Google Scholar 

  28. Im GI, Qureshi SA, Kenney J, Rubash HE, Shanbhag AS (2004) Osteoblast proliferation and maturation by bisphosphonates. Biomaterials 25:4105–4115

    Article  CAS  PubMed  Google Scholar 

  29. Reinholz GG, Getz B, Pederson L, Sanders ES, Subramaniam M, Ingle JN, Spelsberg TC (2000) Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res 60:6001–6007

    CAS  PubMed  Google Scholar 

  30. Back DA, Pauly S, Rommel L, Haas NP, Schmidmaier G, Wildemann B, Greiner SH (2012) Effect of local zoledronate on implant osseointegration in a rat model. BMC Musculoskelet Disord 13:42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Konnecke I, Serra A, El Khassawna T, Schlundt C, Schell H, Hauser A, Ellinghaus A, Volk HD, Radbruch A, Duda GN, Schmidt-Bleek K (2014) T and B cells participate in bone repair by infiltrating the fracture callus in a two-wave fashion. Bone 64:155–165

    Article  PubMed  Google Scholar 

  32. Chen F, Dai Z, Kang Y, Lv G, Keller ET, Jiang Y (2016) Effects of zoledronic acid on bone fusion in osteoporotic patients after lumbar fusion. Osteoporos Int 27:1469–1476

    Article  CAS  PubMed  Google Scholar 

  33. Bobyn J, Rasch A, Kathy M, Little DG, Schindeler A (2014) Maximizing bone formation in posterior spine fusion using rhBMP-2 and zoledronic acid in wild type and NF1 deficient mice. J Orthop Res 32:1090–1094

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Flora Nicholls and Maggy Arras form the Institute of Laboratory Animal Science, University of Zurich, Switzerland for their support concerning the operating procedures, perioperative managing as well as housing of experimental animals and Novartis Switzerland for providing zoledronic acid.

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Author notes

  1. Pawel Zwolak and Jan Farei-Campagna contributed equally to this study.

Authors and Affiliations

  1. Department of Trauma Surgery, University Hospital of Zurich, Rämistrasse 100, 8006, Zurich, Switzerland

    Pawel Zwolak, Jan Farei-Campagna, Thorsten Jentzsch & Clément M. Werner

  2. Vetsuisse Faculty, University of Zurich, Winterthurerstr. 260, 8057, Zurich, Switzerland

    Brigitte von Rechenberg

Authors
  1. Pawel Zwolak
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  2. Jan Farei-Campagna
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Correspondence to Pawel Zwolak.

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The authors declare that they have no conflict of interest.

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There is no funding source.

Ethical approval

All animal experimentation was approved by the relevant Swiss authorities. Zoledronic acid was provided by Novartis Switzerland.

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Zwolak, P., Farei-Campagna, J., Jentzsch, T. et al. Local effect of zoledronic acid on new bone formation in posterolateral spinal fusion with demineralized bone matrix in a murine model. Arch Orthop Trauma Surg 138, 13–18 (2018). https://doi.org/10.1007/s00402-017-2818-4

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