Abstract
Osteonecrosis of the jaws is an emerging pathological condition characterized by un-exposure or exposure of the necrotic bone, independently from the etiology. This term is usually referred to medication-related osteonecrosis of the jaws due to severe adverse reaction to certain medicines, as bisphosphonates, used for the treatment of cancer and osteoporosis. The management of patients with Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ) remains challenging because surgical and medical interventions may not eradicate this pathology. The goal of treatment of patients at risk of developing BRONJ or of those who have active disease is the preservation of quality of life by controlling pain, managing infection, and preventing the development of new areas of necrosis. The treatment of osteonecrosis consists in the surgical removal of necrotic bone followed by antibiotic therapy and application of sterile greasy gauze until the wound closure. The classical medical treatment has been compared with the innovative one consisting in the application of sterile greasy gauze soaked with bovine lactoferrin (bLf) after surgery. Here, for the first time, bLf efficacy on wound repair in subjects suffering from BRONJ with the progressive destruction of bone in the mandible or maxilla has been demonstrated. The positive results consist in a significant shorter time of wound closure (1 or 2 weeks) compared to that observed with classical surgical treatment (2–3 months). These promising results are an interesting tool for the innovative treatment of this pathology and for increasing the quality of life of these patients.
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References
Allen MR, Burr DB (2009) The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg 67:61–70. https://doi.org/10.1016/j.joms.2009.01.007
Allen MR, Chu TM, Ruggiero SL (2013) Absence of exposed bone following dental extraction in beagle dogs treated with 9 months of high-dose zoledronic acid combined with dexamethasone. J Oral Maxillofac Surg 71:1017–1026
Bagan J, Scully C, Sabater V, Jimenez Y (2009) Osteonecrosis of the jaws in patients treated with intravenous bisphosphonates (BRONJ). a concise update. Oral Oncol 45:551–554. https://doi.org/10.1016/j.oraloncology.2009.01.002
Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, Koutsoukou V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E, Dimopoulos MA (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580–8587. https://doi.org/10.1200/JCO.2005.02.8670
Bocanegra-Pérez S, Vicente-Barrero M, Knezevic M, Castellano-Navarro JM, Rodríguez-Bocanegra E, Rodríguez-Millares J, Pérez-Plasencia D, Ramos-Macías A (2012) Use of platelet-rich plasma in the treatment of bisphosphonate-related osteonecrosis of the jaw. Int J Oral Maxillofac Surg 41:1410–1415. https://doi.org/10.1016/j.ijom.2012.04.020
Dodson TB (2015) The frequency of medication-related osteonecrosis of the jaw and its associated risk factors. Oral Maxillofac Surg Clin North Am 27:509–516. https://doi.org/10.1016/j.coms.2015.06.003
Freiberger JJ, Padilla-Burgos R, McGraw T, Suliman HB, Kraft KH, Stolp BW, Moon RE, Piantadosi CA (2012) What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics. J Oral Maxillofac Surg 70:1573–1583. https://doi.org/10.1016/j.joms.2012.04.001
Gallego L, Junquera L, Pelaz A, Hernando J, Megías J (2012) The use of pedicled buccal fat pad combined with sequestrectomy in bisphosphonate-related osteonecrosis of the maxilla. Med Oral Patol Oral Cir Bucal 17:e236–e241
Graziani F, Vescovi P, Campisi G, Favia G, Gabriele M, Gaeta GM, Gennai S, Goia F, Miccoli M, Peluso F, Scoletta M, Solazzo L, Colella G (2012) Resective surgical approach shows a high performance in the management of advanced cases of bisphosphonate-related osteonecrosis of the jaws: a retrospective survey of 347 cases. J Oral Maxillofac Surg 70:2501–2507. https://doi.org/10.1016/j.joms.2012.05.019
Grinnell F (1994) Fibroblasts, myofibroblasts, and wound contraction. J Cell Biol 124:401–404. https://doi.org/10.1083/jcb.124.4.401
Hinson AM, Siegel ER, Stack BC Jr (2015) Temporal correlation between bisphosphonate termination and symptom resolution in osteonecrosis of the jaw: a pooled case report analysis. J Oral Maxillofac Surg 73:53–62. https://doi.org/10.1016/j.joms.2014.07.012
Junquera L, Gallego L, Cuesta P, Pelaz A, de Vicente JC (2009) Clinical experiences with bisphosphonate-associated osteonecrosis of the jaws: analysis of 21 cases. Am J Otolaryngol 30:390–395. https://doi.org/10.1016/j.amjoto.2008.07.014
Kim CW, Lee TH, Park KH, Choi SY, Kim J (2012) Human lactoferrin suppresses TNF-a-induced intercellular adhesion molecule-1 expression via competition with NF-kB in endothelial cells. FEBS Lett 586:229–234. https://doi.org/10.1016/j.febslet.2011.12.011
Kos M, Junka A, Smutnicka D, Bartoszewicz M, Kurzynowski T, Gluza K (2013) Pamidronate enhances bacterial adhesion to bone hydroxyapatite. Another puzzle in the pathology of bisphosphonate-related osteonecrosis of the jaw? J Oral Maxillofac Surg 71:1010–1016. https://doi.org/10.1016/j.joms.2012.12.005
Martin P (1997) Wound healing–aiming for perfect skin regeneration. Science 276:75–81
Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117
Mozzati M, Arata V, Gallesio G (2012) Tooth extraction in patients on zoledronic acid therapy. Oral Onc 48:817–821. https://doi.org/10.1016/j.oraloncology.2012.03.009
Mozzati M, Arata V, Gallesio G (2013) Tooth extraction in osteoporotic patients taking oral bisphosphonates. Osteoporos Int 24:1707–1711. https://doi.org/10.1007/s00198-012-2239-8
Mücke T, Deppe H, Hein J, Wolff KD, Mitchell DA, Kesting MR, Retz M, Gschwend JE, Thalgott M (2016) Prevention of bisphosphonate-related osteonecrosis of the jaws in patients with prostate cancer treated with zoledronic acid—a prospective study over 6 years. J Craniomaxillofac Surg 44:1689–1693. https://doi.org/10.1016/j.jcms.2016.07.026
Naot D, Chhana A, Matthews BG, Callon KE, Tong PC, Lin JM, Costa JL, Watson M, Grey AB, Cornish J (2011) Molecular mechanisms involved in the mitogenic effect of lactoferrin in osteoblasts. Bone 49:217–224. https://doi.org/10.1016/j.bone.2011.04.002
Paesano R, Natalizi T, Berlutti F, Valenti P (2012) Body iron delocalization: the serious drawback in iron disorders in both developing and developed countries. Pathog Glob Health 106:200–216. https://doi.org/10.1179/2047773212Y.0000000043
Pautke C, Bauer F, Otto S, Tischer T, Steiner T, Weitz J, Kreutzer K, Hohlweg-Majert B, Wolff KD, Hafner S, Mast G, Ehrenfeld M, Stürzenbaum SR, Kolk A (2011) Fluorescence-guided bone resection in bisphosphonate-related osteonecrosis of the jaws: first clinical results of a prospective pilot study. J Oral Maxillofac Surg 69:84–91. https://doi.org/10.1016/j.joms.2010.07.014
Raja Sivamani K, Garcia MS, Isseroff RR (2007) Wound re-epithelialization: modulating keratinocyte migration in wound healing. Front Biosci 12:2849–2868. https://doi.org/10.2741/2277
Reid IR, Bolland MJ, Grey AB (2007) Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 41:318–320. https://doi.org/10.1016/j.bone.2007.04.196
Ristow O, Otto S, Geiß C, Kehl V, Berger M, Troeltzsch M, Koerdt S, Hohlweg-Majert B, Freudlsperger C, Pautke C (2017) Comparison of auto-fluorescence and tetracycline fluorescence for guided bone surgery of medication-related osteonecrosis of the jaw: a randomized controlled feasibility study. Int J Oral Maxillofac Surg 46:157–166. https://doi.org/10.1016/j.ijom.2016.10.008
Rollason V, Laverrière A, MacDonald LCI, Walsh T, Tramèr MR, Vogt-Ferrier NB (2016) Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ). Cochrane Database Syst Rev 2:CD008455. https://doi.org/10.1002/14651858.CD008455
Rosa L, Cutone A, Lepanto MS, Paesano R, Valenti P (2017) Lactoferrin: a natural glycoprotein involved in iron and inflammatory homeostasis. Int J Mol Sci. https://doi.org/10.3390/ijms18091985
Ruggiero SL (2007) Guidelines for the diagnosis of bisphosphonate related osteonecrosis of the jaw (BRONJ). Clin Cases Miner Bone Metab 4:37–42. https://doi.org/10.1016/j.joms.2014.04.031
Ruggiero S (2013) Emerging concepts in the management and treatment of osteonecrosis of the jaw. Oral Maxillofac Surg Clin North Am 25:11–20. https://doi.org/10.1016/j.coms.2012.10.002
Ruggiero SL, Fantasia J, Carlson E (2006) Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102:433–441. https://doi.org/10.1016/j.tripleo.2006.06.004
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F, American Associationof Oral and Maxillofacial Surgeons (2014) American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw-2014 update. J Oral Maxillofac Surg 72:1938–1956. https://doi.org/10.1016/j.joms.2014.04.031
Sigua-Rodriguez EA, da Costa Ribeiro R, de Brito AC, Alvarez-Pinzon N, de Albergaria-Barbosa JR (2014) Bisphosphonate-related osteonecrosis of the jaw: a review of the literature. Int J Dent 2014:192320. https://doi.org/10.1155/2014/192320
Stanton DC, Balasanian E (2009) Outcome of surgical management of bisphosphonate related osteonecrosis of the jaws: review of 33 surgical cases. J Oral Maxillofac Surg 67:943–950
Suzuki YA, Wong H, Ashida KY, Schryvers AB, Lönnerdal B (2008) The N1 domain of human lactoferrin is required for internalization by Caco-2 cells and targeting to the nucleus. Biochemistry. https://doi.org/10.1021/bi8012164
Takayama Y, Aoki R (2012) Roles of lactoferrin on skin wound healing. Biochem Cell Biol 90:497–503. https://doi.org/10.1139/o11-054
Takayama Y, Mizumachi K (2001) Effects of lactoferrin on collagen gel contractile activity and myosin light chain phosphorylation in human fibroblasts. FEBS Lett 508:111–116
Valenti P, Antonini G (2005) Lactoferrin: an important host defence against microbial and viral attack. Cell Mol Life Sci 62:2576–2587. https://doi.org/10.1007/s00018-005-5372-0
Vescovi P (2012) Bisphosphonates and osteonecrosis: an open matter. Clin Cases Miner Bone Metab 9:142–144
Vescovi P, Merigo E, Meleti M, Manfredi M (2006) Bisphosphonate-associated osteonecrosis (BON) of the jaws: a possible treatment? J Oral Maxillofac Surg 64:1460–1462. https://doi.org/10.1016/j.joms.2006.05.042
Vescovi P, Meleti M, Merigo E, Manfredi M, Fornaini C, Guidotti R, Nammour S (2013) Case series of 589 tooth extractions in patients under bisphosphonates therapy. Proposal of a clinical protocol supported by Nd:YAG low-level laser therapy. Med Oral Patol Oral Cir Bucal 18:e680–e685
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This work was granted by University of Rome La Sapienza Funds to PV.
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Calvani, F., Cutone, A., Lepanto, M.S. et al. Efficacy of bovine lactoferrin in the post-surgical treatment of patients suffering from bisphosphonate-related osteonecrosis of the jaws: an open-label study. Biometals 31, 445–455 (2018). https://doi.org/10.1007/s10534-018-0081-y
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DOI: https://doi.org/10.1007/s10534-018-0081-y