- Email: [email protected]
Management of Bisphosphonate-Related Osteonecrosis of the Jaw With a Platelet-Rich Fibrin Membrane: Technical Report
PATHOLOGY
Management of Bisphosphonate-Related Osteonecrosis of the Jaw With a Platelet-Rich Fibrin Membrane: Technical Report Sıdıka Sinem Soydan, DDS, PhD,* and Sina Uckan, DDS, PhDy Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a challenging complication resulting from the long-term application of bisphosphonates. In most cases, BRONJ occurs after a surgical procedure involving the jawbone. Currently, the management of BRONJ remains controversial, and there is no definitive treatment other than palliative methods. Platelet-rich fibrin (PRF) represents a relatively new biotechnology for the stimulation and acceleration of tissue healing and bone regeneration. This technical note describes the total closure of moderate bone exposure in persistent BRONJ in 2 weeks with a double-layer PRF membrane. PRF may stimulate gingival healing and act as a barrier membrane between the alveolar bone and the oral cavity. PRF may offer a fast, easy, and effective alternative method for the closure of bone exposure in BRONJ. Ó 2013 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg -:1-5, 2013 Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is characterized by exposed necrotic bone, which can be accompanied by pain, swelling, paresthesia, suppuration, soft tissue ulceration, and intraand extraoral sinus tracts.1,2 The incidence of BRONJ is higher with bisphosphonates (BPs) administered monthly through a parenteral route than with oral BPs taken weekly. Most BRONJ cases occur after surgical procedures of oral tissues. However, 30% of cases occur spontaneously.3 Although the reported frequency of BRONJ is low, it causes complications in dental and oral and maxillofacial surgical treatments of patients receiving BPs. The most effective treatment for BRONJ is still controversial and a challenging issue for oral and maxillofacial surgeons. Although antiresorptive therapies other than BPs and receptor activator of nuclear factor-kB ligand inhibitor therapies are claimed to cause osteonecrosis of the jaws, BPs are responsible for most of the concern. The most accepted pathologic etiology of BRONJ is oversuppression of bone turnover and inhibition of angiogenesis owing to systematic usage of BPs.2,4,5
Despite BPs having a specific effect on osteoclasts and a great affinity to bone, the loss of oral mucosa in almost every BRONJ case raises the question of whether they affect oral soft tissue. Several studies have examined whether BPs have an adverse effect on oral epithelial and mucosal tissues.6-10 The results of these studies have been consistent, showing that nitrogen-containing BPs decrease oral epithelial cell migration, promote apoptosis, disturb cell viability, and impede oral mucosa wound healing. Platelet-rich fibrin (PRF) is a second-generation platelet concentrate (natural autologous fibrin matrix) that was first described by Choukroun et al11 in 2000. It regulates inflammation and stimulates chemotactic factors involved in the immune response.12 PRF contains a substantial quantity of fibrins, platelets, and leukocytes. It secretes 3 proinflammatory cytokines (interleukin-1b, interleukin-6, and tumor necrosis factor-a), an anti-inflammatory cytokine (interleukin-4), and a key promoter of angiogenesis (vascular endothelial growth factor).13 PRF also accelerates angiogenesis, the multiplication of fibroblasts and osteoblasts,
Received from the Department of Oral and Maxillofacial Surgery,
Received June 24 2013
Faculty of Dentistry, Baskent University, Ankara, Turkey.
Accepted July 23 2013
*Fellow.
Ó 2013 American Association of Oral and Maxillofacial Surgeons
yProfessor. Address correspondence and reprint requests to Dr Soydan:
0278-2391/13/00938-5$36.00/0 http://dx.doi.org/10.1016/j.joms.2013.07.027
Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Baskent University, 11. Sokak no 26 Bahcelievler, Cankaya, Ankara, Turkiye; e-mail: [email protected]
1
2
PLATELET-RICH FIBRIN FOR OSTEONECROSIS
FIGURE 1. After 2 months of conservative treatment, gingival inflammation was released and necrotic bone exposure was 5 10 mm. Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
and cicatrization.14 In recent years, PRF has been used as an autologous grafting material because of its ability to accelerate physiologic wound healing and new bone formation. PRF may aid wound healing and the closure of bone in BRONJ. In this technical note, the treatment of moderate bone exposure with a PRF membrane in BRONJ is described.
Technique A 75-year-old man was referred to the authors’ clinic for an unhealed tooth extraction socket and pain after removal of the upper right first premolar tooth. Intraoral findings were an unhealed tooth socket of 4 months’ duration, purulent drainage, inflamed gingiva, and an exposed and necrotic jawbone. The patient had type 2 diabetes, prostate enlargement, and recurrent multiple myeloma. He was taking the following medications: Glucophage (metformin 500 mg 2 times a day; Bristol-Myers Squibb, New York, NY), Flomax (tamsulosin hydrochloride 0.4 mg/day; Flomax, Livermore, CA), and alternating therapy using Zometa (zoledronic acid 4 mg/month; Novartis, Basel, Switzerland) and Aredia (pamidronate disodium 90 mg/month; Novartis). The patient had received intravenous alternating Zometa-Aredia therapy for 3 years for the management of recurrent multiple myeloma. According to the patient’s clinical and radiologic findings, the diagnosis was BRONJ. Superficial curettage was performed at the BRONJ area 2 times a month, and combined antibiotics (amoxicillin/clavulanic acid
1,000 mg + metronidazole 500 mg) were prescribed for 3 weeks. After 2 months conservative treatment, the patient showed no recurrence of gingival inflammation, infection, and suppuration. However, the amount of bone exposure (5 10 mm) remained the same (Fig 1). The patient could not use his dentures comfortably owing to the BRONJ. A drug holiday from Zometa and Aredia was not possible because of the active period of multiple myeloma. The exposed bone was covered with 2 layers of PRF membrane (Fig 2). After removal of the necrotic alveolar bone, the first layer of the PRF membrane was inserted into the alveolar bone cavity. The second layer of the PRF membrane was placed superficially, and the edges of the membrane were placed under the
FIGURE 2. Two pieces of platelet-rich fibrin obtained from 20 mL of autologous venous blood. Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
3
SOYDAN AND UCKAN
FIGURE 3. Two layers of platelet-rich fibrin membrane were adapted to the exposed bone area and a superficial layer was sutured to the surrounding gingiva with 4.0 Vicryl suture. Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
mucoperiosteal flap. The second layer of the PRF membrane was sutured carefully to the surrounding gingiva with 4.0 Vicryl sutures for stabilization (Fig 3). Using this procedure, it was easy to achieve total closure of the exposed bone. The PRF protocol was performed according to the Choukroun procedure and European Directive 2004/ 23/CE of March 31, 2004. The PRF was derived from a 20-mL venous blood sample from the patient before surgery. The blood was placed in 2 10-mL glass test tubes, without anticoagulant, and immediately centrifuged at 3,000 rpm for 10 minutes. The same antibiotic regime (amoxicillin/clavulanic acid 1,000 mg + metronidazole 500 mg) and a mouth rinse (0.2% chlorhexidine digluconate) were prescribed to the patient for 1 week. There was some new gingival tissue formation and no inflammation at postoperative week 1 (Fig 4). The sutures were removed at the end of the second postoperative week.
FIGURE 5. Slight collapse of the alveolar ridge without bone exposure was observed at postoperative 1-month follow-up. Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
Total bone closure was achieved, and new mucosa was visible. Although the soft tissue continuity was perfect, the alveolar ridge was slightly collapsed, possibly because of the previous removal of necrotic alveolar bone at postoperative month 1 (Fig 5). No gingival loss, inflammation, or infection was detected at the postoperative 6-month follow-up (Fig 6), and the patient was able to use his dentures 1 month after the procedure.
Discussion BPs may be released faster from the alveolar crest in the acidic environment of the resorbing lacuna
FIGURE 4. One week postoperatively.
FIGURE 6. No gingival loss, inflammation, or bone exposure was observed at postoperative 6-month follow-up.
Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
4 produced by osteoclasts, resulting in locally high concentrations of BPs. The high concentration of BPs after invasive dental surgical procedures could affect cells other than osteoclasts in the microenvironment, such as osteoblasts, endothelium cells, fibroblasts, and keratinocytes.15 Although BP levels within tooth extraction sites have not been quantified, Landesberg et al7 found that their proliferation in the oral epithelium was inhibited at pamidronate concentrations above 0.1 mmol/L in vitro. Sheper et al9 reported that direct contact of clinically relevant concentrations of zoledronate with epithelial and fibroblast cells induced apoptosis, potentially resulting in BRONJ. Epithelialization is an essential step in the management of BRONJ because alveolar bone exposure in BRONJ exposes the bone to the unique infectious microenvironment of the oral cavity. A biofilm forms on the exposed bone surface, and actinomyces facilitate the adherence of other microflora, which results in a heterogeneous population of bacteria primed for the development of persistent infection.16 Infection contributes to the pathophysiology of BRONJ by enhancing osteoclast-independent bone resorption.17 The elimination of dental plaque, which contains a substantial quantity of oral bacteria, with superficial curettage, combined with antibiotic therapy, ameliorates BRONJ-related symptoms and aids bone healing.18 In the presented case, a protocol comprising 2 months conservative treatment was applied for the management of suppuration, infection, and gingival ulceration. Although the conservative treatment resolved the patient’s complaints, additional treatment was needed to manage the prolonged bone exposure, which showed no improvement at the 2-month follow-up. There was insufficient surrounding gingival tissue for tension-free closure of the exposed area. In addition, it is known that coercive closure of the bone results in increased bone exposure in BRONJ cases. Therefore, the bone was closed with 2 layers of PRF membrane. Some previous studies have reported that a combination of necrotic bone curettage and platelet-rich plasma (PRP) seems to be promising for the treatment of refractory BRONJ.19,20 PRP can enhance wound healing and bone maturation. However, there is no current consensus on whether it promotes soft tissue healing in BRONJ cases. PRP is used as an adjunct in a gel formulation, which is formed by mixing (derived from the centrifugation of autologous whole blood) bovine thrombin concentrate and calcium chloride. PRF does not require heterogeneous agents, and it can be used as a graft material or barrier membrane. Therefore, the producing and application procedures with PRF are not as
PLATELET-RICH FIBRIN FOR OSTEONECROSIS
complicated as those with PRP. PRF also contains more growth factors (7 times higher) than PRP.21 Pripatnanont et al22 found that PRF was composed of densely thick fibrin networks, with activated platelets meshed among the fibrins. These dense fibrins provide a natural matrix scaffold for the storage and attachment of tissue cells and the stimulation of angiogenesis. In addition to the matrix scaffold, platelets provide and sustain the release of growth factors in the wound area.14 Many growth factors, such as platelet-derived growth factor and transforming growth factor-b, are released by PRF.23 A recent study has reported the slow release of key growth factors by PRF, with the growth factors released for at least 1 week and up to 28 days.24 Therefore, PRF could stimulate the release of growth factors for a significant time during wound healing. With PRF, fibrin membranes enriched with platelets and growth factors can be obtained from anticoagulant-free blood.12 The PRF membrane has a similar network to fibrin and leads to more efficient cell migration and proliferation and thus cicatrization. Recent studies have described the ability of PRF to increase cell proliferation in rat osteoblasts, human osteoblasts, human periodontal ligament fibroblasts, and human pulp fibroblasts by upregulating osteoprotegerin and alkaline phosphatase.25-28 PRF also has been reported to stimulate the proliferation of gingival fibroblasts and to accelerate soft tissue healing. However, neither PRF nor PRF membranes have been used in the treatment of BRONJ. PRF membranes are an easy, cheap, and rapid alternative treatment approach for the closure of bone exposure in BRONJ. PRF promotes gingival healing and acts as a barrier membrane between the alveolar bone and the oral cavity. More comprehensive studies are needed to understand the physiologic and histologic efficiency of PRF membranes with regard to soft tissue healing.
References 1. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115, 2003 2. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527, 2004 3. Ruggiero SL, Dodson TB, Assael LA, et al: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 Update. J Oral Maxillofac Surg 67:2, 2009 4. Marx RE, Fortin M, Broum V: Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention and treatment. J Oral Maxillofacial Surg 63: 1567, 2005 5. Migliorati CA: Bisphosphonates and oral cavity avascular bone necrosis. J Clin 21:4253, 2003 6. Reid IR: Osteonecrosis of the jaw: Who gets it, and why? Bone 44:4, 2009
5
SOYDAN AND UCKAN 7. Landesberg R, Cozin M, Cremers S, et al: Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg 66:839, 2008 8. Kim RH, Lee RS, Williams D, et al: Bisphosphonates induce senescence in normal human oral keratinocytes. J Dent Res 90: 810, 2011 9. Sheper MA, Badros A, Chaisuparat R, et al: Effect of zoledronic acid on oral fibroblasts and epithelial cells: A potential mechanism of bisphosphonate-associated osteonecrosis. Br J Haematol 144:667, 2009 10. Kobayashi Y, Hiraga T, Ueda A, et al: Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice. J Bone Miner Metab 28:165, 2010 11. Choukroun J, Adda F, Schoeffer C, et al: PRF: An opportunity in perio-implantology. Implantodontie 42:55, 2000 12. Dhoan DM, Choukroun J, Diss A, et al: Platelet-rich fibrin (PRF): A second-generation platelet concentrate. Part II: Plateletrelated biologic features. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 101:45, 2006 13. Choukroun J, Diss A, Simonpieri A, et al: Platelet-rich fibrin (PRF): A second-generation platelet concentrate. Part V: Histologic evaluation of PRF effect on bone allograft maturation in sinus lift. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 101: 299, 2006 14. Dhoan DM, Choukroun J, Diss A, et al: Platelet-rich fibrin (PRF): A second-generation platelet concentrate. Part III: Leucocyte activation: A new feature for platelet concentrate? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 101:51, 2006 15. Walter C, Klein MO, Pabst A, et al: Influence of bisphosphonates on endothelial cells, fibroblasts, and osteogenic cells. Clin Oral Investig 14:35, 2010 16. Sedghizadeh PP, Kumar SK, Gorur A, et al: Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg 66:767, 2008 17. Hansen T, Kunkel M, Weber A, et al: Osteonecrosis of the jaws in patients treated with bisphosphonates—Histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 35:155, 2006 18. Dimopoulos MA, Kastritis E, Bamia C, et al: Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 20:117, 2009 Curi MM, Cossolin GS, Koga DH, et al: Bisphosphonate-related osteonecrosis of the jaws—An initial case series report of treatment combining partial bone resection and autologous platelet-rich plasma. J Oral Maxillofac Surg 69:2465, 2011 Lee CY, David T, Nishime M: Use of platelet- rich plasma in the management of oral bisphosphonate-associated osteonecrosis of the jaw: A report of 2 cases. J Oral Implantol 33: 371, 2007 Dohan DM, Choukroun J, Diss A, et al: Platelet-rich fibrin (PRF): A second-generation platelet concentrate. Part I: Technological concepts and evolution. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 101:e37, 2006 Pripatnanont P, Nuntanaranont T, Vongvatcharanon S, et al: The primacy of platelet-rich fibrin on bone regeneration of various grafts in rabbit’s calvarial defects. J Craniomaxillofac Surg, 2013 [Epub ahead of print] Dohan Ehrenfest DM, de Peppo GM, Doglioli P, et al: Slow release of growth factors and thrombospondin-1 in Choukroun’s platelet-rich fibrin (PRF): A gold standard to achieve for all surgical platelet concentrates technologies. Growth Factors 27:63, 2009 He L, Lin Y, Hu X, et al: A comparative study of platelet-rich fibrin (PRF) and platelet-rich plasma (PRP) on the effect of proliferation and differentiation of rat osteoblasts in vitro. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 108:707, 2009 Simon BJ, Gupta P, Tajbakhsh S: Quantitative evaluation of extraction socket healing following the use of autologous platelet rich fibrin matrix in humans. Int J Periodontics Restorative Dent 31:284, 2011 Chang YC, Zhao JH: Effects of platelet-rich fibrin on human periodontal ligament fibroblasts and application for periodontal infra bony defects. Aust Dent J 56:365, 2011 Chang IC, Tsai CH, Chang YC: Platelet-rich fibrin modulates the expression of extracellular signal-regulated protein kinase and osteoprotegerin in human osteoblasts. J Biomed Mater Res A 95:327, 2010 Huang FM, Yang SF, Zhao JH, et al: Platelet-rich fibrin increases proliferation and differentiation of human dental pulp cells. J Endod 36:1628, 2010
Management of Bisphosphonate-Related Osteonecrosis of the Jaw With a Platelet-Rich Fibrin Membrane: Technical Report Sıdıka Sinem Soydan, DDS, PhD,* and Sina Uckan, DDS, PhDy Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a challenging complication resulting from the long-term application of bisphosphonates. In most cases, BRONJ occurs after a surgical procedure involving the jawbone. Currently, the management of BRONJ remains controversial, and there is no definitive treatment other than palliative methods. Platelet-rich fibrin (PRF) represents a relatively new biotechnology for the stimulation and acceleration of tissue healing and bone regeneration. This technical note describes the total closure of moderate bone exposure in persistent BRONJ in 2 weeks with a double-layer PRF membrane. PRF may stimulate gingival healing and act as a barrier membrane between the alveolar bone and the oral cavity. PRF may offer a fast, easy, and effective alternative method for the closure of bone exposure in BRONJ. Ó 2013 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg -:1-5, 2013 Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is characterized by exposed necrotic bone, which can be accompanied by pain, swelling, paresthesia, suppuration, soft tissue ulceration, and intraand extraoral sinus tracts.1,2 The incidence of BRONJ is higher with bisphosphonates (BPs) administered monthly through a parenteral route than with oral BPs taken weekly. Most BRONJ cases occur after surgical procedures of oral tissues. However, 30% of cases occur spontaneously.3 Although the reported frequency of BRONJ is low, it causes complications in dental and oral and maxillofacial surgical treatments of patients receiving BPs. The most effective treatment for BRONJ is still controversial and a challenging issue for oral and maxillofacial surgeons. Although antiresorptive therapies other than BPs and receptor activator of nuclear factor-kB ligand inhibitor therapies are claimed to cause osteonecrosis of the jaws, BPs are responsible for most of the concern. The most accepted pathologic etiology of BRONJ is oversuppression of bone turnover and inhibition of angiogenesis owing to systematic usage of BPs.2,4,5
Despite BPs having a specific effect on osteoclasts and a great affinity to bone, the loss of oral mucosa in almost every BRONJ case raises the question of whether they affect oral soft tissue. Several studies have examined whether BPs have an adverse effect on oral epithelial and mucosal tissues.6-10 The results of these studies have been consistent, showing that nitrogen-containing BPs decrease oral epithelial cell migration, promote apoptosis, disturb cell viability, and impede oral mucosa wound healing. Platelet-rich fibrin (PRF) is a second-generation platelet concentrate (natural autologous fibrin matrix) that was first described by Choukroun et al11 in 2000. It regulates inflammation and stimulates chemotactic factors involved in the immune response.12 PRF contains a substantial quantity of fibrins, platelets, and leukocytes. It secretes 3 proinflammatory cytokines (interleukin-1b, interleukin-6, and tumor necrosis factor-a), an anti-inflammatory cytokine (interleukin-4), and a key promoter of angiogenesis (vascular endothelial growth factor).13 PRF also accelerates angiogenesis, the multiplication of fibroblasts and osteoblasts,
Received from the Department of Oral and Maxillofacial Surgery,
Received June 24 2013
Faculty of Dentistry, Baskent University, Ankara, Turkey.
Accepted July 23 2013
*Fellow.
Ó 2013 American Association of Oral and Maxillofacial Surgeons
yProfessor. Address correspondence and reprint requests to Dr Soydan:
0278-2391/13/00938-5$36.00/0 http://dx.doi.org/10.1016/j.joms.2013.07.027
Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Baskent University, 11. Sokak no 26 Bahcelievler, Cankaya, Ankara, Turkiye; e-mail: [email protected]
1
2
PLATELET-RICH FIBRIN FOR OSTEONECROSIS
FIGURE 1. After 2 months of conservative treatment, gingival inflammation was released and necrotic bone exposure was 5 10 mm. Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
and cicatrization.14 In recent years, PRF has been used as an autologous grafting material because of its ability to accelerate physiologic wound healing and new bone formation. PRF may aid wound healing and the closure of bone in BRONJ. In this technical note, the treatment of moderate bone exposure with a PRF membrane in BRONJ is described.
Technique A 75-year-old man was referred to the authors’ clinic for an unhealed tooth extraction socket and pain after removal of the upper right first premolar tooth. Intraoral findings were an unhealed tooth socket of 4 months’ duration, purulent drainage, inflamed gingiva, and an exposed and necrotic jawbone. The patient had type 2 diabetes, prostate enlargement, and recurrent multiple myeloma. He was taking the following medications: Glucophage (metformin 500 mg 2 times a day; Bristol-Myers Squibb, New York, NY), Flomax (tamsulosin hydrochloride 0.4 mg/day; Flomax, Livermore, CA), and alternating therapy using Zometa (zoledronic acid 4 mg/month; Novartis, Basel, Switzerland) and Aredia (pamidronate disodium 90 mg/month; Novartis). The patient had received intravenous alternating Zometa-Aredia therapy for 3 years for the management of recurrent multiple myeloma. According to the patient’s clinical and radiologic findings, the diagnosis was BRONJ. Superficial curettage was performed at the BRONJ area 2 times a month, and combined antibiotics (amoxicillin/clavulanic acid
1,000 mg + metronidazole 500 mg) were prescribed for 3 weeks. After 2 months conservative treatment, the patient showed no recurrence of gingival inflammation, infection, and suppuration. However, the amount of bone exposure (5 10 mm) remained the same (Fig 1). The patient could not use his dentures comfortably owing to the BRONJ. A drug holiday from Zometa and Aredia was not possible because of the active period of multiple myeloma. The exposed bone was covered with 2 layers of PRF membrane (Fig 2). After removal of the necrotic alveolar bone, the first layer of the PRF membrane was inserted into the alveolar bone cavity. The second layer of the PRF membrane was placed superficially, and the edges of the membrane were placed under the
FIGURE 2. Two pieces of platelet-rich fibrin obtained from 20 mL of autologous venous blood. Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
3
SOYDAN AND UCKAN
FIGURE 3. Two layers of platelet-rich fibrin membrane were adapted to the exposed bone area and a superficial layer was sutured to the surrounding gingiva with 4.0 Vicryl suture. Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
mucoperiosteal flap. The second layer of the PRF membrane was sutured carefully to the surrounding gingiva with 4.0 Vicryl sutures for stabilization (Fig 3). Using this procedure, it was easy to achieve total closure of the exposed bone. The PRF protocol was performed according to the Choukroun procedure and European Directive 2004/ 23/CE of March 31, 2004. The PRF was derived from a 20-mL venous blood sample from the patient before surgery. The blood was placed in 2 10-mL glass test tubes, without anticoagulant, and immediately centrifuged at 3,000 rpm for 10 minutes. The same antibiotic regime (amoxicillin/clavulanic acid 1,000 mg + metronidazole 500 mg) and a mouth rinse (0.2% chlorhexidine digluconate) were prescribed to the patient for 1 week. There was some new gingival tissue formation and no inflammation at postoperative week 1 (Fig 4). The sutures were removed at the end of the second postoperative week.
FIGURE 5. Slight collapse of the alveolar ridge without bone exposure was observed at postoperative 1-month follow-up. Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
Total bone closure was achieved, and new mucosa was visible. Although the soft tissue continuity was perfect, the alveolar ridge was slightly collapsed, possibly because of the previous removal of necrotic alveolar bone at postoperative month 1 (Fig 5). No gingival loss, inflammation, or infection was detected at the postoperative 6-month follow-up (Fig 6), and the patient was able to use his dentures 1 month after the procedure.
Discussion BPs may be released faster from the alveolar crest in the acidic environment of the resorbing lacuna
FIGURE 4. One week postoperatively.
FIGURE 6. No gingival loss, inflammation, or bone exposure was observed at postoperative 6-month follow-up.
Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
Soydan and Uckan. Platelet-Rich Fibrin for Osteonecrosis. J Oral Maxillofac Surg 2013.
4 produced by osteoclasts, resulting in locally high concentrations of BPs. The high concentration of BPs after invasive dental surgical procedures could affect cells other than osteoclasts in the microenvironment, such as osteoblasts, endothelium cells, fibroblasts, and keratinocytes.15 Although BP levels within tooth extraction sites have not been quantified, Landesberg et al7 found that their proliferation in the oral epithelium was inhibited at pamidronate concentrations above 0.1 mmol/L in vitro. Sheper et al9 reported that direct contact of clinically relevant concentrations of zoledronate with epithelial and fibroblast cells induced apoptosis, potentially resulting in BRONJ. Epithelialization is an essential step in the management of BRONJ because alveolar bone exposure in BRONJ exposes the bone to the unique infectious microenvironment of the oral cavity. A biofilm forms on the exposed bone surface, and actinomyces facilitate the adherence of other microflora, which results in a heterogeneous population of bacteria primed for the development of persistent infection.16 Infection contributes to the pathophysiology of BRONJ by enhancing osteoclast-independent bone resorption.17 The elimination of dental plaque, which contains a substantial quantity of oral bacteria, with superficial curettage, combined with antibiotic therapy, ameliorates BRONJ-related symptoms and aids bone healing.18 In the presented case, a protocol comprising 2 months conservative treatment was applied for the management of suppuration, infection, and gingival ulceration. Although the conservative treatment resolved the patient’s complaints, additional treatment was needed to manage the prolonged bone exposure, which showed no improvement at the 2-month follow-up. There was insufficient surrounding gingival tissue for tension-free closure of the exposed area. In addition, it is known that coercive closure of the bone results in increased bone exposure in BRONJ cases. Therefore, the bone was closed with 2 layers of PRF membrane. Some previous studies have reported that a combination of necrotic bone curettage and platelet-rich plasma (PRP) seems to be promising for the treatment of refractory BRONJ.19,20 PRP can enhance wound healing and bone maturation. However, there is no current consensus on whether it promotes soft tissue healing in BRONJ cases. PRP is used as an adjunct in a gel formulation, which is formed by mixing (derived from the centrifugation of autologous whole blood) bovine thrombin concentrate and calcium chloride. PRF does not require heterogeneous agents, and it can be used as a graft material or barrier membrane. Therefore, the producing and application procedures with PRF are not as
PLATELET-RICH FIBRIN FOR OSTEONECROSIS
complicated as those with PRP. PRF also contains more growth factors (7 times higher) than PRP.21 Pripatnanont et al22 found that PRF was composed of densely thick fibrin networks, with activated platelets meshed among the fibrins. These dense fibrins provide a natural matrix scaffold for the storage and attachment of tissue cells and the stimulation of angiogenesis. In addition to the matrix scaffold, platelets provide and sustain the release of growth factors in the wound area.14 Many growth factors, such as platelet-derived growth factor and transforming growth factor-b, are released by PRF.23 A recent study has reported the slow release of key growth factors by PRF, with the growth factors released for at least 1 week and up to 28 days.24 Therefore, PRF could stimulate the release of growth factors for a significant time during wound healing. With PRF, fibrin membranes enriched with platelets and growth factors can be obtained from anticoagulant-free blood.12 The PRF membrane has a similar network to fibrin and leads to more efficient cell migration and proliferation and thus cicatrization. Recent studies have described the ability of PRF to increase cell proliferation in rat osteoblasts, human osteoblasts, human periodontal ligament fibroblasts, and human pulp fibroblasts by upregulating osteoprotegerin and alkaline phosphatase.25-28 PRF also has been reported to stimulate the proliferation of gingival fibroblasts and to accelerate soft tissue healing. However, neither PRF nor PRF membranes have been used in the treatment of BRONJ. PRF membranes are an easy, cheap, and rapid alternative treatment approach for the closure of bone exposure in BRONJ. PRF promotes gingival healing and acts as a barrier membrane between the alveolar bone and the oral cavity. More comprehensive studies are needed to understand the physiologic and histologic efficiency of PRF membranes with regard to soft tissue healing.
References 1. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115, 2003 2. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527, 2004 3. Ruggiero SL, Dodson TB, Assael LA, et al: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 Update. J Oral Maxillofac Surg 67:2, 2009 4. Marx RE, Fortin M, Broum V: Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention and treatment. J Oral Maxillofacial Surg 63: 1567, 2005 5. Migliorati CA: Bisphosphonates and oral cavity avascular bone necrosis. J Clin 21:4253, 2003 6. Reid IR: Osteonecrosis of the jaw: Who gets it, and why? Bone 44:4, 2009
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