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Table of Contents   
CASE REPORT  
Year : 2020  |  Volume : 31  |  Issue : 5  |  Page : 813-818
Usefulness of advanced-platelet rich fibrin (A-PRF) and injectable-platelet rich fibrin (i-PRF) in the management of a massive medication-related osteonecrosis of the jaw (MRONJ): A 5-years follow-up case report


1 School of Dentistry, Department of Health Sciences; Unit of Oral and Maxillofacial Surgery, “Magna Græcia” University of Catanzaro, Italy
2 School of Dentistry, Department of Health Sciences, “Magna Græcia” University of Catanzaro, Italy

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Date of Submission03-Sep-2019
Date of Decision12-Dec-2019
Date of Acceptance29-Jun-2020
Date of Web Publication08-Jan-2021
 

   Abstract 


Medication-related osteonecrosis of the jaw (MRONJ) is a recurring complication resulting from the long-term therapy with bisphosphonates or antiresorptive drugs such as denosumab or antiangiogenic drugs. This paper describes a 5-years follow-up case of Stage 3 of MRONJ (AAOMS) in a 69-year-old patient treated with piezosurgery and topical application of platelet-rich fibrin (PRF). Medical treatment included antibiotic therapy and a topical treatment with PRF in solid and liquid form. This treatment showed initially the reduction of pain and leakage exudate and a complete wound healing in 25 days. The Injectable-Platelet Rich Fibrin (i-PRF) injections led to a complete resolution of oro-cutaneous fistulas in 50 days showing its ability of releasing growth factors and chemotaxis agents involved in tissue repair mechanisms. Preparation simplicity and the low cost of PRF allow to consider this method as an excellent alternative treatment for the healing of tissues in MRONJ patients.

Keywords: Bisphosphonate, bone metabolic disease, osteonecrosis, platelet-rich fibrin

How to cite this article:
Giudice A, Antonelli A, Muraca D, Fortunato L. Usefulness of advanced-platelet rich fibrin (A-PRF) and injectable-platelet rich fibrin (i-PRF) in the management of a massive medication-related osteonecrosis of the jaw (MRONJ): A 5-years follow-up case report. Indian J Dent Res 2020;31:813-8

How to cite this URL:
Giudice A, Antonelli A, Muraca D, Fortunato L. Usefulness of advanced-platelet rich fibrin (A-PRF) and injectable-platelet rich fibrin (i-PRF) in the management of a massive medication-related osteonecrosis of the jaw (MRONJ): A 5-years follow-up case report. Indian J Dent Res [serial online] 2020 [cited 2021 Jan 28];31:813-8. Available from: https://www.ijdr.in/text.asp?2020/31/5/813/306458



   Introduction Top


Medication-related osteonecrosis of the jaw (MRONJ) is a complication characterized by exposed necrotic bone for a minimum period of 8 weeks in patients treated with bisphosphonates and other antiresorptive drugs such as denosumab or antiangiogenic drugs and no previous radiation therapy to the jaws.[1],[2] Although the reported frequency of spontaneous MRONJ is low, the majority of affected patients experience this complication following oral and maxillofacial surgical treatments.[2] Many options were suggested for the treatment of each MRONJ degree and the choice of the most effective therapy represents a current challenge for the physician. In recent years autologous platelet concentrates have been used in addition to the surgical necrotic bone removal due their ability to improve many types of wound healing. Platelet-rich fibrin (PRF) is a second generation platelet concentrate described by Choukroun et al. that contains high values of platelet, fibrins, and leucocyte.[3] It has the ability of regulating inflammation and chemotaxis secreting several proinflammatory cytokines (IL-1β, IL-6, and TNFα) and a basic promoter of angiogenesis (VEGF).[4]

We present a patient treated with alendronate for severe osteoporotic disease and developed MRONJ in the posterior right mandible region with presence of multiple oro-cutaneous fistulas in the mental region (Stage 3 AAOMS, 2014). The necrotic lesions were treated with piezoelectric surgery combined to platelet-rich fibrin (PRF) membranes, the fistulas were treated with injections of PRF in liquid form (i-PRF) using the chemotaxis and neoangiogenetic properties of PRF.


   Case Report Top


A 69-year-old male patient presented to our hospital in September 2014 with pain and swelling in the mandible. The right lower premolars and first molar were extracted four months previously by a general dentist and was followed up. However, the patient was referred to our department for a comprehensive examination four months later because of the lack of extraction socket healing and continued pain and swelling.

Extraoral examination showed leakage of exudate with multiple fistulas in the symphysis area [Figure 1]. The intraoral evaluation showed halitosis, poor dental hygiene, widespread periodontal disease, and exposure of necrotic bone in the right mandibular region with presence of an exudate [Figure 2]. The patient reported paresthesia on the right side of mandible and in the mental region. Patient's past medical history included hypertension, hypercholesterolemia, and severe osteoporotic disease and he reported a previous smoking history (more than 20 cigarettes/day) until 2014. The patient reported L1-L2 fracture in 2012 due to osteoporotic illness. He had been using Enalapril (20 mg/day) for hypertension and Lovastatin (20 mg/day) for the hypercholesterolemia; the patient received Alendronate per os (70 mg/week) for 10 years for the management of the severe osteoporotic disease.
Figure 1: Extraoral examination, oro-cutaneous fistulas drain exudate in symphysis area

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Figure 2: Intraoral examination, necrotic bone exposed draining exudate in the right mandibular region

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A CT and an OPG were obtained for more detailed examination [Figure 3]. These revealed changes to trabecular pattern dense woven bone and persistence of unremodeled bone in the right posterior mandible area.
Figure 3: Arrows indicate the radiolucency in the right posterior mandible area. It evidences changes to trabecular pattern dense woven bone and persistence of unremodeled bone

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In the first step a provisional diagnosis of odontogenic abscess was made due to the presence of massive purulent exudate in the mental region. However, there was no signs of inflammatory periapical lesions and all teeth were vital without pulpitis. Osteoradionecrosis was excluded as the patient reported no previous history of tumors to the head and neck region.

The positive amino bisphosphonate administration (Alendronate) history, no wound healing within eight weeks, exposed necrotic bone presence and radiological findings suggested the diagnosis of Stage 3 MRONJ according to AAOMS classification (2014). Alendronate therapy was ceased on the advice of the rheumatologist and orthopaedician.

The patient was initially treated conservatively with antibiotic, professional dental hygiene, and mouth rinse with nystatin and chlorhexidine 0.2%. Antibiotic therapy included Amoxicillin/clavulanic acid 1000 mg and metronidazole 500 mg. After one week of full-dose antibiotic therapy and 0.2% chlorhexidine mouthwash we noted a little improvement of local conditions with a reduction of intraoral exudate. However, after 3 weeks there were still persistent orocutaneous fistulas and leakage of exudate from the mental region. Surgery was performed under local anesthesia and the protocol included the resection of all infected and necrotic bone with piezoelectric surgery [Figure 4]. Adequate resection of bone margins were determined by the clinical appearance of bleeding bone. During the surgery right lower canine was extracted due the lack of healthy bone support; all bone margins were rounded. Bone samples were analyzed to confirm ONJ diagnosis and histopathological analysis excluded any presence of bone metastasis. After bone resection the surgical site was filled with autologous platelet-rich fibrin (PRF) membranes (A-PRF, Process For PRF, Nice, France) for wound closure [Figure 5]. To prepare the A-PRF 40 ml of autologous venous blood was collected into four tubes (in glass without additives) of of 10 mL each. These were then immediately centrifuged at 1,300 rpm for eight minutes. Both PRF membrane were putted in the wound and sutured to the surrounding gingiva with 4.0 resorbable suture to improve wound healing. Simultaneously PRF in liquid form (i-PRF, Process For PRF, Nice, France) was injected around surgery and fistula site using an insulin syringe [Figure 6] and [Figure 7]. i-PRF was prepared collecting 20 ml of autologous venous blood into two tubes (in plastic without additives) of 10 mL each, which were immediately centrifuged at 700 rpm for three minutes. Sutures were removed seven days after surgery. Antibiotic therapy and i.PRF injections were carried out for two weeks after the surgery.
Figure 4: Surgery included the resection of all infected and necrotic bone

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Figure 5: Autologous platelet-rich fibrin (PRF) membranes putted into the bone defect to improve wound healing

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Figure 6: i-PRF injections performed after necrotic bone resection

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Figure 7: i-PRF injections performed around the fistulas in the mental region

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The use of autologous PRF in the treatment of ONJ showed a clear improvement with an epithelisation occurred within 4 weeks after treatment. Healing process was initially characterized by the reduction of pain and leakage exudate. A complete wound healing was obtained in 25 days after the topic application of PRF membranes when a successful new gingival tissue formation has been completed [Figure 8] and [Figure 9].
Figure 8: New gingival tissue formation was observed in 25 days after the topic application of PRF membranes

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Figure 9: Complete healing of the necrotic area

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A complete resolution of oro-cutaneous fistulas were observed after two i-PRF injections and there was no noted leakage of exudate from the symphysis area after 50 days [Figure 10]. After 4 months follow-up, the patient appears clinically free of disease as demonstrated also by clinical absence of necrotic bone in oral cavity, absence of necrotic bone radiological signs [Figure 11], absence of pain and exudate leakage and oro-cutaneous fistulas healing. The patient was followed up for one year [Figure 12] and [Figure 13] and at five year follow-up there was no recurrence or necrotic bone exposure [Figure 14] and [Figure 15].
Figure 10: Complete resolution of oro-cutaneous fistulas were observed after i.PRF injections and there was no noted leakage of exudate from the symphysis area after 50 days

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Figure 11: Radiological images showed surgical results and absence of necrotic bone

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Figure 12: Check of oral cavity at 1-year follow-up. There was no signs of disease recurrence

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Figure 13: There was no recurrence of oro-cutaneous fistulas in the symphisis zone at 1-year follow-up

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Figure 14: Intraoral examination shows the absence of pathological signs at 5-years follow-up

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Figure 15: Patient appears clinically free of disease at postoperative 5-years follow-up. There was no recurrence or necrotic bone exposure

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   Discussion Top


Patients undergoing intravenous administration of bisphosphonate over a long period of time may be predisposed to “bisphosphonate-related osteonecrosis of the jaws, or antiresorptive drug related osteonecrosis of the jaw (MRONJ).” This is a critical side effect in the oro-maxillo-facial region of exposed bone in the jaw persisting for more than eight weeks with no history of radiation therapy.[1],[2]

In 2014 the American Association of Oral and Maxillofacial Surgeons (AAOMS) suggested a MRONJ staging system to define the most appropriate management strategy for patients with MRONJ based on the disease stage.[2]

Over the years, many protocols have been suggested for the treatment of patients affected by MRONJ. Many authors expressed controversies about the most suitable therapeutic approach for the different stages of this pathology.[5],[6] Although conservative management may resolve early stages, for cases where prolonged bone exposure shows no improvement, additional treatments are needed. Typically, in those patients in Stage II or III the quality of life is deeply influenced by necrosis and bone exposure. The lack of epithelization exposes the patient to the unique infectious microenvironment of the oral cavity which results in a development of persistent and recurrent infections. Recently surgical therapy combined with the use of bone fluorescence to detect necrotic zone have been proposed.[7] To improve patient's quality of life and wound healing, some researchers started to use autologous platelet concentrates (APC) combined with surgical therapy.[6],[8]

Autologous platelet concentrates are obtained by centrifuging human blood and Robert Marx proposed for the first time in 1998 the use of APC to improve bone and wound healing in oral and maxillofacial surgery. Since then, the APC's family included many tools like PRGF, PRP and PRF.

Choukroun et al. showed the efficacy of PRF use in a wide range of medication, from the cutaneous ulcers treatment to bone regeneration. The high concentration of fibrin contained in PRF allows to improve a more efficient healing.[3] Furthermore this biotechnological tool is able to release growth factors (platelet derived growth factor [PDGF], transforming growth factor [TGF α & β], epidermal growth factor [EGF], fibroblast growth factor [FGF], tumor necrosis factor alpha [TNFα]) involved in tissue repair mechanisms such as cell proliferation, angiogenesis, chemotaxis, and antimicrobial effect.[3]

Many authors assessed the role of APC in the treatment of MRONJ showing its ability of improvement in soft and bone tissue healing with angiogenesis properties. A study of Del Fabbro et al. considered the important analgesic, anti-inflammatory, and antimicrobial action of APC in the early post-surgical period, however they suggested to interpret this results with caution due the low evidence level studies included in this review.[8] In particular, the use of PRP and PRGF was investigated in the treatment of MRONJ with similar positive results.[8] Unlike the traditional APC, Choukroun's PRF not requiring any addition or manipulation is considered a physiologic concentrate and its production is more easy respect the PRP.[3] Furthermore, Choukroun's PRF appear to be stable up to two weeks after application; the fibrin matrix is slowly remodelled in a similar way to a natural blood clot. Platelets are activated during the process, which leads to a substantial embedding of platelet and leucocyte growth factors into the fibrin matrix.

Few reports analyzed feasible use of PRF combined with necrotic bone debridement. In 2016 Nørholt et al. realized a prospective study of 15 patients affecting by MRONJ evaluating PRF role. In 14 of the 15 cases the association of surgical treatment and PRF membranes had a successful outcome to ensure a multi-layered closure.[9] A technical report by Soydan and Uckan showed the use of PRF membranes for an ONJ treatment. They described a total bone closure with new gingival formation and no presence of any inflammation or infection signs detected at the postoperative 6 months follow-up.[10] Several authors found a significant improvement of clinical parameters of all patients after surgery combining the potential benefits of platelets and fibrin matrices with a faster wound healing during the early stage of treatment.[6],[8]

In this case report PRF membranes and PRF injections were used for the treatment of Stage 3 (AAOMS classification) MRONJ. Initially this topical treatment allowed to reduce the infection and the patient's pain. PRF injections allowed to produce a faster healing of the oro-cutaneous fistulas. Although the findings in this study may not be conclusive, the results with a combination of necrotic bone removal/curettage and PRF application seem to be useful for the treatment of refractory MRONJ and in terms of quality of life. Preparation simplicity and the low cost of PRF allow to consider this method as an excellent alternative treatment for the healing of tissues in MRONJ patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 2003;61:1115-7.  Back to cited text no. 1
    
2.
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg 2014;72:1938-56.  Back to cited text no. 2
    
3.
Choukroun J, Diss A, Simonpieri A, Girard M-O, Schoeffler C, Dohan SL, et al. Platelet-rich fibrin (PRF): A second-generation platelet concentrate. Part IV: Clinical effects on tissue healing. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101:e56-60.  Back to cited text no. 3
    
4.
Choukroun J, Diss A, Simonpieri A, Girard M-O, Schoeffler C, Dohan SL, et al. Platelet-rich fibrin (PRF): A second-generation platelet concentrate. Part V: Histologic evaluations of PRF effects on bone allograft maturation in sinus lift. Oral Sur Oral Med Oral Pathol Oral Radiol Endod 2006;101.3:299-303.  Back to cited text no. 4
    
5.
Rupel K, Ottaviani G, Gobbo M, Contardo L, Tirelli G, Vescovi P, et al. A systematic review of therapeutical approaches in bisphosphonates-related osteonecrosis of the jaw (BRONJ). Oral Oncol 2014;50:1049-57.  Back to cited text no. 5
    
6.
Giudice A, Barone S, Giudice C, Bennardo F, Fortunato L. Can platelet-rich fibrin improve healing after surgical treatment of medication-related osteonecrosis of the jaw? A pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol 2018;126:390-403.  Back to cited text no. 6
    
7.
Giudice A, Bennardo F, Barone S, Antonelli A, Figliuzzi MM, Fortunato L, et al. Can autofluorescence guide surgeons in the treatment of medication-related osteonecrosis of the jaw? A prospective feasibility study. J Oral Maxillofac Surg 2018;76:982-95.  Back to cited text no. 7
    
8.
Del Fabbro M, Gallesio G, Mozzati M. Autologous platelet concentrates for bisphosphonate-related osteonecrosis of the jaw treatment and prevention. A systematic review of the literature. Eur J Cancer 2015;51:62-74.  Back to cited text no. 8
    
9.
Nørholt SE, Hartlev J. Surgical treatment of osteonecrosis of the jaw with the use of platelet-rich fibrin: A prospective study of 15 patients. Int J Oral Maxillofac Surg 2016;45:1256-60.  Back to cited text no. 9
    
10.
Soydan SS, Uckan S. Management of bisphosphonate-related osteonecrosis of the jaw with a platelet-rich fibrin membrane: Technical report. J Oral Maxillofac Surg 2014;72:322-6.  Back to cited text no. 10
    

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Correspondence Address:
Dr. Alessandro Antonelli
School of Dentistry, Department of Health Sciences, “Magna Graecia” University of Catanzaro, Viale Europa, Località Germaneto – 88100, Catanzaro
Italy
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdr.IJDR_689_19

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15]



 

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