Plasma rico en fibrina (PRF) y placa de titanio en el tratamiento exitoso de un defecto óseo asociado a osteonecrosis causado por bisfosonatos: reporte de caso

RESUMEN

La osteonecrosis de la mandíbula asociada a bisfosfonatos (BRONJ) es una afección progresiva que aún no tiene consenso sobre su tratamiento ideal. La terapia con plasma rico en fibrina (PRF) ha demostrado ser efectiva en BRONJ. El presente caso relata el tratamiento de un paciente masculino de 76 años que asistió quejándose de dolor en la boca durante 8 meses. Su historial médico reportó metástasis de mieloma múltiple y uso de bisfosfonatos, que había dejado de tomar tres meses antes. En la mandíbula posterior izquierda, la evaluación clínica intraoral presentó supuración y exposición ósea de aproximadamente 4 cm; en la radiografía panorámica se identificó una imagen radiotransparente y desorganización de trabéculas óseas; en la tomografía computarizada fue evidente cierta destrucción de la cortical lingual y bucal, que sugirió secuestro óseo. El diagnóstico fue osteonecrosis asociada a bisfosfonatos. El tratamiento consistió en extraer el hueso necrótico y llenar el defecto con PRF obtenido de la sangre del paciente. Se consiguió el cierre completo de la herida. Después de 2 meses, el paciente volvió a quejarse de dolor, una radiografía panorámica mostró una línea radiolúcida de discontinuidad, sugestiva de fractura mandibular en la zona tratada previamente. Se realizó una segunda cirugía con acceso extraoral ya que la mucosa oral se encontraba completamente sana. Se extrajo el hueso necrótico y se colocaron placas de titanio. Después de 3 meses de seguimiento, hubo signos de consolidación ósea y ausencia de dolor; el paciente pudo comer adecuadamente y su calidad de vida mejoró.

Palabras clave: Osteonecrosis de la mandíbula; oteonecrosis asociada a bisfosfonatos; ácido zoledrónico; plasma rico en fibrina.

ABSTRACT

Bisphosphonate related osteonecrosis of the jaw (BRONJ) is a progressive condition that still has no consensus about its ideal treatment. Fibrin-rich plasma (FRP) therapy shows effectiveness on BRONJ’s treatment by clinicians. A 76-year-old male patient attended for our evaluation complaining of pain in his mouth for 8 months. The medical history showed multiple myeloma metastasis and the use of bisphosphonate (BP) for metastasis control. On intraoral clinical evaluation, suppuration and exposed bone was evident on posterior left mandible measuring approximately 4 centimeters. On panoramic radiograph, we observed a radiolucent image and an area of osseous trabeculae disorganization on left mandible. Computed Tomography (CT) image showed some destruction of lingual and buccal cortical, suggestive of bone sequestration. The treatment was to remove all necrotic bone and fill the defect with FRP from the patient's own blood. Sutures were placed to provide wound primary closure and after 2 months without evidence of exposed bone, the patient came complaining with pain again. After a panoramic radiograph, it was clearly observed a radiolucent image with an image of a jaw discontinuity line, suggestive of mandible fracture in the same side treated before. New surgery was performed and as the intraoral mucosa was perfectly healthy, an extraoral access was made. All the necrotic bone was removed and titanium plates were placed. After 3 months following up, there were signs of bone consolidation and no pain complaint by patient. The patient was able to eating properly and had his quality of life improved.

Keywords: Osteonecrosis of the jaw; bisphosphonate-associated osteonecrosis; zoledronic acid; fibrin-rich plasma.

RESUMO

A osteonecrose da mandíbula associada aos bisfosfonatos (BRONJ) é uma condição progressiva que ainda não tem consenso sobre seu tratamento ideal. A terapia de Plasma Rico em Fibrina (PRF) tem demostrado ser eficaz no BRONJ. O presente caso relata o tratamento de um paciente do sexo masculino, 76 anos, que se apresentou com manifestação de dor na boca por 8 meses. Seu histórico médico relatou metástase de mieloma múltiplo e uso de bisfosfonatos, que ele havia parado de tomar três meses antes. Na mandíbula posterior esquerda, a avaliação clínica intraoral apresentou supuração e exposição óssea de aproximadamente 4 cm; na radiografia panorâmica, foi identificada uma imagem radiolúcida e desorganização das trabéculas ósseas; Na tomografia computadorizada, foi evidente alguma destruição do córtex lingual e bucal, o que sugeria sequestro ósseo. O diagnóstico foi oseonecrose associada a bisfosfonatos. O tratamento consistiu na extração do osso necrótico e preenchimento do defeito com PRF obtido do sangue do paciente. Foi alcançado o fechamento completo da lesão. No entanto, após 2 meses, o paciente apresentou novamente dor, uma radiografia panorâmica mostrou uma linha radiolúcida de descontinuidade, sugestiva de fratura mandibular na área previamente tratada. Uma segunda cirurgia foi realizada com acesso extra-oral, pois a mucosa oral estava completamente saudável. O osso necrótico foi removido e as placas de titânio foram colocadas. Após 3 meses de acompanhamento, houve sinais de consolidação óssea e ausência de dor; o paciente que poderia comer adequadamente e sua qualidade de vida melhorou.

Palavras-chave: Osteonecrose da mandíbula; osteonecrose associada a bisfosfonato; ácido zoledrónico; plasma rico em fibrina.

The term antiresorptive agent-related osteonecrosis of the jaw (ARONJ) have been used for designate all bone necrosis that are caused by those medications, like bisphosphonates (BPs), denosumab and monoclonal antibody against receptor activator of NFκB ligand (RANKL). Some bone necrosis can occur using antiangiogenic therapy such as angiostatin, 4-platelet factor, endostatins and thalidomide or long-term systemic corticosteroid. BPs are drugs considered as antiresorptive agents used to treat patients with osteoporosis, metastatic bone cancer, or with some bone pathology with bone loss due to the increased bone resorption. Bisphosphonate related osteonecrosis of the jaw (BRONJ) are bone exposures on the maxillofacial region that does not heal after 8 week in patients with no previous craniofacial region irradiation, Marx et al., 2005¹.

Marx RE, 2003², reported for the first time on the exposure of the jaw and jaw bones of patients receiving bisphosphonates and subsequently, several authors reported additional cases. The prevalence is considered quite low and ranges between 0.1% and 0.21% for patients who take these drugs orally with longer than 4 years of use and between 0,7% and 6.7% for under intravenous (IV) treatment with zolendronic acid (ZA), Ruggiero et al., 2014³. Mostly BRONJ are cause by some manipulation on bone or soft tissues in oral cavity (oral extractions or dental implant placement), but it can occur by spontaneously, Miniello et al., 2015⁴. It depends on several factors such as therapeutic indication, medication administration route, dose, time of use, among others, Ruggiero et al., 2014³.

Despite these low percentages, its management is always an enigma and in some cases, non resolutive therapeutic choices can affect patient's quality of life. Many points about BRONJs remain obscure and treatment still don´t has, until now, a consensus about an ideal or more resolutive. Most publications advice regarding prevention and management of this condition, which is not yet well established, Marx, 2003²; Marx et al., 2005¹; Ruggiero et al., 2004³. Some care for prevention include routine oral hygiene to reduce caries risk and periodontal disease, regular visits to dentist for reevaluation and clinical healthy preservation, Tong et al., 2010⁵.

Treatments with the use of antibiotics (ATB) and hygiene with 0.12% cloredixidine gluconate are considered conservative, however, are more effective when combined with others treatments like bone debridement and/or resections surgery, considered invasive, Miniello et al., 2019⁶. Some others treatments have been related as PENTO (pentoxifylline and tocopherol) protocol, platelet-rich plasma (PRP), fibrin-rich plasma (FRP), low-level laser therapy (LLLT), hyperbaric oxygenation (HBO), antimicrobial photodynamic therapy (aPDT), among others.

A literature review in PubMed (articles in English ranging from 1983 to 2017) selected and analyzed about BRONJ and their treatments. Protocol with PENTO associated with ATB did not showed good results (only 17% of success) in healing of BRONJ. HBO had contrasting results with varying success rates between 25% and 90%, depending on the year of publication of the study analyzed. LLLT was presented as a more efficient approach when combined with ATB and bone debridement. The most effective was PRP, succeeding in over 80% of cases. Even so, surgery is the treatment option more adopted for BRONJ, Schubert et al., 2012⁷. A varying success rate among cases reported in literature, average treatment success with conservative surgery and extensive surgery are 53% and 67%, respectively. Therefore, the study concluded that these are challenging diseases with no specific treatment, Ribeiro et al., 2018⁸.

The purpose of this paper is to relate a case about BRONJ treatment in a myeloma multiple patient in use of ZA that attended for our evaluation.

A 76-year-old male patient attended for our evaluation complaining of pain in his mouth after 8 months having consulted with several professionals. The medical history showed multiple myeloma metastasis and the use of BP, more specifically the ZA for metastasis control. On intraoral clinical evaluation, suppuration and exposed bone was evident on posterior left mandible measuring approximately 4 centimeters. On panoramic radiograph, we observed a radiolucent image and an area of osseous trabeculae disorganization on left mandible (figure 1).

Computed Tomography (CT) image showed some destruction of lingual and buccal cortical, suggestive of bone sequestration (figure 1). Based on clinical and imaging features, treatment consisted on remove all necrotic bone and fill the defect with FRP from the patient's own blood. Sutures were placed to provide wound primary closure (figures 2 and 3). Intra oral soft tissue showed signs of favorable healing (figure 4).

After 2 months without evidence of exposed bone, the patient came complaining with pain again. After a panoramic radiograph, it was clearly observed a radiolucent image with an image of a jaw discontinuity line, suggestive of mandible fracture in the same side treated before. Therefore, under general anesthesia, new surgery was performed, however, as the intraoral mucosa was perfectly healthy, it was an extraoral access in this time. All the necrotic bone was removed and titanium plates were placed for favoring bone consolidation (figure 5).

After 3 months following up, there were signs of bone consolidation and no pain complaint by patient. The intraoral mucosa remained intact and no bone exposure was observed until 7 months following up. The patient was able to eating properly and had his quality of life improved (figure 6).

Current studies found in literature indicate BRONJ lesions treatment with PRP and platelet-rich fibrin (PRF). Very few studies report the use of FRP. With this case report we have demonstrated the possibility that this treatment can be effective and promising. Valente et al., 2019⁹, performed a retrospective study that analyzed records from patients with documented ARONJ treated in their unit. They analyzed data between June 2016 and January 2017of 15 patients, with mean age of 64 years. About 60% of the sample used zolendronate or denosumab and causative factors like dental extraction trigger rate of 33.3%, a spontaneous ARONJ 40%. Treatment success rate of 73.3%, but the authors report that the surgical treatment had to be repeated more than once. Of 14 cases that were treated with PRF following bone debridement led to the resolution of 11 patients (78,6%). Failure in this study rate of 26.6%, so, they concluded that PRF showed potential benefits in the in ARONJ resolution, but make it clear that this treatment has to be investigate in future studies.

Until now we didn't find many studies about FRP and osteonecrosis. Another preventive study with PRF was authored by of Asaka et al. 2017¹⁰, that had an objective to evaluate the effectiveness of PRF as a healing accelerating agent in patients undergoing oral BP therapy (average of 32 months of use) and requiring dental extractions. They analyzed 102 patients divided into a PRF group and control group. There were no intraoperative complications and none of the patients had onset BRONJ. Delayed recovery was observed in 9 of 73 control patients (12%) and this was significantly higher in the control group than in the PRF group. The authors concluded that early epithelialization has been confirmed in all patients and that PRF may reduce the risk of delayed recovery in patients undergoing oral BP therapy and play a key role in preventing BRONJ.

Much has also been said about the role of leukocyte-rich and platelet-rich fibrin (L-PRF) in the treatment of BRONJ. Given the controversy and current lack of consensus regarding BRONJ therapy in patients, new techniques have been developed including the use of L-PRF. The purpose of the review by Cano-Durán et al. 2017¹¹, was to evaluate whether L-PRF would be really effective in BRONJ. The results showed that the use of L-PRF for the treatment of BRONJ is really effective, especially when performed with simultaneous application of L-PRF and morphogenetic protein-2 (BMP-2). Therefore, the authors concluded that the current literature demonstrates the efficacy of L-PRF use in osteonecrosis, and that can be considered a real alternative in the treatment of this disease. However, more clinical studies are needed to really evaluate this new therapy and success depends on several factors, such as the previous existence of infection or the clinical stage the patient is in.

The analysis of our study can set the standard for the initiation of new studies that aim to seek the effectiveness in the treatment of BRONJ, since there is no fully effective one reported to date. According to current studies, platelet concentrates have been widely used in a variety of medical fields to promote soft and hard tissue regeneration by generating many growth factors and promoting wound healing; which is also found in the FRP, Babade et al., 2016¹².

In this particular case, as FRP initially helped complete healing of intraoral soft tissue, extraoral access was a more palatable option on second surgery for removal all affected bone tissue. However, even if the use of plates is not very common in patients using or who have already used BP, in this case it was the only option for a possible bone consolidation in the mandibular fracture region. Therefore, after 3 months by titanium plates placed, there were signs of bone consolidation. The patient was able to eating properly and had his quality of life improved, with no pan complaint or other complications.


	Ricardo, Ramalho; https://orcid.org/0000-0002-2338-5535
	Thaís, Miniello; https://orcid.org/0000-0002-0670-5373