/home/opencode/cpanel/stomaeduj_hacked/uploads/2019/10/art-Chandra-193-198.pdf MAXILLOFACIAL SURGERY DOWNGRADING ADVANCED STAGE MEDICATION RELATED OSTEONECROSIS OF Case Rreports JAW (MRONJ) USING PEDICLED FLAP- TECHNICAL REVIEW WITH CASE REPORT Srinivasa Rama Chandra1a* , Holley Tyler J1b, Ruxandra-Gabriela Coropciuc2c , Constantinus Politis2,3d 1 Division of Oral & Maxillofacial Surgery, Department of Surgery, College of Medicine, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 984125, Omaha, NE 68198, USA 2 Department of Oral & Maxillofacial Surgery, Faculty of Medicine, University Hospitals Leuven, UZ Leuven, Campus Sint-Rafaël, Kapucijnenvoer 33, BE-3000 Leuven, Belgium 3 OMFS IMPATH research group, Department of Imaging & Pathology, Faculty of Medicine, KU Leuven, Campus Sint-Rafaël, Kapucijnenvoer 33, BE-3000 Leuven, Belgium a MD, BDS, FDSRCS(Eng), FIBCSOMS(Onc-Recon), Assistant Professor b MD, DDS, Resident Surgeon c MD, DDS, Staff Member d MD, DDS, MHA, MM, PhD, Professor and Head ABSTRACT DOI: https://doi.org/10.25241/stomaeduj.2019.6(3).art.6 OPEN ACCESS This is an Open Access article under the CC BY-NC 4.0 license. Introduction: Medication related osteonecrosis of the jaw (MRONJ) is a Peer-Reviewed Article locally destructive, and potentially devastating disease process that occurs Citation: Chandra SR, Tyler H, Coropciuc R-G, Politis C. in patients with a history of antiresorptive or antiangiogenic therapy. A Downgrading advanced stage Medication Related Osteonecrosis of Jaw (MRONJ) using pedicled flap- Technical review with case widely accepted practice of surgical intervention in the management of report.Stoma Edu J. 2019;6(3):193-198. advanced stage MRONJ involves segmental resection of the affected bone. Received: September 08, 2019 Aim: We propose to downgrade the stage with pedicled flaps for Revised: September 18, 2019 Accepted: September 24, 2019 eradication of biofilm and vascular coverage with load sharing or load Published: September 25, 2019 bearing constructs of the skeleton. As patients that receive antiresorptive *Corresponding author: or antiangiogenic therapy often have multiple medical comorbidities, this Srinivasa R. Chandra, MD, BDS, FDSRCS(Eng), FICSOMS (Onc-Recon) limits their surgical options and precludes them from being able to undergo Head and Neck Oncology and Microvascular Reconstructive Surgery expansive segmental resections or microvascular free tissue transfers and | Fred & Pamela Buffett Cancer Center| Asst. Prof of Surgery, Div. of OMFS, Dept. of Surgery; are left with palliative measures, thus compromising their care. Adjunct appointment in Dermatology; University of Nebraska Medical Center, 984125 Summary: Either concept of MRONJ progression- bone metabolism Omaha, NE 68198, USA or vascular breakdown is treated with immediate advancement of a Tel: / Fax: 402.559.5600, e-mail: srinivasa.chandra@unmc.edu pedicled local tissue flap and is performed for soft tissue coverage, thus Copyright: © 2019 the Editorial Council for the Stomatology Edu Journal. providing a new vascular envelope and decreasing soft tissue toxicity to halt furtherance of the disease. Submental island flaps, nasolabial flaps, pedicled buccal fat pad flaps, and facial artery musculomucosal flaps have demonstrated success for longer than two years. This technique addresses downgrading MRONJ stage II and III in the mandible as a possible long- term treatment. This unreported innovative approach consists of marginal resection of the involved alveolar bone, while preserving the affected basal bone and subsequently provides reinforcement with a titanium bone plate, decreasing the chance of pathologic fracture. Keywords: MRONJ; Flap; Pedicled flap; Medication related osteonecrosis of the jaw; Bisphosphonate related osteonecrosis of the jaw. 1. Introduction a precipitating trauma to the maxilla or mandible, Medication related osteonecrosis of the jaw such as a dentoalveolar procedure [1,2]. MRONJ has (MRONJ) is defined as exposed or probable bone a spectrum of presentation, as represented in its in the maxillofacial region without resolution in staging [1]: 8-12 weeks in persons with a history of treatment MRONJ Staging with an antiresorptive or antiangiogenic therapy At Risk: No apparent necrotic bone in patients who who have not received radiation therapy to the have been treated with oral or IV bisphosphonates. jaws [1]. This is an iatrogenic process with an Stage 0: No clinical evidence of necrotic bone, but elevated potential for morbidity and decreased non-specific clinical findings, radiographic changes quality of life. MRONJ typically occurs in patients and symptoms with a history of long-term bisphosphonate, RANK Stage 1: Exposed and necrotic bone for more than ligand inhibitor, or angiogenesis inhibitor use with 8 weeks, or fistulae that probes to bone in patients Stomatology Edu Journal 193 DOWNGRADING ADVANCED STAGE MEDICATION RELATED OSTEONECROSIS OF JAW (MRONJ) USING PEDICLED FLAP- TECHNICAL REVIEW WITH CASE REPORT Case Rreports Table 1. Summary of the stages 0-3 on the left column; middle column is the current and the right column proposes the modification in management especially in the stage 2 & 3. MRONJ Staging Standard Treatment Strategies Proposed Treatment Strategies At Risk: No apparent necrotic bone in - No Treatment indicated No changes patient who have been treated with oral - Patient education or IV bisphosphonates. Stage 0: No clinical evidence of necrotic Systemic management No changes bone, but non-specific clinical findings, - Analgesics radiographic changes and symptoms - Antibiotics Stage 1: Exposed and necrotic bone, or - Antibacetial mouth rinse No changes fistulae that probe to bone in patients - Clinical follow-up who are asymptomatic and have no - Patient education and review of evidence of infection indications for antiresorptive and antiangiogenic therapies. Stage 2: Exposed and necrotic bone, or - Symptomatic treatment with oral - Symptomatic treatment fistulae that probe to bone, associated antibiotics with oral antibiotics with infection as evidenced by pain and - Oral antibacterial mouth rise - Oral antibacterial mouth erythema in the region of the exposed - Pain control rise bone with or without purulent drainage - Debridement to relieve soft tissue - Pain control irritation and infection control - Debridement of alveolar bone and immediate advancement of a pedicled local tissue flap Stage 3: Exposed and necrotic bone or - Antibacterial mouth rinse - Antibacterial mouth rinse fistula that probes to bone in patients - Antibiotic therapy and pain control - Antibiotic therapy and pain with pain, infection, and one or more of - Surgical debridement /resection control the following: exposed or necrotic bone for linger term palliation of infection - Surgical debridement / extending beyond the region of the and pain resection of alveolar bone, alveolar bone, resulting in pathologic leaving basilar bone intact, fracture, extra-oral fistula, oroantral/ placement of a supra or oronasal communication, or osteolysis subperiosteal titanium extending to the inferior boarder of the bone plate and immediate mandible or sinus floor. advancement of a pedicled local tissue flap Table 2. The table highlights the advantages to the Table 3. Key notable points prior to sequestrum removal vascular flap coverage to MRONJ management. and vascular coverage of MRONJ. Advantages of Vascular Coverage Critical Steps Prior to Vascular Soft Tissue Coverage 1. Improved blood supply to underlying bone 1. Obtain cultures 2. Improved medication delivery to underlying bone 2. Review imaging to determine the presence of 3. Eradication of chronic biofilm colonization pathologic fracture or need for internal fixation 4. Decreased inflammation 3. Biopsy for recurrence of neoplastic process. 5. Halts disease progression Example– recurrence of multiple myeloma who are asymptomatic and have no evidence of To date, there is no consensus on the MRONJ stage III infection treatment protocol. Stage 2: Exposed and necrotic bone, or fistulae The current management options range from the that probe to bone, associated with infection as non-invasive, antibacterial mouth rinse, systemic evidenced by pain and erythema in the region of the treatment with oral antibiotics, and close follow up, exposed bone with or without purulent drainage to invasive management of potentially extensive Stage 3: Exposed and necrotic bone or fistula that debridement/resection of the maxilla or mandible. probes to bone in patients with pain, infection, and Conservative therapy is defined as no surgical one or more of the following: exposed or necrotic intervention. This category includes the use of bone extending beyond the region of the alveolar antibacterial mouth rinses and antibiotics and the bone, resulting in pathologic fracture, extra-oral removal of sequestra without local anesthetics. fistula, oroantral/oronasal communication, or Ozone therapy and hyperbaric oxygen therapy are osteolysis extending to the inferior boarder of the considered conservative therapeutic approaches, mandible or sinus floor. even though for neither of these evidence-based 194 Stoma Edu J. 2019;6(3): 193-198. http://www.stomaeduj.com DOWNGRADING ADVANCED STAGE MEDICATION RELATED OSTEONECROSIS OF JAW (MRONJ) USING PEDICLED FLAP- TECHNICAL REVIEW WITH CASE REPORT Case Rreports Figure 1. MRONJ and bony sequestrum of right mandible in patient with history of antiangiogenic therapy. proof of benefit is available. Conservative surgical therapy is defined as a sequestrectomy, without resection or removal of non-sequestrated bone. Figure 2. Resection of necrotic alveolar bone is done, basal bone Whenever no mucoperiostal flap is used a retained can be reinforced by plating (load bearing or sharing as needed) sequestrectomy is considered limited surgical and submental island flap harvested using the same neck incision. therapy. Invasive surgical treatment includes anything from a sequestrectomy (starting with the use of mucoperiostal flaps), with a resection of the typically have numerous medical co-morbidities affected bone up to the bleeding margins of bone, to that often do not allow them to undergo extensive segmental mandibulectomies and reconstructions debridement/resection of the affected bone and with pedicled or microvascular free flaps. reconstruction. Patients who are not able to undergo Conservative management alone is insufficient to their indicated surgical treatment typically suffer achieve full mucosal healing, but can be useful to deterioration of MRONJ and their antiresorptive or stabilize disease progression in patients unfit for antiangiogenic therapy is often discontinued. This surgery. The use of hyperbaric oxygen therapy has leaves the patient vulnerable to advancement of no role in MRONJ grade III. The conservative surgical their cancer-related condition and their inadequate approach provides better results than a purely treatment allows for progression of MRONJ leading conservative approach: 75% achieve an improved to involvement of previously unaffected bone, condition, and of these, 54% achieve full mucosal pathologic fractures and extra-oral and oronasal/ healing. However, this group consists of a relatively oroantral fistula development. Soft tissue toxicity has small number of patients (n=48, distributed over been proposed in the pathogenesis of MRONJ. The four studies) [3,4,5]. The best treatment results for mechanism is thought to involve the toxic effects MRONJ stage III are observed in patients treated of deposited bisphosphonates to local soft tissue with invasive surgery. Invasive surgery without and this might contribute to osteonecrosis of the microvascular flap reconstruction yields a full jaw (ONJ) [2,15,16]. The inhibition of a variety of cell mucosal healing rate of 85%, when six studies are types to grow on bone surfaces previously treated combined [6-11]. This approach outperforms the with bisphosphonates has been demonstrated [17]. 54% healing rate achieved with the limited surgical However, no tissue toxicity has been reported with approach. This finding suggests that extensive RANK-L inhibitors. Given these considerations, we bony resection up to the bleeding margins is more have developed a less invasive technique for the efficient than a sequestrectomy to achieve full treatment of MRONJ while providing a vascularized mucosal healing in MRONJ stage III. Invasive surgery soft tissue envelope and down grading the disease, with microvascular flap reconstruction yields even irrespective of the cause of MRONJ. better results, with a full mucosal healing rate of 97% [12,13]. However, many patients cannot undergo this 2. Technique kind of procedure, due to underlying comorbidity The current standard practice in the treatment of [14]. Bisphosphonate, RANK ligand inhibitor, and MRONJ is to resect the affected portion of the jaws angiogenesis inhibitors are most commonly used for until the necrotic portion has been removed and cancer-related conditions, and thus these patients bleeding bone is encountered [18]. As MRONJ is Stomatology Edu Journal 195 DOWNGRADING ADVANCED STAGE MEDICATION RELATED OSTEONECROSIS OF JAW (MRONJ) USING PEDICLED FLAP- TECHNICAL REVIEW WITH CASE REPORT a generalized affliction of the skeleton, the idea special precautions during administration [19]. Case Rreports of debridement is to eradicate the biofilm of the One of the facets to our proposed technique is exposed bone and aid in soft tissue coverage. In to provide a new soft tissue envelope by way of patients with progressive or advanced stages of the advancing a pedicled flap. This not only provides a disease, large amounts of the supporting basilar more robust blood supply to the underlying bone, bone is often removed, creating a loss of structure but it allows for increased delivery of medications. and scaffolding for the surrounding soft tissues. It also eradicates the chronic colonization of debris In these cases, we propose solely removing the and biofilm that causes persistent inflammation. Our affected alveolar portion of the bone, leaving the observations show that this technique has been able affected portions of basilar bone intact (Table I). to halt furtherance of the disease. Due to the inherent lack of strength of the necrotic As previously discussed, MRONJ has a spectrum of basilar bone, a supra or subperiosteal titanium bone presentation, as represented in its staging. Multiple plate is placed spanning the length of the affected studies have suggested treatment of the early portion of the jaw. stage MRONJ as more significant debilitation to the This plate is anchored with bicortical locking screws quality of life and pathological fractures happen on the proximal and distal aspects of the span. in advanced stages of MRONJ. By removing the From there, soft tissue coverage is provided by overlying infected soft tissue, debriding the alveolar way of a pedicled local flap (Table II), Depending bone and providing a new soft tissue coverage, on the location and size of the soft tissue defect, a this technique successfully downgrades MRONJ flap is raised and rotated over the soft tissue defect, to a less severe state so that local measures, such creating a tension-free closure. Submental island as antibacterial mouth wash, are able to keep the flaps, nasolabial flaps, pedicled buccal fat pad flaps, symptom manageable. and facial artery musculomucosal flaps can be used Several other authors agree that a new vascular to cover the defect. soft tissue coverage is essential to the long-term Local pedicled flaps also help in oroantral fistulas treatment of MRONJ (Table III) [20]. Commonly and tori coverage. So far three patients with stage III clinic based plain panoramic imaging in outpatients MRONJ have been treated with this technique with and cone beam computed tomographic imaging a minimum follow-up of 13 months. All patients may be adequate to monitor bone status if there is kept the necrotic basilar bone, protected by a lower appropriate soft tissue coverage. border reconstruction plate, and no intraoral fistula Bone isotope studies are more specific for the recurred during the follow-up period. The technique turnover with biocontamination of the exposed is depicted in Figures 1-2. bone. Additionally, osteoporosis from bacterial biofilm burden of the area is reduced from good 3. Discussion vascularized soft tissue coverage as proposed here. MRONJ has several proposed hypotheses of pathophysiology, including bone remodeling 4. Conclusion inhibition, inflammation and infection, angiogenesis This technique demonstrates a novel approach to in inhibition, and immunity disfunction. MRONJ treatment. Our more conservative technique Given the fact that MRONJ occurs in patients with of alveolar bone debridement, leaving the basilar a history of antiresorptive and antiangiogenic bone intact, placement of a titanium bone plate for therapies and a host of different backgrounds most reinforcement and advancement of a local tissue authors agree that the MRONJ pathogenesis is likely flap for soft tissue coverage is ideal for patients multifactorial. who are unable to undergo a microvascular free One of the earlier noted hypotheses was that tissue transfer or who should not terminate their bisphophates, especially nitrogen-containing antiresorptive or antiangiogenic therapy. bisphosphonates, caused direct soft tissue toxicity, inducing apoptosis and decreased proliferation of Conflict of Interest oral epithelial cells [2,15]. Invitro studies demonstrate All authors have no conflict of interest to declare. that nitrogen containing bisphosphonates localize to epithelial tissue and bone and that alendronate Funding is associated with esophageal irritation, requiring No sources of funding were obtained for this study. 196 Stoma Edu J. 2019;6(3): 193-198. http://www.stomaeduj.com DOWNGRADING ADVANCED STAGE MEDICATION RELATED OSTEONECROSIS OF JAW (MRONJ) USING PEDICLED FLAP- TECHNICAL REVIEW WITH CASE REPORT References Case Rreports 1. Ruggiero SL, Dodson TB, Fantasia J, et al. American 11. Pichardo SE, Kuijpers SC, Van Merkesteyn JP. Association of Oral and Maxillofacial Surgeons position Bisphosphonate-related osteonecrosis of the jaws: Cohort paper on medication-related osteonecrosis of the jaw-- study of surgical treatment results in seventy-four stage II/ 2014 update. J Oral Maxillofac Surg. 2014;72(10):1938-1956. III patients. J Craniomaxillofac Surg. 2016;44(9):1216-1220. [CrossRef ] Google Scholar Scopus [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus 2. Reid IR, Cornish J. Epidemiology and pathogenesis of 12. Mücke T, Jung M, Koerdt S, et al. Free flap reconstruction for osteonecrosis of the jaw. Nat Rev Rheumatol. 2011;8(2):90-96. patients with bisphosphonate related osteonecrosis of the jaws [CrossRef ] Google Scholar Scopus after mandibulectomy. J Craniomaxillofac Surg. 2016;44(2):142-147. 3. Coropciuc RG, Grisar K, Aerden T, et al. Medication- [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus related osteonecrosis of the jaw in oncological patients 13. Caldroney S, Ghazali N, Dyalram D, Lubek JE. Surgical with skeletal metastases: conservative treatment is effective resection and vascularized bone reconstruction in up to stage 2. Br J Oral Maxillofac Surg. 2017;55(8):787-792. advanced stage medication-related osteonecrosis of [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus the jaw. Int J Oral Maxillofac Surg. 2017;46(7):871-876. 4. Aljohani S, Gaudin R, Weiser J, et al. Osteonecrosis of the [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus jaw in patients treated with denosumab: A multicenter 14. Sacco R, Sacco N, Hamid U, et al. Microsurgical case series. J Craniomaxillofac Surg. 2018;46(9):1515-1525. reconstruction of the jaws using vascularised free flap [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus technique in patients with medication-related osteonecrosis: 5. Nisi M, Karapetsa D, Gennai S, et al. Conservative surgical a systematic review. Biomed Res Int. 2018;2018:9858921. treatment of medication related osteonecrosis of the [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus jaw (MRONJ) lesions in patients affected by osteoporosis 15. Reid IR, Bolland MJ, Grey AB. Is bisphosphonate- exposed to oral bisphosphonates: 24 months follow- associated osteonecrosis of the jaw caused by up. J Craniomaxillofac Surg. 2018;46(7):1153-1158. soft tissue toxicity? Bone. 2007;41(3):318-320. [Full text links] [CrossRef ] [PubMed] Google Scholar [Full text links] [CrossRef ] [PubMed] Google Scholar 6. Lopes RN, Rabelo GD, Rocha AC, et al. Surgical 16. Landesberg R, Cozin M, Cremers S, et al. Inhibition of oral therapy for bisphosphonate-related osteonecrosisof mucosal cell wound healing by bisphosphonates. J Oral Maxillofac the jaw: six-year experience of a single institution. Surg 66:839, 2008. J Oral Maxillofac Surg. 2008;66(5):839-847. J Oral Maxillofac Surg. 2015;73(7):1288-1295. [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus [Full text links] [CrossRef ] [PubMed] Google Scholar 17. Cornish J, Bava U, Callon K, et al. Bone-bound 7. Favia G, Tempesta A, Limongelli L, et al. Medication- bisphosphonate inhibits growth of adjacent related osteonecrosis of the jaw: surgical or non- non-bone cells. Bone. 2011;49(4):710-716. surgical treatment? Oral Dis. 2018;24(1-2):238-242. [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus [CrossRef ] Google Scholar Scopus 18. Carlson ER, Basile JD. The role of surgical resection in 8. Blus C, Giannelli G, Szmukler-Moncler S, Orru G. Treatment the management of bisphosphonate-related osteonecrosis of medication-related osteonecrosis of the jaws (MRONJ) of the jaws. J Oral Maxillofac Surg. 2009;67(5 Suppl):85-95. with ultrasonic piezoelectric bone surgery. A case series [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus of 20 treated sites. Oral Maxillofac Surg. 2017;21(1):41-48. 19. Watts NB, Diab DL. Long-term use of bisphosphonates in [Full text links] [CrossRef ] [PubMed] Google Scholar osteoporosis. J Clin Endocrinol Metab. 2010;95(4):1555-1565. 9. Berrone M, Florindi FU, Carbone V, et al. Stage 3 medication- [Full text links] [CrossRef ] [PubMed] Google Scholar related osteonecrosis of the posterior maxilla: Surgical 20. Khan AA, Morrison A, Hanley DA, et al. Diagnosis and treatment using a pedicled buccal fat pad flap: Case management of osteonecrosis of the jaw: A systematic review Reports. J Oral Maxillofac Surg. 2015;73(11):2082-2086. and international consensus. J Bone Miner Res. 2015;30(1):3-23. [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus 10. Klingelhöffer C, Zeman F, Meier J, et al. Evaluation of surgical outcome and influencing risk factors in patients with medication-related osteonecrosis of the jaws. J Craniomaxillofac Surg. 2016;44(10):1694-1699. [Full text links] [CrossRef ] [PubMed] Google Scholar Scopus Srinivasa Rama CHANDRA MD, BDS, FDSRCS(Eng), FICSOMS(Onc-Recon) Assistant Professor Head and Neck Oncology and Microvascular Reconstructive Surgery Fred & Pamela Buffett Cancer Center| Division of Oral & Maxillofacial Surgery Department of Surgery, College of Medicine Adjunct appointment in Dermatology University of Nebraska Medical Center, 984125 Omaha, NE 68198, USA CV Dr. Srinivasa Rama Chandra is a Maxillofacial Surgery Specialist in Seattle, Washington. Having more than 24 years of wide experience, especially in Maxillofacial Surgery, Dr. Srinivasa Rama Chandra is affiliated with the Head and Neck Oncological and Microvascular reconstructive surgery at the Fred and Buffett Cancer Center and collaboratively operates with surgical oncologists, neurosurgeons and dermatologists. Srinivasa Rama Chandra currently works at the Head and Neck Oncology and Reconstructive Microvascular- Oral and Maxillofacial Surgery, University of Nebraska Medical Center. Srinivasa conducts research in Head and Neck Oncology, Oral and Maxillofacial Surgery and Pathology. He specializes in Reconstructive, open skull base access and reconstruction, dermatological pathology and has additional appointment in dermatology. Stomatology Edu Journal 197 DOWNGRADING ADVANCED STAGE MEDICATION RELATED OSTEONECROSIS OF JAW (MRONJ) USING PEDICLED FLAP- TECHNICAL REVIEW WITH CASE REPORT Questions Case Rreports 1. MRONJ in which there is exposed and necrotic bone, or fistulae that probes to bone, associated with infection as evidenced by pain and erythema in the region of the exposed bone with or without purulent drainage is: qa. MRONJ stage 0; qb. MRONJ stage 1; qc. MRONJ stage 2; qd. MRONJ stage 3. 2. Denosumab (monoclonal antibody) inhibits maturation of osteoclasts by binding to and inhibiting: qa. RANK-Ligand; qb. Osteoprotegerin; qc. WNT-ligand; qd. Sclerostin. 3. One of following treatments does not belong to the standard of care in MRONJ: qa. Hyperbaric oxygen; qb. Antibiotics; qc. Sequestrectomy; qd. Regional or distant soft tissue flaps. 4. XGEVA® is a: qa. Nitrogen containing bisphosphonate; qb. Non-nitrogen nitrogen containing bisphosphonate; qc. Diphosphonic acid; qd. Fully human monoclonal antibody to RANKL. www.bds.dentaleaders.com 198 Stoma Edu J. 2019;6(3): 193-198. http://www.stomaeduj.com