art-Chandra-193-198
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
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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
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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
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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.
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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