2022 Aaoms意见书：药物相关性颌骨坏死（更新版）

PATHOLOGY
1 57
2 58
3 59
4
5
American Association of Oral and 60
61
6
7 Maxillofacial Surgeons’ Position Paper 62
63
8 64
9 on Medication-Related Osteonecrosis 65
10 66
11 Q1 of the Jaw—2022 Update 67
12 68
13 Q12 Salvatore L. Ruggiero, DMD, MD,* Thomas B. Dodson, DMD, MPH,y 69
14 Tara Aghaloo, DDS, MD, PhD,z Eric R. Carlson, DMD, MD, EdM,x 70
15 Brent B. Ward, DDS, MD,k and Deepak Kademani, DMD, MD# 71
16 72
17 Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaws 73
18 (MRONJ) – formerly referred to as bisphosphonate-related osteonecrosis of the jaws (BRONJ)—were set 74
19 forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007, 75
20 Q9 2009 and 2014. The position papers were developed by a committee appointed by the AAOMS Board 76
21 of Trustees and comprising clinicians with extensive experience in caring for these patients, as well as clin- 77
22 ical and basic science researchers. The knowledge base and experience in addressing MRONJ continues to 78
23 evolve and expand, necessitating modifications and refinements to the previous position papers. Three 79
24 members of the AAOMS Committee on Oral, Head, and Neck Oncologic and Reconstructive Surgery (COH- 80
25 NORS) and three authors of the 2014 position paper were appointed to serve as a working group to analyze 81
26 the current literature and revise the guidance as indicated to reflect current knowledge in this field. This 82
27 update contains revisions to diagnosis and management strategies and highlights the current research sta- 83
28 tus. AAOMS maintains that it is vitally important for this information to be disseminated to other relevant 84
29 healthcare professionals and organizations. 85
30 Ó 2022 American Association of Oral and Maxillofacial Surgeons 86
31 J Oral Maxillofac Surg -:1-24, 2022 87
32 88
33 Medications prescribed for dental and medical condi- wide and complications are readily corrected, deci- 89
34 tions have potential side effects that warrant a risk- sions are implemented in a straightforward fashion. 90
35 benefit discussion. Where therapeutic margins are Where therapeutic margins are wide but 91
36 92
37 *Clinical Professor, Division of Oral and Maxillofacial Surgery, Private practice, Minnesota Oral and Facial Surgery and Minnesota 93
38 Stony Brook School of Dental Medicine, Hofstra North Shore-LIJ Head and Neck Surgery, Minneapolis, Minn. 94
39 School of Medicine, New York Center for Orthognathic and Conflict of Interest Disclosures: Dr Ruggiero serves as a consul- Q8 95
40 Maxillofacial Surgery, Lake Success, NY. tant for Amgen. Dr Dodson serves as a consultant for AAOMS. Dr 96
41 yProfessor and Chair, University of Washington School of Aghaloo has received research grant from OMSF and Amgen. Dr Carl- 97
42 Dentistry, Department of Oral and Maxillofacial Surgery, Seattle, son receives book royalties from Wiley Blackwell, Quintessence, and 98
43 Wash. Elsevier. Dr Ward serves as a consultant for AAOMS, AACMES, and 99
44 zProfessor, Oral and Maxillofacial Surgery, UCLA School of OsteoScience. Dr Kademani serves as a consultant for AAOMS and 100
45 Dentistry, Los Angeles, Calif. is the director of ABOMS. Q3 101
46 xProfessor and Kelly L. Krahwinkel Endowed Chairman, Address correspondence and reprint requests to Dr Ruggiero: 102
47 Department of Oral and Maxillofacial Surgery, University of Clinical Professor, Division of Oral and Maxillofacial Surgery, Stony 103
48 Tennessee Graduate School of Medicine, Knoxville, Tenn. Brook School of Dental Medicine, Hofstra North Shore-LIJ School 104
49 kChalmers J Lyons Professor of Oral and Maxillofacial Surgery, of Medicine, New York Center for Orthognathic and Maxillofacial 105
50 Associate Professor of Dentistry, Chair of the Department of Oral Surgery, Lake Success, NY; e-mail: sruggie@optonline.net 106
51 and Maxillofacial Surgery/ Hospital Dentistry in the School of Received December 29 2021 107
52 Dentistry and Associate Professor of Surgery for the Medical Accepted February 15 2022 108
53 School, University of Michigan Hospital, Ann Arbor, Mich. Ó 2022 American Association of Oral and Maxillofacial Surgeons 109
54 #Chief of Staff North Memorial Health, Fellowship Director, Oral/ 0278-2391/22/00148-3 110
55 Head and Neck Oncologic and Reconstructive Surgery Attending https://doi.org/10.1016/j.joms.2022.02.008 111
56 Surgeon, North Memorial Health and the University of Minnesota. 112
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113 complications are significant, deciding to proceed a. The differential diagnosis of MRONJ in pa- 169
114 with pharmacologic treatment becomes more chal- tients with a history of exposure to antiresorp- 170
115 lenging. In most cases of MRONJ, local therapies can tive medications. 171
116 be successful. The fact that more complex treatment b. MRONJ prevention measures and manage- 172
117 is required for a few patients should not impact ment strategies for patients with MRONJ 173
118 decision-making for all other patients with osteonecro- based on the disease stage. 174
119 sis of the jaws. The medications associated with 175
120 MRONJ have proved to be safe and effective in clinical 176
121 trials and postmarketing analyses for most patients and 177
122 should continue as a mainstay therapy when indi- 178
Medications Q4
123 cated. Communicating the risks of MRONJ to patients 179
124 and providers is critical to ensure appropriate medical Bisphosphonates (BPs) are antiresorptive medica- 180
125 management for the primary disease. tions that are effective in managing cancer-related con- 181
126 Undoubtedly, risk profiles may change as new med- ditions, including hypercalcemia of malignancy, spinal 182
127 ications come to market. In addition, our understand- cord compression, and pathologic fractures (skeletal- 183
128 ing of disease pathophysiology, risk modifiers, and related events [SREs]) associated with bone metastases 184
129 treatment strategies will continue to evolve. It is of in the context of solid tumors (such as breasxt, pros- 185
130 the utmost importance that clinicians base their pa- tate, and lung cancers) and multiple myeloma.4-13 186
131 tient treatment decisions on currently available scien- While the potential for BPs to improve cancer- 187
132 tific evidence. specific survival remains controversial, these medica- 188
133 Strategies for management of patients at risk for or tions have had a significant positive effect on the qual- 189
134 with MRONJ were set forth in American Association ity of life for patients with advanced cancer involving 190
135 of Oral and Maxillofacial Surgeons (AAOMS) Position the skeleton and reducing or preventing skeletal- 191
136 Papers in 2007,1 2009,2 and 2014.3 These position pa- related events. 192
137 pers were developed by a committee appointed by the Bisphosphonates also are used for the prevention of 193
138 AAOMS Board of Trustees and comprised of clinicians osteoporosis-related fractures (fragility fractures) in 194
139 with extensive experience in caring for these patients, patients with osteoporosis and osteopenia.14-16 BPs 195
140 as well as clinical and basic science researchers. The administered orally–including alendronate (Fosa- 196
141 knowledge base and experience in addressing MRONJ maxÒ), risedronate (ActonelÒ) or parenterally (zole- 197
142 continues to evolve and expand, necessitating modifi- dronic acid [ReclastÒ]), and ibandronate 198
143 cations and refinements to the previously published (BonivaÒ)—can result in a significant reduction in 199
144 position papers. A working group comprised of three vertebral and nonvertebral fractures for patients with 200
145 members of the AAOMS Committee on Oral, Head, and osteoporosis.17-20 201
146 Neck Oncologic and Reconstructive Surgery (COH- Bisphosphonate therapy also is indicated for other 202
147 NORS) and three authors of the 2014 paper convened metabolic bone diseases such as Paget’s disease of 203
148 remotely in the fall of 2020 to appraise the current bone and osteogenesis imperfecta.21-23 However, 204
149 literature and revise the guidelines as indicated to clinical trials have not demonstrated the efficacy of 205
150 reflect the current knowledge in this field. This update bisphosphonate therapy in the management of 206
151 contains revisions to the pathogenesis and manage- fibrous dysplasia.24 207
152 ment strategies and highlights the current research sta- Denosumab (DMB), a receptor activator of nuclear 208
153 tus. AAOMS maintains it is vitally important for this factor kappa-B ligand (RANK-L), is an antiresorptive 209
154 information to be disseminated to other relevant agent that exists as a fully humanized antibody against 210
155 healthcare professionals and organizations. RANK ligand and inhibits osteoclast function and asso- 211
156 ciated bone resorption. When denosumab (ProliaÒ) is 212
157 administered subcutaneously every 6 months, there is 213
158 PURPOSE a significant reduction in the risk of vertebral, nonver- 214
159 The purpose of this position paper is to provide up- tebral, and hip fractures in osteoporotic patients.25-28 215
160 dates regarding: Denosumab (XgevaÒ) also is effective in reducing 216
161 SREs related to metastatic bone disease from solid 217
162 1. Risk estimates for developing MRONJ. tumors when administered monthly.29-31 218
163 2. Comparisons of the risks and benefits of medica- RANK ligand inhibitors also have proven efficacy in 219
164 tions related to osteonecrosis of the jaw in order the treatment of giant cell tumors of bone and fibrous 220
165 to facilitate medical decision-making for the treat- dysplasia.32-36 In contrast to BPs, RANK-L inhibitors do 221
166 ing physician, dentist, dental specialist, and pa- not bind to bone, and their effects on bone remodeling 222
167 tient with the establishment of algorithms. are mostly diminished within 6 months of treat- 223
168 3. Guidance to clinicians regarding: ment cessation. 224

RUGGIERO ET AL 3
225 Romosozumab is a new monoclonal antibody used tient at risk, but the diagnostic information is not 281
226 for fracture prevention in osteoporotic women. Romo- conclusive.39 AAOMS believes the Stage 0 category 282
227 sozumab, administered subcutaneously, works via the for MRONJ is analogous in principle and does account 283
228 Wnt pathway by binding to and inhibiting sclerostin, for the wide-ranging radiographic presentation of 284
229 resulting in increased bone formation and decreased MRONJ that exists prior to overt bone exposure. 285
230 bone resorption.37 Therefore, AAOMS has decided to maintain the current 286
231 classification system with no modifications. 287
232 MRONJ Case Definition 288
233 PATIENTS AT-RISK 289
234 MRONJ should be distinguished from other forms of No apparent necrotic bone in asymptomatic pa- 290
235 osteonecrosis (ONJ) conditions and identified by his- tients who have been treated with IV or oral antire- 291
236 tory and clinical exam. The clinical criteria required sorptive therapy. 292
237 to establish a diagnosis of MRONJ have remained un- 293
238 changed from the previous position paper.3 STAGE 0 (NONEXPOSED BONE VARIANT) 294
239 The case definition of MRONJ includes all the 295
Patients with no clinical evidence of necrotic bone
240 following elements: 296
but who present with nonspecific symptoms or clin-
241 297
1. Current or previous treatment with antiresorp- ical and radiographic findings, such as:
242 298
243 tive therapy alone or in combination with im- 299
mune modulators or antiangiogenic medications. Symptoms
244 300
245 2. Exposed bone or bone that can be probed 301
Odontalgia not explained by an odontogenic
246 through an intraoral or extraoral fistula(e) in 302
cause.
247 the maxillofacial region that has persisted for 303
Dull, aching bone pain in the jaw, which may
248 more than 8 weeks. 304
radiate to the temporomandibular joint region.
249 3. No history of radiation therapy to the jaws or 305
Sinus pain, which may be associated with inflam-
250 metastatic disease to the jaws. 306
mation and thickening of the maxillary sinus wall.
251 307
Altered neurosensory function.
252 308
253 309
Staging
254 310
255 A staging system for MRONJ was introduced in the Clinical Findings 311
256 2009 AAOMS position paper and then modified in 312
Loosening of teeth not explained by chronic peri-
257 the 2014 position paper to characterize more accu- 313
odontal disease.
258 rately all aspects of the clinical presentation of MRONJ. 314
259 Intraoral or extraoral swelling. 315
Since these modifications, the AAOMS staging system
260 has continued to be a straightforward and relevant sys- 316
261 tem to properly stratify these patients. It has been 317
262 adopted by several professional societies and research Radiographic Findings 318
263 organizations. The staging system facilitates the crea- 319
264 tion of rational treatment guidelines and guides data Alveolar bone loss or resorption not attributable 320
265 collection to assess the prognosis and outcomes for to chronic periodontal disease. 321
266 MRONJ patients. While AAOMS recognizes that Changes to trabecular pattern sclerotic bone and 322
267 different classification systems are being used by other no new bone in extraction sockets. 323
268 organizations,38 the Association considers the AAOMS Regions of osteosclerosis involving the alveolar 324
269 system to be a useful and widely implemented assess- bone and/or the surrounding basilar bone. 325
270 ment tool guiding clinicians involved in the care of Thickening/obscuring of periodontal ligament 326
271 MRONJ patients. AAOMS remains concerned that over- (thickening of the lamina dura, sclerosis, and 327
272 emphasizing variable radiographic features often decreased size of the periodontal ligament 328
273 attributed to MRONJ may overestimate the true dis- space).40 329
274 ease frequency by including false positives in the 330
275 numerator (eg, cases with radiographic findings sug- These nonspecific findings, which characterize this 331
276 gestive of MRONJ), but these patients do not fit the variant of MRONJ without bone exposure, may occur 332
277 criteria for the diagnosis of MRONJ. In the orthopedic in patients with a prior history of Stage 1, 2, or 3 dis- 333
278 literature, the usefulness of a Stage 0 category has been ease who have been healed and have no clinical evi- 334
279 established for staging avascular necrosis (AVN) of the dence of exposed bone. Progression to Stage 1 335
280 femoral head when there is a suspicion of AVN in a pa- disease has been reported in up to 50 percent of 336

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337 patients with Stage 0 disease41 and, therefore, AAOMS to an antiresorptive medication. Studies have reported 393
338 deems it prudent to consider Stage 0 disease as a po- jaw necrosis in antiresorptive na€ıve patients in which 394
339 tential precursor to MRONJ. necrosis was linked to bacterial, viral, or fungal infec- 395
340 tions, trauma, smoking, steroids, immunocompro- 396
341 STAGE 1 mised host, autoimmune diseases, diabetes, and 397
342 Exposed and necrotic bone or fistula that probes to chemotherapy.43-57 Furthermore, patient 398
343 the bone in patients who are asymptomatic and have populations, such as those with osteogenesis 399
344 no evidence of infection/inflammation. These patients imperfecta have been treated with antiresorptive 400
345 also may present with radiographic findings agents without reports of MRONJ.58 Many patients 401
346 mentioned for Stage 0 that are localized to the alveolar receiving medications associated with MRONJ have 402
347 bone region. other comorbidities, which are likely exacerbating or 403
348 contributing factors. In combination, these confound- 404
349 ing variables make incidence and prevalence difficult 405
STAGE 2
350 to estimate. 406
351 Exposed and necrotic bone, or fistula that probes to Clinical trials, while being the gold standard for effi- 407
352 the bone, with evidence of infection/inflammation. cacy and safety data, are seldom powered to demon- 408
353 These patients are symptomatic. These patients also strate uncommon events. Prior to the discovery of 409
354 may present with radiographic findings mentioned MRONJ, large randomized prospective trials of BPs 410
355 for Stage 0 localized to the alveolar bone region. with up to 10 years of patient data did not reveal any 411
356 jaw bone necrosis as a complication.17,59 More 412
357 STAGE 3 recently, the HORIZON Pivotal Fracture trial tested 413
358 Exposed and necrotic bone or fistulae that probes to 3,889 randomized patients given annual zoledronic 414
359 the bone, with evidence of infection, and one or more acid versus placebo for 3 years; one patient developed 415
360 of the following: MRONJ in the intervention group and one in the pla- 416
361 cebo group.18 Extension of this trial for up to 6 years 417
362 Exposed necrotic bone extending beyond the re- resulted in one additional MRONJ patient in the treat- 418
363 gion of alveolar bone (ie, inferior border and ment group.60 Extension to 9 years resulted in no addi- 419
364 ramus in the mandible, maxillary sinus, and tional confirmed cases of MRONJ.61 420
365 zygoma in the maxilla) Definitive causality, taken as a whole, remains a diffi- 421
366 Pathologic fracture. cult task to prove in general, let alone in individual pa- 422
367 Extraoral fistula. tients presenting with clinical symptoms. Clinicians 423
368 Oral antral/oral-nasal communication. should be aware of these facts in decisions regarding 424
369 Osteolysis extending to the inferior border of the treatment recommendations. 425
370 mandible or sinus floor. 426
371 427
Pathophysiology
372 428
373 Since the AAOMS position paper in 2014, significant 429
Causality
374 knowledge has been gained regarding MRONJ patho- 430
375 It is important to understand that patients at risk for physiology from both clinical and particularly preclin- 431
376 or with established MRONJ also can present with ical animal studies. It should be noted that animal 432
377 other common clinical conditions not to be confused studies have a number of limitations, are most often us- 433
378 with MRONJ. Commonly misdiagnosed conditions ing supratherapeutic doses and likely do not truly 434
379 may include but are not limited to alveolar osteitis, mirror the clinical environment. That said, they are 435
380 sinusitis, gingivitis/periodontitis, caries, periapical pa- critical in understanding disease mechanisms and 436
381 thology, odontalgia, atypical neuralgias, fibro-osseous can serve as one reference point to evidence-based 437
382 lesions, sarcoma, chronic sclerosing osteomyelitis, clinical decision-making. 438
383 and temporomandibular joint (TMJ) disorders. It also Much debate persists among clinicians and re- 439
384 is important to remember that delayed healing, searchers, contributing to the various treatment proto- 440
385 exposed bone or sequestra (ie, osteonecrosis [ONJ]), cols utilized for patients today.62-65 Disease specificity 441
386 can occur in patients not exposed to antiresorp- unique to the jaws has focused leading hypotheses to 442
387 tive agents.42 include bone remodeling inhibition, inflammation or 443
388 Proving causality of any medication-related compli- infection, angiogenesis inhibition, innate or acquired 444
389 cation is challenging from an epidemiologic perspec- immune dysfunction, as well as genetic 445
390 tive. It is well-known that MRONJ is a rare entity, predisposition.3,65 Both animal and human studies 446
391 multifactorial in nature, and patients with the same suggest that an antiresorptive medication, coupled 447
392 clinical presentation exist who have not been exposed with inflammation or infection, is necessary and 448

RUGGIERO ET AL 5
449 sufficient to induce MRONJ. However, as more knowl- clear that most extracted teeth had pre-existing peri- 505
450 edge is gained on the subject, it is becoming increas- odontal or periapical disease.3,64,83,84 From this pa- 506
451 ingly apparent that MRONJ is multifactorial, and it is tient information, animal models of inflammation or 507
452 likely that multiple hypotheses can explain the overall infection were developed to replicate clinical, radio- 508
453 pathophysiology of this disease.3,65 graphic, and histologic features of MRONJ.85-88 509
454 Presence of inflammatory cytokines, specifically at 510
455 BONE REMODELING INHIBITION the site of MRONJ, also support the strong role of 511
456 inflammation.89 As evidence of increased systemic 512
The definition of MRONJ includes oral or parenteral
457 inflammation and its contribution to MRONJ develop- 513
administration of antiresorptive medications, such
458 ment, mice with experimentally induced rheumatoid 514
that bone remodeling suppression is a central hypoth-
459 arthritis demonstrated more severe MRONJ with 515
esis in its pathophysiology. Antiresorptive medica-
460 increased oral bone exposure, more pronounced 516
tions, including BPs and denosumab (DMB), have
461 radiographic features, intense local inflammatory infil- 517
direct effects on osteoclast formation, differentiation,
462 trate, and larger areas of histologic necrosis.90 Further 518
or function. In osteoporosis, BPs are a first-line therapy
463 support for the inflammatory etiology showed that 519
to decrease bone remodeling, increase bone mineral
464 removal of the inflammatory nidus in ligature- 520
density, and decrease vertebral and long bone frac-
465 induced periodontitis ameliorated MRONJ develop- 521
tures.66,67 BPs, in higher doses, also are utilized in pri-
466 ment in mice, demonstrating reduced inflammation 522
mary bone malignancy and bone metastases to
467 and prevention of disease progression.91 Moreover, 523
decrease SREs, including hypercalcemia of malig-
468 transplantation of peripheral blood mononuclear cells 524
nancy, reduce severe bone pain, and improve quality
469 with anti-inflammatory properties reduced MRONJ 525
of life.68-72 Although DMB has only been approved
470 prevalence by improving soft-tissue healing, 526
for use since 2010, its use has increased significantly
471 decreasing inflammatory polymorphonuclear cells 527
for both osteoporosis and malignancy in the last
472 and inflammatory marker expression, as well as 528
decade. Prevalence of MRONJ with DMB users is at
473 enhancing vascularity.92 These preclinical findings 529
least as high as BP users, likely due to its increased
474 confirm the irrefutable role of inflammation or infec- 530
potency to inhibit bone resorption.30,73-75 This is
475 tion in MRONJ disease prevalence, severity and 531
supported in the jaws as animal studies demonstrate
476 resolution. 532
absent osteoclasts around the alveolar bone of DMB-
477 The presence of bacteria on the exposed necrotic 533
treated mice.76 Human bone specimens also show an
478 bone also contributes to disease severity, where pain 534
increased number of nonfunctional osteoclasts sur-
479 and signs of infection define Stage 2 MRONJ.3,93,94 535
rounding necrotic bone in BP-treated patients,77
480 This is not surprising since poor oral hygiene and bio- 536
further reinforcing bone remodeling inhibition as a
481 film presence are associated with MRONJ develop- 537
leading hypothesis in MRONJ pathophysiology. With
482 ment,95,96 and oral health maintenance and dental 538
the appearance of MRONJ in DMB-treated patients, it
483 prophylaxis before initiating antiresorptive therapy 539
becomes increasingly apparent that the underlying
484 can decrease MRONJ prevalence.97,98 Importantly, 540
pathophysiology involves dysfunctional osteoclasts.
485 clinical treatment protocols to reduce the biofilm 541
Animal studies evaluating withdrawal of BPs or DMB
486 and eradicate infection have emerged as important al- 542
further highlight the importance of bone remodeling
487 ternatives to debridement and resection in patients 543
in MRONJ prevention and resolution. Rodents with es-
488 who may not be ideal surgical candidates.63 544
tablished ONJ failed to resolve when antiresorptive
489 545
were withdrawn. However, discontinuing DMB, but
490 546
not BPs, prior to tooth extraction successfully pre- ANGIOGENESIS INHIBITION
491 547
vented MRONJ development in rats.78,79 Moreover,
492 Osteonecrosis is traditionally defined as avascular 548
parathyroid hormone, which acts directly on osteo-
493 necrosis or aseptic necrosis, most commonly charac- 549
blasts to induce bone formation and indirectly in-
494 terized as osteocyte death after decreased blood flow 550
creases osteoclastic bone resorption and overall
495 to the femoral head.99 However, MRONJ is defined as 551
remodeling, has been shown to prevent MRONJ and
496 necrotic bone in the maxillofacial region after expo- 552
improve extraction socket healing in rodents and pre-
497 sure to either antiresorptive or antiangiogenic medica- 553
liminarily in patients.80-82 This observation provides
498 tions.3 BPs such as zoledronic acid directly inhibit 554
further support for the central role of osteoclast
499 angiogenesis in vitro and in vivo100-103 and animal 555
inhibition in MRONJ pathogenesis.
500 models demonstrate decreased vascularity in sites of 556
501 MRONJ and decreased microvessel numbers during 557
502 INFLAMMATION OR INFECTION early stages of bone healing.104 In addition, angiogen- 558
503 Although most studies report tooth extraction as the esis normally seen during extraction socket healing 559
504 major inciting event for MRONJ development, it is is inhibited by BPs, and both BPs and DMB have 560

6 ---
561 been shown to decrease arterial area, venous area, and collagen formation, or certain metabolic bone dis- 617
562 overall vascularity of periodontal tissues during early eases. Indeed, increasing evidence is available to sup- 618
563 and late MRONJ development.105,106 Importantly, anti- port the role of single-nucleotide polymorphisms 619
564 angiogenic medications, such as VEGF inhibitors, tyro- (SNPs) with MRONJ.126,127 Specific links to sirtuin-1 620
565 sine kinase receptor inhibitors, and (SIRT1), a bone remodeling regulator that promotes 621
566 immunomodulatory drugs,107-109 can be associated bone formation, may be protective against MRONJ if 622
567 with MRONJ. Moreover, patients with multiple upregulated.128 SIRT1 also is involved in both reduc- 623
568 myeloma receiving both antiresorptive and tion of inflammation and induction of angiogenesis, 624
569 antiangiogenic medications, as shown in several suggesting a role in several of the leading MRONJ hy- 625
570 studies,110-114 have a higher MRONJ prevalence. potheses.128 Other genes also have been reported to 626
571 Important aspects of MRONJ treatment include increase MRONJ risk through their role in angiogen- 627
572 determining disease margins, which can be esis, bone remodeling, and immune responses, 628
573 challenging as microvascular mucosal abnormalities including PPAR gamma, CYP2C8, and many others.129 629
574 can be seen adjacent to frank MRONJ lesions.115 It is Collectively, these studies suggest that MRONJ is a 630
575 important to note that the incidence of MRONJ in pa- multifactorial disease and that genetic factors may 631
576 tients on antiangiogenics is much lower than those tak- play a role in its development.130 Overall, however, 632
577 ing antiresorptive medications. current studies document either a weak or no associa- 633
578 tion between genetic factors measured and risk for 634
579 INNATE OR ACQUIRED IMMUNE DYSFUNCTION MRONJ.131 To determine predisposition, studies with 635
580 larger sample sizes should be performed, with genetic 636
Although animal studies confirm that an antiresorp-
581 risks confirmed in both BPs and DMB-treated patients 637
tive medication—coupled with inflammation or infec-
582 who have breast or prostate cancer metastases, multi- 638
tion—is necessary and sufficient to produce MRONJ,
583 ple myeloma, or osteoporosis. 639
not all patients with dental infections develop the dis-
584 640
ease. It is well-known that patients with medical co-
585 Risk Factors for MRONJ 641
morbidities such as diabetes or rheumatoid arthritis
586 642
or immunocompromised states are at significantly MEDICATION-RELATED RISK FACTORS
587 643
higher risk for MRONJ with or without exposure to
588 To estimate the risk for medications associated with 644
antiresorptive agents.3,64,114,116 Patients with metasta-
589 MRONJ, the primary parameter to be considered is the 645
tic or primary bone malignancies have a compromised
590 therapeutic indication for treatment (eg, malignancy 646
immune system.117 This also has been confirmed with
591 or osteoporosis/osteopenia). The data suggest that 647
animal studies, where chemotherapy, steroids, and
592 antiresorptive medications (eg, BPs and DMB) are asso- 648
disease-modifying antirheumatic drugs (DMARDs),
593 ciated with an increased risk for developing MRONJ. 649
combined with antiangiogenic medications and an
594 The risk of MRONJ is considerably higher in the malig- 650
antiresorptive, increase MRONJ severity or preva-
595 nancy group (<5%) than in the osteoporosis group 651
lence.118-120 Moreover, higher rates of MRONJ occur
596 (<0.05%). Current data are insufficient to identify 652
in patients with multiple myeloma who receive
597 other medications as risk factors for devel- 653
multiple chemotherapeutic agents.110,121
598 oping MRONJ. 654
Replenishing the area of nonhealing MRONJ lesions
599 655
with mesenchymal stem cells (MSCs) to overcome im-
600 MRONJ risk among cancer patients 656
mune dysfunction is a potential area of therapeutic in-
601 For estimating the risk for MRONJ among patients 657
terest, especially in patients who are
602 exposed to a medication, the risk for MRONJ in pa- 658
immunocompromised. A recent study showed altered
603 tients not exposed to antiresorptive medications 659
numbers and patterns of T-cells in human and rat
604 must be estimated (Table 1). The risk for MRONJ 660
MRONJ necrotic bone samples as compared to healthy
605 among cancer patients enrolled in clinical trials and as- 661
patients and non-MRONJ sites.122 Preclinical studies
606 signed to placebo groups ranges from 0 percent to 0.7 662
also demonstrate healing or prevention of MRONJ le-
607 percent.132-138 663
sions after systemic infusion with adipose or bone
608 664
marrow-derived MSCs.123-125
609 a. Among cancer patients exposed to zoledronate, 665
610 the cumulative risk of MRONJ clusters in the 666
611 GENETIC FACTORS low single digits, <5 percent, and ranges from 667
612 In the 2014 paper, the authors identified several re- 0 percent to 18 percent.113,132,133,137-144 The 668
613 ports describing single-nucleotide polymorphisms wide variation in estimates may be explained by 669
614 (SNPs) that were associated with the development of the varying durations of follow-up, one to 670
615 MRONJ. Most of these SNPs were located within re- 10 years, reported in the various studies. The 671
616 gions of the gene associated with either bone turnover, risk of MRONJ among cancer patients exposed 672

RUGGIERO ET AL 7
673 Table 1. MRONJ DISEASE FREQUENCY GROUPED BY DISEASE STATUS VERSUS MEDICATION*. MEDICATIONS
729
674 730
675 Indications for 731
676 Treatment Placebo Zoledronate Oral BPs Denosumab Romosozumab Study design 732
677 733
678 Malignancy 734
679 Coleman (2020)138 0.2% (2,218)* 5% (2,241) RCTy 735
680 O’Carrigan et al, 0.7% (6,788) 0.4% (6,788) Systematic review 736
681 (2017)137 737
O’Carrigan et al, 0% (3,060) 1% (3,078) Systematic review
682 738
(2017)137
683 Macherey et al, 0.7% (818) 1.5% (808) Systematic review
739
684 (2017)136 740
685 Gnant et al, 0% (903) 0% (900) RCT 741
686 (2015)247 742
687 Coleman et al, 0% (1,679) 1.7% (1,681) RCT 743
688 (2014)133 744
689 Valachis et al, 0% (3,039) 0.52% (4,774) Systemic review 745
690 (2013)132 746
691 Boquete-Castro 0.1% 1.14% 1.7% Systematic review 747
692 et al, (2016)135 748
Coleman (2020)138 0.2% (2,218) 5.4% (2,214) RCT
693 749
Gnant et al, 0% (1,709) 0% (1,711) RCT
694 (2015)247
750
695 Raje et al, (2018)113 2.8% (82) 4.1% (850) RCT 751
696 Himelstein 1.5% (1,822) RCT 752
697 (2017)140 753
698 Henry (2014)141 1.1% (786) 0.8% (792) RCT 754
699 Yang et al, 2% (8,525) Systematic review 755
700 (2019)248 756
701 Peddi et al, 1.3% (2,846) 1.8% (2,885) Systematic review 757
702 (2013)142 758
703 Ng et al, (2021)145 1.6-4%y 1.9%y Systematic review 759
3.8-18%z 6.9%z
704 760
Wang et al, 1.4% (1,013) 2% (1,020) Systematic review
705 (2014)144
761
706 Osteoporosis 762
707 Papapoulos et al, 0% (3,383) 0.04% (4,549) RCT 763
708 (2012)26 764
709 Grbic et al, 0.02% (4,945) 0.02% (5,864) Systematic review 765
710 (2010)150 766
711 Cosman et al, 0% (3,322) 0.03% (3,321) RCT 767
712 (2016)151 768
713 Saag et al, (2017)37 0.05% (2,047) 0.05% (2,046) RCT 769
714 Bone et al, 0.3% (2,343) RCT 770
(2017)153 10-yr f/u
715 771
Hallmer et al, 0.043% Population study (50,000)
716 (2018)75
772
717 Nonmalignant bone 773
718 disease 774
719 Chawla et al, 5% (532) Prospective case series 775
720 (2019)156 776
721 Rutkowski155 0.7% (138) Retrospective case series 777
722 x Q6 778
Randomized clinical trial.
723 * Sample size in parentheses 779
724 y <2 years of follow-up. 780
725 z >2 years of follow-up. 781
726 Ruggiero et al. ---. J Oral Maxillofac Surg 2022. 782
727 783
728 784

8 ---
785 to zoledronate ranges between 2-10 times higher percent, almost an order of magnitude higher than 841
786 than cancer patients treated with placebo. for BPs.153 842
787 b. Among cancer patients exposed to DMB, the risk 843
788 of MRONJ ranges from 0 percent to 6.9 percent, c. The risk for MRONJ when exposed to romosozu- 844
789 with most studies reporting rates <5 mab (0.03 percent to 0.05 percent) is comparable 845
790 percent.113,134,135,138,141,142,144,145 The risk for to alendronate (0.05 percent).37,151 In the pla- 846
791 MRONJ among cancer patients exposed to DMB cebo group, there were no cases of MRONJ.151 847
792 is comparable to the risk of MRONJ in cancer pa- It will be important to continue to monitor romo- 848
793 tients exposed to zoledronate.135,141,142,144,145 sozumab to assess its role as a risk factor for 849
794 MRONJ. 850
795 Since the 2014 update, investigators have impli- 851
796 cated numerous families of medications as risk factors The risk for MRONJ among osteoporosis patients 852
797 for MRONJ.146-149 These medications include tyrosine treated with BPs ranges from 0.02 percent to 0.05 853
798 kinase inhibitors (TKIs) such as sunitinib, monoclonal percent and overlaps the risk for MRONJ of patients 854
799 antibodies (bevacizumab), fusion proteins enrolled in placebo groups (0 percent to 0.02 855
800 (aflibercept), mTOR inhibitors (everolimus), percent). The risk for MRONJ among patients treated 856
801 radiopharmaceuticals (radium 223), selective with denosumab, however, has a larger range—from 857
802 estrogen receptor modulators (raloxifene), and 0.04 percent to 0.3 percent. As such, additional 858
803 immunosuppressants (methotrexate and research will be needed to better estimate the risk of 859
804 corticosteroids). MRONJ among patients receiving denosumab. The 860
805 When compared to antiresorptive medications, the risk of MRONJ for patients exposed to romosozumab 861
806 level of evidence supporting other medication fam- (0.03 percent to 0.05 percent) more closely aligns 862
807 ilies as risk factors for MRONJ is level 5 (eg, isolated with the risk associated with BPs.37,151 However, given 863
808 case reports or mini-case series [<5 cases]).146-149 its recent introduction as a therapeutic agent, addi- 864
809 Given that the poly-pharmaceutical management of tional research will be needed to refine its association 865
810 cancer patients combined with the fact that cancer and risk estimate for MRONJ. 866
811 and immunosuppression are risk factors for MRONJ Based on this current review of data, the risk of 867
812 without exposure to antiresorptive agents, AAOMS developing MRONJ among osteoporotic patients 868
813 believes that identifying a single medication as being exposed to BPs, DMB, and romosozumab is low. The 869
814 the etiologic agent for MRONJ seems unlikely in case occurrence of cases seen is best explained by a rare 870
815 reports or mini-case series. Further controlled pro- event among a large number of patients, 5.1 million 871
816 spective studies will be required to measure the over the age of 55, exposed to these drugs.154 872
817 risk of MRONJ associated with nonantiresorp- 873
818 tive agents. 874
819 MRONJ Risk Among Patients with Nonmalignant 875
820 Bone Disease 876
MRONJ Risk Among Osteoporosis Patients
821 Most dentists and oral and maxillofacial surgeons 877
a. AAOMS identified two studies where DMB was
822 evaluate patients in their practices exposed to antire- 878
used to manage aggressive giant cell tumors of
823 sorptive therapy for management of osteopo- 879
bone.155,156 The risk of developing MRONJ in
824 rosis (Table 1). 880
the two studies was broad and ranged from 0.7
825 881
percent to 5 percent. This is comparable to the
826 a. Risk for MRONJ among osteoporotic patients 882
risks of developing MRONJ in subjects treated
827 exposed to BPs. 883
with DMB for malignancies (range = 0 percent
828 884
to 6.9 percent). Additional studies will be needed
829 885
The risk of MRONJ among study subjects assigned to to confirm the risk estimate for MRONJ among
830 886
placebo groups enrolled in osteoporosis clinical trials patients with nonmalignant bone disease treated
831 887
ranged from 0 percent to 0.02 percent.26,150,151 with antiresorptives.
832 888
Among study subjects treated with BPs, the risk of b. There are very limited data describing the occur-
833 889
MRONJ is 0.02 percent to 0.05 percent.37,75,152 rence of MRONJ in the pediatric population for
834 890
835 osteogenesis imperfecta and other conditions. 891
b. MRONJ risk among osteoporotic patients In a systematic review estimating the risk of
836 exposed to RANK-L inhibitors. 892
837 MRONJ among children with osteogenesis imper- 893
838 fecta, there were no cases of MRONJ identified in 894
839 After 10 years of follow-up, among patients exposed a sample of 486 subjects treated for 4.5 to 895
840 to DMB, the risk for MRONJ was reported to be 0.3 6.8 years.157 In a different systematic review 896

RUGGIERO ET AL 9
897 that estimated the risk for MRONJ among those risk for developing MRONJ following tooth extraction 953
898 under the age of 24 for several conditions treated (or other dentoalveolar procedures such as implant 954
899 using BPs, no cases of MRONJ were reported.158 placement or periodontal procedures)?’’ Current esti- 955
900 The overall quality of the studies included in both mates for the risk of MRONJ among osteoporotic pa- 956
901 systematic reviews was limited by small sample tients exposed to BPs following tooth extraction 957
902 sizes or lack of MRONJ-related risk factors. range from 0 percent to 0.15 percent.161,162 For osteo- 958
903 porotic patients exposed to DMB, the risk for MRONJ 959
904 following tooth extraction was 1 percent.163 960
905 Duration of Medication Therapy as a Risk Factor For cancer patients exposed to BPs, the risk of devel- 961
906 for MRONJ oping MRONJ after tooth extraction ranges from 1.6 962
907 Regardless of indications for therapy, the duration percent to 14.8 percent.164-166 In a small case series, 963
908 of antiresorptive therapy is a risk factor for developing n = 61 subjects having 102 extractions, the risk for 964
909 MRONJ. Among cancer patients exposed to zoledro- MRONJ after tooth extraction was 13.1 percent.167 965
910 nate or DMB (n = 5,723), the risk of developing In a systematic review by Gaudin et al, the risk for 966
911 MRONJ was, respectively, 0.5 percent and 0.8 percent MRONJ after tooth extraction (n = 564) was estimated 967
912 at 1 year, 1.0 percent and 1.8 percent at 2 years, and to be 3.2 percent.162 While the estimates for devel- 968
913 1.3 percent and 1.8 percent at 3 years.141 In a study oping MRONJ in high-risk patients undergoing tooth 969
914 by Saad et al, the investigators combined three- extraction vary, they cluster between 1 percent and 970
915 blinded phase three trials and found similar results, 5 percent, similar to estimates of osteoradionecrosis 971
916 including a plateau after 2 years for patients exposed following tooth extraction in irradiated patients. 972
917 to DMB.5 In a more recent systematic review by Ng The risk of developing MRONJ among patients who 973
918 et al, the risk of MRONJ among cancer patients treated have been exposed to antiresorptive medications for 974
919 with zoledronate, was 1.6 percent to 4 percent after other dentoalveolar operations such as dental implant 975
920 2 years of treatment and 3.8 percent to 18 percent placement and endodontic or periodontal procedures 976
921 with more than 2 years of treatment.145 Likewise, for is unknown.168 The risk for MRONJ after implant 977
922 DMB, the risks for developing MRONJ were 1.9 placement among patients treated with DMB has 978
923 percent and 6.9 percent with <24 months and been reported to be 0.5 percent.163 Absent better 979
924 >24 months of exposure, respectively.145 data, AAOMS cautions the use of these procedures in 980
925 For patients receiving bisphosphonate therapy to cancer patients exposed to antiresorptive therapies 981
926 manage osteoporosis, data regarding duration are and recommends osteoporosis patients be informed 982
927 mixed. Early on, the prevalence of MRONJ was re- of potential risks, albeit low, including development 983
928 ported as increasing over time from near 0 percent of MRONJ, early and late implant failure all of which 984
929 at baseline to 0.21 percent after four or more years have been described in case reports and clinical trials. 985
930 of BP exposure based on retrospective analysis.152,159 986
931 More recent data from a large prospective, randomized Anatomic Factors 987
932 placebo controlled trial demonstrate no significant in- Limited new information regarding anatomic risk 988
933 crease in MRONJ in patients treated for up to factors for MRONJ is available. MRONJ is more likely 989
934 9 years.18,60,61 In addition, there are no postmarketing to appear in the mandible (75 percent) than the 990
935 data or general clinical experience to support an maxilla (25 percent) but can appear in both jaws 991
936 MRONJ prevalence of 0.21 percent in any (4.5 percent).5,75 Denture use was associated with 992
937 osteoporosis-treated group. Therefore, while duration an increased risk for MRONJ among cancer patients 993
938 may be a risk factor, the overall risk remains low. exposed to zoledronate (OR = 4.9; 95 percent 994
939 CI = 1.2 to 20.1).169 In a study by Vahtsevanos et al, 995
940 a sample of 1,621 cancer patients treated with intrave- 996
941 B. LOCAL FACTORS nous zoledronate, ibandronate or pamidronate, there 997
942 Dentoalveolar Operations was a two-fold increased risk for MRONJ among den- 998
943 Dentoalveolar operations are the most common ture wearers.170 999
944 identifiable predisposing factor for developing 1000
945 MRONJ. Several studies report that among patients Concomitant Oral Disease 1001
946 with MRONJ, tooth extraction is cited as a predispos- Pre-existing inflammatory dental disease such as 1002
947 ing event ranging from 62 percent to 82 periodontal disease or periapical pathology is cited 1003
948 percent.5,75,160 While this information is important, as a risk factor.75,168 Among cancer patients with 1004
949 it is not what most patients or clinicians want to MRONJ, the pre-existing inflammatory dental disease 1005
950 know. Most providers and patients want an answer was a risk factor among 50 percent of the cases.5,165 1006
951 to the following clinical question: ‘‘Among patients Given that a common treatment of inflammatory 1007
952 exposed to antiresorptive medications, what is the dental disease is tooth extraction, pre-existing dental 1008

10 ---
1009 disease may confound the relationship between tooth very low regardless of drug type (BPs, DMB, romoszu- 1065
1010 extraction and risk for MRONJ. Tooth extraction may mab) or dosing schedule. 1066
1011 expose MRONJ as opposed to being the precipitating 1067
1012 event. It would be valuable to see an estimate of the as- 1068
1013 sociation between tooth extraction and MRONJ Management Strategies 1069
1014 adjusted for pre-existing inflammatory dental disease. 1070
TREATMENT GOALS
1015 After tooth extraction and periodontal disease, the 1071
1016 next most common risk factor is reported as ‘‘sponta- The major goals of treatment for patients at risk of 1072
1017 neous’’ MRONJ with no identifiable dental developing or who have established MRONJ are: 1073
1018 risk factor.168 1074
1019 Prevention of MRONJ (see section MRONJ risk 1075
1020 among cancer patients below). 1076
1021 Prioritization and support of continued oncologic 1077
1022 DEMOGRAPHIC AND SYSTEMIC FACTORS AND treatment in patients receiving antiresorptive 1078
1023 OTHER MEDICATIONS therapy alone or in combination with immune 1079
1024 Age and sex are variably reported as risk factors for modulators or antiangiogenic medications: 1080
1025 MRONJ.5,165,169-171 The higher prevalence of MRONJ B Oncology patients benefit from the therapeu- 1081
1026 in the female population is likely a reflection of the tic effect of antiresorptive therapy by control- 1082
1027 underlying disease for which the agents are being ling bone pain and reducing the incidence of 1083
1028 prescribed (eg, osteoporosis, breast cancer). other SREs. 1084
1029 As noted previously, those under the age of 24 Prioritization and support of continued bone 1085
1030 treated with antiresorptives for benign bone diseases health and the prevention of fragility fractures 1086
1031 have not demonstrated any risk for MRONJ even after B Patients with osteoporosis, osteopenia, and 1087
1032 an extended duration of therapy. The overall quality of other metabolic bone diseases benefit from 1088
1033 the studies included even in systematic reviews is antiresorptive therapy by significantly 1089
1034 based on small sample sizes and the lack of other reducing the risk of fragility fractures and 1090
1035 MRONJ-related risk factors. The risk of developing other skeletal-related events. 1091
1036 MRONJ in the pediatric population requires continued 1092
Preservation of quality of life through:
1037 surveillance. 1093
B Patient education and reassurance.
1038 Corticosteroids are associated with an increased risk 1094
B Control of pain.
1039 for MRONJ.5,168,171 There are concerns that corticoste- 1095
B Control of secondary infection.
1040 roids increase the risk for MRONJ when given in 1096
B Prevention of extension of lesion and develop-
1041 conjunction with antiresporptive agents. 1097
ment of new areas of necrosis.
1042 Comorbid conditions are inconsistently reported to 1098
1043 be associated with an increased risk for MRONJ, 1099
1044 including anemia (hemoglobin < 10 g/dL) and dia- Prevention of MRONJ 1100
1045 betes.5,171 Cancer type also is variably reported as a Numerous studies demonstrate potentially modifi- 1101
1046 risk factor.170,172 able factors for reducing the risk of MRONJ, including 1102
1047 Tobacco use is variably reported as a risk factor for performing high-risk surgical procedures prior to initi- 1103
1048 MRONJ. In a case-control study, tobacco use ap- ating therapy,95,173-175 using preoperative and 1104
1049 proached statistical significance as a risk factor for postoperative antibiotics and antimicrobial mouth 1105
1050 MRONJ in cancer patients (OR = 3.0; 95 percent rinses,174,176-180 primarily closing extractions 1106
1051 CI = 0.8 to 10.4).169 In a more recent case-controlled sites,176-178 and maintaining good oral 1107
1052 study, tobacco use was not associated with ONJ in a hygiene.95,166,176,177,181 Maximizing overall patient 1108
1053 sample of cancer patients exposed to zolendronate.171 health is always indicated, such as smoking cessation 1109
1054 Vahtsevanos did not report an association between to- and diabetes optimization. Although no individual 1110
1055 bacco use and MRONJ.170 strategy nor collection of strategies eliminates all 1111
1056 In brief, after chemotherapy and corticosteroid MRONJ risks, these preventive procedures are 1112
1057 exposure, the next most reported comorbidity is ‘‘no recommended. 1113
1058 comorbidity.’’168 The prevention of MRONJ begins with the realiza- 1114
1059 In summary, the current literature reaffirms that the tion that patients receiving antiresorptive therapies 1115
1060 risk of MRONJ is significantly greater in cancer pa- may have altered osseous wound-healing capacity, 1116
1061 tients receiving antiresorptive therapy compared to which may also be a risk for developing MRONJ. 1117
1062 patients receiving antiresorptive therapy for osteopo- Similar to other common preventive strategies in med- 1118
1063 rosis. Moreover, the risk of MRONJ in osteoporosis pa- icine and dentistry, healthcare providers need to 1119
1064 tients receiving antiresorptive therapy continues to be recognize the importance of coordinated dental care 1120

RUGGIERO ET AL 11
1121 and pretreatment management in minimizing the risk An additional benefit of early dental consultation, 1177
1122 of MRONJ. This requires a continuous effort to educate when the use of antiresorptive therapy is being 1178
1123 patients, dentists, and medical professionals about the considered, is that the patient is informed of the 1179
1124 real risks associated with these therapies and clinical risk associated with these drug therapies and the 1180
1125 prevention paradigms that can mitigate MRONJ risk incurred by not undergoing recommended 1181
1126 development. dental preventive measures before consenting 1182
1127 AAOMS re-emphasizes the importance of a multidis- to treatment. 1183
1128 ciplinary approach to the treatment of patients who 1184
1129 are receiving antiresorptive therapies. This may also CESSATION OF AT-RISK MEDICATION THERAPY 1185
1130 apply to other immune modulators or targeted thera- (DRUG HOLIDAY) PRIOR TO TOOTH EXTRACTION OR 1186
1131 pies taken alone or in combination with antiresorp- OTHER PROCEDURES THAT INVOLVE OSSEOUS 1187
1132 tives. This approach includes consultation with an INJURY (EG, 1DENTAL IMPLANT PLACEMENT, 1188
1133 appropriate dental professional when it is determined PERIODONTAL OR APICAL ENDODONTIC 1189
1134 a patient would benefit from these therapies. TREATMENT) 1190
1135 The clinical practice of antiresorptive drug holidays 1191
1136 to mitigate MRONJ risk in patients undergoing dentoal- 1192
1137 veolar surgery was controversial at the time of the pre- 1193
1138 OPTIMIZATION OF ORAL HEALTH vious AAOMS position paper in 2014 and remained the 1194
1139 The 2014 AAOMS position paper identified valid case in 2021. While the practice of a drug holiday has 1195
1140 prophylactic treatment strategies that reduce the inci- been accepted and recommended by several interna- 1196
1141 dence of MRONJ. The efficacies of these strategies tional professional societies,3,38,182,183,198 the evi- 1197
1142 remain validated by subsequent studies that demon- dence to support or refute such positions remains 1198
1143 strate the importance of pretreatment dental inconclusive. The difficulty in establishing or refuting 1199
1144 screening and regimented dental surveillance. There the efficacy of drug holidays is due to the rarity of 1200
1145 is a robust level of support for early screening and initi- MRONJ in these patient populations. Therefore, since 1201
1146 ation of appropriate dental care prior to the initiation few events are reported, randomized-controlled trials 1202
1147 of antiresorptive therapy.38,182-186 provide insufficient data to create sound treatment 1203
1148 These preventive management strategies not only protocols. In a 2020 systematic review that studied 1204
1149 decrease the risk for MRONJ but accrue the benefits the efficacy of antiresorptive drug holiday in prevent- 1205
1150 that all patients enjoy with optimum oral health.186-193 ing MRONJ, a variety of papers were identified with 1206
1151 In a prospective study of prostate cancer patients differing conclusions suggesting that a high level of ev- 1207
1152 with bone metastasis, instituting a more regimented idence for supporting or refuting the use of a holiday is 1208
1153 dental health surveillance system resulted in a 2.5- missing.199 1209
1154 fold reduction in relative risk compared to symptomat- The historical use of a drug holiday was intended to 1210
1155 ically driven dental treatment.186 In a systematic re- decrease the prevalence of MRONJ subsequent to the 1211
1156 view aimed at identifying prevention strategies performance of high-risk surgical procedures. The 1212
1157 associated with tooth extractions in patients at risk concern regarding this practice is the loss of efficacy 1213
1158 for MRONJ, no randomized clinical trials were re- of antiresorptive therapy with the development of 1214
1159 ported.194 However, there are many animal studies SREs and fragility fractures. Among others, factors for 1215
1160 that demonstrate that periodontal or periapical inflam- consideration may include disease-related risk (cancer 1216
1161 mation plays a key role in creating a local environment vs osteoporosis), drug-dosing frequency, duration of 1217
1162 that supports the development of bone necrosis in the therapy, comorbidities, other medications (especially 1218
1163 context of systemic antiresorptive therapy.85,91,195,196 chemotherapy, steroids, or antiangiogenics), degree 1219
1164 Treatment planning for patients at risk of devel- of underlying infection/inflammation, and extent of 1220
1165 oping MRONJ should include a thorough examination surgery to be performed. 1221
1166 of the oral cavity and a radiographic assessment when Of note, the working group was unable to reach a 1222
1167 indicated. It is important to identify both acute infec- consensus regarding a recommendation on drug holi- 1223
1168 tion and sites of potential infection to prevent future days and was evenly split between offering drug holi- 1224
1169 sequelae that could be exacerbated once drug thera- days to patients on a case-by-case basis using prior 1225
1170 pies begin. Considerations during the clinical and recommendations and those who never recommend 1226
1171 radiographic assessment include patient motivation, drug holidays, believing that the risks of potential dele- 1227
1172 patient education regarding dental care, fluoride appli- terious effects of suspending antiresorptive therapy 1228
1173 cation, chlorhexidine rinses, tooth mobility, peri- may outweigh a benefit. 1229
1174 odontal disease, presence of root fragments, caries, A special concern should be considered for sus- 1230
1175 periapical pathology, edentulism, and denture pending RANKL inhibitors in osteoporosis patients. 1231
1176 stability.197 Several studies have demonstrated a rebound increase 1232

12 ---
1233 Table 2. MRONJ PREVENTION STRATEGIES

1289
1234 1290
1235 Pretherapy (Nonmalignant Educate Patient About the Potential Risks Associated with Long-term ART.* 1291
1236 Disease) Optimization of dental Health can Occur Concurrent with ART. 1292
1237 Pretherapy (malignant disease) Educate patients about the higher risk of MRONJ and the importance of re- 1293
gimented dental care.
1238 Optimization of the dental health prior to the initiation of ART if systemic
1294
1239 conditions permit (extraction of nonrestorable teeth or teeth with a poor 1295
1240 prognosis). 1296
1241 During antiresorptive therapy No alteration of operative plan for most patients. 1297
1242 (nonmalignant disease) Considerations include drug schedule, duration of therapy, comorbidities, 1298
1243 other medications (especially chemotherapy, steroids, or antiangiogenics), 1299
degree of underlying infection/inflammation, and extent of surgery to be
1244 performed. Drug holidays are controversial.
1300
1245 BTMy are not a useful tool to assess MRONJ risk. 1301
1246 During antiresorptive therapy/ Educate patients about the higher MRONJ risk in the setting of malignant 1302
1247 targeted therapies (malignant disease. 1303
1248 disease) Educate the patient about the importance of regimented dental care and 1304
1249 prevention. 1305
1250 Avoid dentoalveolar surgery if possible. 1306
Consider root retention techniques to avoid extractions.
1251 1307
Dental implants are contraindicated.
1252 1308
Drug holidays are controversial.
1253 1309
1254 * Antiresorptive therapies. 1310
1255 y Bone turnover markers (CTX). 1311
1257 1313
1258 1314
in bone resorption following the discontinuation of Prevention Strategies
1259 DMB, resulting in an increased risk of multilevel verte- 1315
1260 PATIENTS SCHEDULED TO INITIATE ANTIRESORPTIVE 1316
bral fractures.200-202 If DMB is to be suspended, the
1261 TREATMENT FOR CANCER THERAPY 1317
timing and duration of the holiday should be
1262 optimized in order to minimize this risk. The The treatment objective for this group of patients is 1318
1263 planned dentoalveolar surgery can be completed 3- to minimize the risk of developing MRONJ (Table 2). 1319
1264 4 months following the last dose of DMB when the Although a small percentage of patients receiving anti- 1320
1265 level of osteoclast inhibition is waning. It can then resorptives develop osteonecrosis of the jaw sponta- 1321
1266 be reinstituted 6-8 weeks postsurgery. This neously, the majority of affected patients experience 1322
1267 management strategy minimizes the length of the this complication following dentoalveolar sur- 1323
1268 drug holiday while maintaining a favorable gery.5,112,165,206,207 Therefore, if systemic conditions 1324
1269 environment for bone healing. permit, initiation of antiresorptive therapy should be 1325
1270 delayed until dental health is optimized.173,208 This de- 1326
1271 cision must be made in conjunction with the treating 1327
1272 BONE TURNOVER MARKERS physician and dentist and other specialists involved 1328
1273 Since the 2014 AAOMS position paper, there has in the care of the patient. There is widespread 1329
1274 been a shift away from bone turnover markers. No bio- consensus that optimizing dental health prior to initi- 1330
1275 markers are validated for clinical decision-making, and ating therapy is efficacious and of paramount impor- 1331
1276 continued research and prospective studies are tance.38,185,186,209 Medical oncologists should 1332
1277 required before these markers can be considered effi- educate their patients about the importance of dental 1333
1278 cacious tools in estimating MRONJ risk. health and the efficacy of prophylactic dental treat- 1334
1279 ment in the prevention of MRONJ. Similar to patients 1335
1280 who are to receive radiation therapy, optimizing the 1336
1281 OTHER BIOMARKERS dental health in patients receiving antiresorptives or 1337
1282 Biomarkers related to angiogenesis, VEGF activity, other therapies that can compromise bone healing is 1338
1283 endocrine function, and PTH have more recently essential. The pretreatment evaluation of dental health 1339
1284 been described.203-205 These markers remain at an must extend beyond a review of systems and include a 1340
1285 exploratory stage and are not yet validated for physical and radiographic exam. Therefore, a compre- 1341
1286 clinical decision-making. hensive dental examination performed by a dental 1342
1287 1343
1288 1344

RUGGIERO ET AL 13
1345 health professional would be a prudent approach for tients receiving oncologic doses of BPs and those 1401
1346 all patients prior to receiving antiresorptive therapy receiving osteoporotic doses of BPs were similar. A 1402
1347 for malignant disease. This level of dental health assess- plateau and a decline in the use of BPs for osteoporosis 1403
1348 ment is most appropriately performed by a dental was noted in 2006 and is hypothesized to be associ- 1404
1349 health professional. ated with various safety concerns, such as MRONJ. Pa- 1405
1350 The importance of minimizing the burden of dental tients are becoming increasingly more reluctant to 1406
1351 infection and inflammation prior to dentoalveolar sur- begin or comply with their antiresorptive therapy. Cur- 1407
1352 gery in this cohort of patients with an elevated MRONJ rent evidence also confirms an increase in fragility frac- 1408
1353 risk cannot be over-emphasized. Nonrestorable teeth tures with significant associated morbidity. As one 1409
1354 and those with a poor prognosis should be extracted. salient example, hip fracture rates in the United States 1410
1355 Other necessary elective dentoalveolar surgery also declined each year from 2002 to 2012 and then pla- 1411
1356 should be completed at this time. It remains advisable teaued at levels higher than projected for 2013 to 1412
1357 that antiresorptive therapy should be delayed, if sys- 2015, attributable to an ‘‘osteoporosis treatment 1413
1358 temic conditions permit, until the surgical site(s) gap.’’210 Hip fracture carries significant morbidity, 1414
1359 have mucosalized or until there is adequate osseous with only 40 percent to 60 percent of individuals 1415
1360 healing. Dental prophylaxis, caries control, conserva- recovering their prefracture level of mobility and abil- 1416
1361 tive restorative dentistry, and nonoperative endodon- ity to perform instrumental activities of daily living.211 1417
1362 tic therapy are critical to maintaining functionally These data are representative of a true health crisis. 1418
1363 sound teeth. This level of care must be continued on The documented risk for developing MRONJ is low; 1419
1364 a frequent and indefinite basis.185 however, the patient-perceived risk is not. As such, pa- 1420
1365 The posterior lingual plate region is a common site tients are unwilling to start or continue antiresorptive 1421
1366 for trauma and mucosal irritation in denture medical therapy. Patients are irrationally denying 1422
1367 wearers.5,75,170 Therefore, patients with full or partial themselves the tangible therapeutic benefit of antire- 1423
1368 dentures should be examined for areas of mucosal sorptive therapy to minimize the risk of fragility frac- 1424
1369 trauma, especially along the lingual flange region. It tures in order to prevent a minuscule risk of 1425
1370 also is critical that patients be educated as to the developing MRONJ. 1426
1371 importance of dental hygiene and regular dental eval- It is clear the benefit of fracture prevention out- 1427
1372 uations, and specifically instructed to report any weighs the risk of MRONJ development in osteopo- 1428
1373 pain, swelling, or exposed bone. rotic patients.212 This benefit is even more favorable 1429
1374 in the cancer population where bone-stabilizing med- 1430
1375 ications significantly improve quality of life, and it is 1431
1376 PATIENTS SCHEDULED TO INITIATE ANTIRESORPTIVE detrimental when antiresorptives are withheld due 1432
1377 TREATMENT FOR OSTEOPOROSIS. to MRONJ safety concerns. 1433
1378 Patients who are scheduled to receive antiresorptive 1434
1379 therapy for the prevention of fragility fractures assume 1435
1380 a significantly lower risk of MRONJ. Therefore, the ur- 1436
1381 gency and the timing of optimizing the dental health ASYMPTOMATIC PATIENTS RECEIVING 1437
1382 are not as crucial. However, at the initiation of treat- ANTIRESORPTIVE THERAPIES FOR CANCER. 1438
1383 ment, it would be prudent to educate patients Maintaining good oral hygiene and dental care is of 1439
1384 regarding the potential risks of MRONJ. The impor- paramount importance in preventing dental disease 1440
1385 tance of optimizing dental health throughout this treat- that may require eventual extractions or other dentoal- 1441
1386 ment period and beyond cannot be underestimated. veolar surgery. Procedures that involve direct osseous 1442
1387 It is not uncommon for patients to seek the consul- injury should be avoided if possible. If a dentoalveolar 1443
1388 tation of an oral and maxillofacial surgeon in guiding surgical procedure is unavoidable (eg, fractured tooth, 1444
1389 their decision about starting or continuing antiresorp- advanced periodontal disease), patients should be 1445
1390 tive therapy. In this scenario, the consulting oral and informed of the associated risks. The benefit of a 1446
1391 maxillofacial surgeon should use this opportunity to drug holiday remains unsubstantiated in this setting. 1447
1392 place the risks and benefits into the proper perspec- Nonrestorable teeth may be treated by removal of 1448
1393 tive. More specifically, patients should be reminded the crowns and endodontic treatment of the remain- 1449
1394 of the benefits associated with antiresorptive therapies ing roots.213 Teeth may be extracted if necessary. 1450
1395 in preventing fragility fractures and an acknowledg- Placement of dental implants should be avoided in 1451
1396 ment of the rare occurrence of MRONJ. the oncology patient receiving parenteral antiresorp- 1452
1397 The initial enthusiasm and attention associated with tive therapy or antiangiogenic medications. Case series 1453
1398 the discovery of MRONJ have had unintended conse- and systematic reviews have reported necrosis associ- 1454
1399 quences. When initially described, a ‘‘class effect’’ ated with antiresorptive therapy and implant place- 1455
1400 was observed, suggesting that MRONJ rates for pa- ment.194,214-216 1456

14 ---
1457 ASYMPTOMATIC PATIENTS RECEIVING inhibitors or other targeted therapies, AAOMS con- 1513
1458 ANTIRESORPTIVE THERAPY FOR OSTEOPOROSIS. siders this to have a similar level of risk. 1514
1459 Since the 2014 position paper, epidemiologic data In summary, robust data do not exist, and available 1515
1460 regarding the risk of MRONJ in patients receiving anti- data are conflicting. Therefore, AAOMS suggests that 1516
1461 resorptive therapy for osteoporosis remain limited due if dental implants are placed, informed consent should 1517
1462 to the lack of sound prospective studies with sufficient be provided to include the low risk of MRONJ, as well 1518
1463 power. Nevertheless, the risk for developing MRONJ is as early and late implant failure. These patients should 1519
1464 between 0.02 percent and 0.04 percent for BPs and 0.3 be placed on a regular long-term recall schedule. 1520
1465 percent for DMB. (see Table 1). Sound recommenda- 1521
1466 tions based on strong clinical research design are still Treatment Strategies 1522
1467 lacking for patients taking oral BPs. 1523
1468 In general, elective dentoalveolar surgery does not AAOMS has developed a series of treatment algo- 1524
1469 appear to be contraindicated in this group. Risk assess- rithms to streamline the evaluation (Fig 1) and manage- 1525
1470 ment for the development of MRONJ in these patients ment strategies (Figs 2-4) for patients with MRONJ. 1526
1471 includes the above-stated data and the discussion These strategies are based on a current review of 1527
1472 above related to drug holidays. nonoperative and operative therapies and their 1528
1473 The placement of dental implants in the context of associated outcomes. Emphasis is placed on both 1529
1474 antiresorptive therapy for osteoporosis continues to nonoperative and operative management being 1530
1475 be an area of research interest. Several systematic re- acceptable for all stages of disease based on surgical 1531
1476 views have acknowledged the lack of quality data judgment and patient factors in a shared decision- 1532
1477 and randomized clinical trials. Some studies have rec- making model. 1533
1478 ommended caution, especially with a longer dura- 1534
1479 tion of therapy or steroid use.194,216 For example, NONOPERATIVE THERAPY 1535
1480 in their systematic review, Granate et al,216 identified The efficacy of nonoperative therapies in the man- 1536
1481 several studies that reported an elevated MRONJ risk agement of MRONJ is documented in the literature 1537
1482 associated with implants placed in the posterior jaw and provides a useful adjunct to the spectrum of man- 1538
1483 if the duration of bisphosphonate therapy exceeded agement strategies that also include operative treat- 1539
1484 3 years and if the patients were receiving systemic ment (Fig 2). Nonoperative strategies can be useful 1540
1485 corticosteroids. In contrast to these studies, system- in all stages, especially where significant comorbidities 1541
1486 atic reviews by Gelazius et al, and Stavropoulos et al, preclude operative treatment. They may also result in 1542
1487 reported no increase in risk.214,217 A recent retro- stabilization of disease or cure in earlier stages. The 1543
1488 spective propensity-matched cohort study of goal of both operative and nonoperative therapies re- 1544
1489 44,900 patients reported a decreased risk of ONJ in mains the same: curative therapy and quality-of-life 1545
1490 osteoporosis patients receiving implants compared improvement. Nonoperative therapy heavily focuses 1546
1491 to matched controls who did not have implants. Of on patient education, reassurance, control of pain, 1547
1492 note, 9,738 patients had a history of BP use, and and control of secondary infection to allow for seques- 1548
1493 the results for implants was in contrast to risk in- tration of the exposed, necrotic bone.3,63 1549
1494 crease for patients who underwent tooth Decisions on operative versus nonoperative therapy 1550
1495 extraction.218 should be patient-specific and tailored to individual 1551
1496 Reports of implant-related (MRONJ) necrosis can be needs. The risk versus benefit ratio (including quality 1552
1497 divided into the early (implant surgery-triggered) or of life with their current symptomology), ability to 1553
1498 late (implant presence-triggered) category.215,219,220 perform good wound care to prevent infection and dis- 1554
1499 In these reviews, the majority of the implant-related ease spread, morbidity from a major surgical proced- 1555
1500 necrosis were not related to the initial implant surgery ure, as well as oral function or dental rehabilitation 1556
1501 but occurred late (>12 months) and often at sites after marginal or segmental resection should be 1557
1502 where implants were placed prior to the initiation of considered. Radiographic imaging is of utmost impor- 1558
1503 bisphosphonate therapy. The common presentation tance in the evaluation of MRONJ lesions. Three- 1559
1504 was an en bloc failure, where the osseointegration of dimensional imaging can identify forming or fully 1560
1505 the implants is maintained within the seques- formed sequestra and potentially decrease the inva- 1561
1506 trum.220,221 This has been recognized as a separate siveness of a surgical procedure. Maintenance of 1562
1507 pattern of failure that is distinct from the common maxillary or mandibular integrity is desirable, as the 1563
1508 peri-implantitis failure and considered by some to be reconstruction of surgical defects in this population 1564
1509 pathognomonic of MRONJ. Although there are no pro- can be challenging.63,222 1565
1510 spective studies or systematic reviews pertaining to Stage 1 patients can be managed with chlorhexidine 1566
1511 implant-related necrosis associated with RANKL wound care and improved oral hygiene to remove the 1567
1512 1568

RUGGIERO ET AL 15
1569 1625
1570 1626
1571 1627
1572 1628
1573 1629
1574 1630
1575 1631
1576 1632
1577 1633
1578 1634
1579 1635
1580 1636
1581 1637
1582 1638
1583 1639
1584 1640
1585 1641
1586 1642
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1587 1643
1588 1644
1589 1645
1590 1646
1591 FIGURE 1. XXX. Q7 1647
1593 1649
1594 1650
1595 biofilm from the necrotic bone surface.63 Surgery may require antibiotics for symptom control. Those pa- 1651
1596 not be indicated in the absence of disease progression, tients who remain refractory to nonoperative treat- 1652
1597 with patient adequate quality of life.63,223 Stage 2 pa- ment or those patients who cannot maintain 1653
1598 tients may struggle with local wound care and may adequate hygiene may benefit from operative therapy. 1654
1599 1655
1600 1656
1601 1657
1602 1658
1603 1659
1604 1660
1605 1661
1606 1662
1607 1663
1608 1664
1609 1665
1610 1666
1611 1667
1612 1668
1613 1669
1614 1670
1615 1671
1616 1672
1617 1673
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1618 1674
1619 1675
1620 1676
1621 1677
1622 1678
1623 FIGURE 2. XXX. 1679

16 ---
1681 1737
1682 1738
1683 1739
1684 1740
1685 1741
1686 1742
1687 1743
1688 1744
1689 1745
1690 1746
1691 1747
1692 1748
1693 1749
1694 1750
1695 1751
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1696 1752
1697 1753
1698 1754
1699 1755
1700 FIGURE 3. XXX. 1756
1701 Ruggiero et al. ---. J Oral Maxillofac Surg 2022.
1757
1702 1758
1703 1759
1704 In the presence of developing or established bony studies and controlled trials have yet to demonstrate 1760
1705 sequestra, nonoperative therapy may be indicated to the efficacy of the aforementioned treatments.226-229 1761
1706 allow for ultimate sequestrectomy. Exfoliation of the Therefore, these therapies should not be 1762
1707 exposed, necrotic bone will often result in disease res- recommended as a mainstay of treatment at this time. 1763
1708 olution.63,224,225 Therefore, for those patients with The use of vitamin E and pentoxifylline as an adjunct 1764
1709 Stage 2 or 3 diseases who are poor surgical candidates, to standard MRONJ therapies have been reported only 1765
1710 nonoperative therapies may be indicated (Fig 2). in case studies. A randomized, prospective, placebo- 1766
1711 There is little evidence to suggest that the use of controlled trial of vitamin E and pentoxifylline is un- 1767
1712 adjunctive therapies, such as hyperbaric oxygen or derway and will provide additional information about 1768
1713 ozone therapy, can lead to MRONJ resolution. Larger this treatment modality. Teriparatide, one of the few 1769
1714 1770
1715 1771
1716 1772
1717 1773
1718 1774
1719 1775
1720 1776
1721 1777
1722 1778
1723 1779
1724 1780
1725 1781
1726 1782
1727 1783
1728 1784
1729 1785
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1730 1786
1731 1787
1732 1788
1733 1789
1734 1790
1735 FIGURE 4. XXX. 1791

RUGGIERO ET AL 17
1793 anabolic agents used for the treatment of osteoporosis, of antiresorptive therapy for all stages of MRONJ dis- 1849
1794 also has shown promise as an adjunct for the treatment ease.245 The benefit of drug holidays for the operative 1850
1795 of MRONJ in osteoporotic patients.230 intervention of MRONJ has not been substantiated. 1851
1796 1852
1797 1853
1798 OPERATIVE THERAPY 1854
1799 While nonoperative therapy continues to be a treat- 1855
Future Research
1800 ment option for MRONJ, operative therapy is increas- 1856
1801 ingly reported as a viable option with high success AAOMS realizes that MRONJ is a complex disease 1857
1802 Q5 rates for all stages of the disease (Figs 3 and 4). process with a multifactorial etiology for which 1858
1803 Numerous reports have identified high success rates many questions remain unanswered. Continued pre- 1859
1804 associated with resection of MRONJ lesions.231-237 clinical and clinical data are required, especially in 1860
1805 Importantly, one must consider that MRONJ may the form of prospective studies. Continued research 1861
1806 progress over time, albeit in an unpredictable efforts and the outcomes that result should be consid- 1862
1807 manner.238 Furthermore, adopting a nonoperative ered the foundation upon which recommendations 1863
1808 approach to MRONJ does not uniformly result in are developed that will guide patients and providers. 1864
1809 sequestration of the exposed necrotic bone with dis- While the data supporting the conclusion that antire- 1865
1810 ease resolution.239 Thus, operative intervention sorptives represent genuine risk factors are robust, 1866
1811 should be explored and presented as a treatment op- this is not the case for other classifications of medica- 1867
1812 tion in an attempt to reduce the progression of disease tions (eg, antiangiogenics, corticosteroids, immune 1868
1813 with the recognition that early surgical intervention modulators). Published studies have reported a rela- 1869
1814 can predict beneficial patient outcomes.240 tionship of certain dosing practices (eg, transition 1870
1815 Segmental or marginal resection of the mandible from BPs to DMB) or a synergistic effect between anti- 1871
1816 and partial maxillectomy are effective methods to con- resorptive medications and antiangiogenic medication 1872
1817 trol MRONJ.231-238,241 This approach can be applied to with a risk of MRONJ. These associations, however, are 1873
1818 patients with all stages of MRONJ, including Stage 1 based on case reports and small case series. It also has 1874
1819 disease.169 These resections require margins beyond been hypothesized that the total exposure to an antire- 1875
1820 the borders of the necrotic bone to an area of vital, sorptive medication is a risk factor for developing 1876
1821 bleeding bone. Additional reports have identified suc- MRONJ. However, this has been difficult to demon- 1877
1822 cess when surgical resection of MRONJ was per- strate, possibly as a result of not having a good measure 1878
1823 formed by experienced surgeons.242,243 Consistent of exposure other than years of treatment. Similar to 1879
1824 with surgical principles, control of comorbid condi- the cancer risk associated with tobacco use (eg, 1880
1825 tions is paramount in managing MRONJ.241 Physiolog- pack/years), the antiresorptive exposure risk MRONJ 1881
1826 ically compromised patients, such as those with an may be better defined as a cumulative dose load (eg, 1882
1827 increasing burden of distant metastatic disease, may mg equivalent of BP/years of exposure) that would ac- 1883
1828 not respond favorably to resection of their osteone- count for risk associated with different medications 1884
1829 crotic jaw, and may occasionally develop refractory and dosing schedules over time. Dose-reduction proto- 1885
1830 disease.241 Finally, surgical resection for MRONJ in pa- cols and individualized strategies for antiresorptive 1886
1831 tients with metastatic cancer may identify metastases therapy in long-term cancer survivors with a metasta- 1887
1832 in the jaw specimen, albeit in a minority of patients.62 tic bone disease are being explored. It remains to be 1888
1833 Active clinical and radiographic surveillance is crit- determined if these protocols will reduce the risk of 1889
1834 ical in the nonoperative management of patients MRONJ in this patient cohort.246 AAOMS acknowl- 1890
1835 with Stage 1, 2, and 3 diseases to monitor for signs of edges the challenge of elucidating potential risks asso- 1891
1836 disease progression. In patients who demonstrate ciated with nonantiresorptive therapies, alone or in 1892
1837 the failure of nonoperative therapy, early operative combination with antiresorptive medications, and 1893
1838 intervention is recommended. In patients with a pro- therefore considers it imperative that research efforts 1894
1839 gressive clinical or radiographic disease or more continue in the form of prospective studies. 1895
1840 advanced disease at presentation, surgical resection A review of the current literature also failed to pro- 1896
1841 of MRONJ should be performed without first insti- vide sound data in the form of randomized, controlled 1897
1842 tuting prolonged nonoperative measures. MRONJ rep- trials that would establish the effectiveness of bio- 1898
1843 resents a complex wound whereby operative therapy markers and drug holidays or validate a risk relation- 1899
1844 can be performed in a timely fashion.241,244 Although ship with genetic markers and MRONJ. Until these 1900
1845 controversy between operative and nonoperative relationships are established or refuted, AAOMS con- 1901
1846 therapies exist, operative treatment of patients has siders it prudent to recognize that these factors may 1902
1847 demonstrated maintenance of mucosal coverage, play a role in the development and management 1903
1848 improved quality of life, and expedient resumption of MRONJ. 1904

18 ---
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2022 Aaoms意见书：药物相关性颌骨坏死（更新版）

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PATHOLOGY

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1233 Table 2. MRONJ PREVENTION STRATEGIES

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