Medication-Related Osteonecrosis of the Jaw: Successful Medical Management of Complex Maxillary Alveolus with Sinus Involvement.

Introduction

Medication-related osteonecrosis of the jaw (MRONJ) is defined as exposed dental bone present longer than 8 weeks, that can be probed through an intraoral or extraoral fistula in patients with a history of treatment with antiresorptive or antiangiogenic medication(s) with no history of radiation therapy or metastatic disease to the jaw [1–3] . MRONJ staging has been proposed to guide clinical care ( Table 1 ) [2, 3] . The pathobiology of MRONJ is thought to include medication-related cytotoxicity affecting osteocytes, osteoblasts, osteoblasts, fibroblasts, as well as bone marrow cells, resulting in microcirculatory dysfunction and connective tissue destruction [2, 4] . These changes appear to primarily impact the connective tissue cellular elements, reducing angiogenesis, bone repair, and remodeling, with secondary inflammation or infection leading to MRONJ. Several risk factors have been identified for MRONJ ( Table 2 ) [5–7] .

Oral surgical procedures involving bones represent a high-risk factor for the triggering of MRONJ. However, dental and periodontal infection and inflammation are frequently present, leading to the necessary dental procedure, and may represent an independent risk factor if left untreated [3] . Dental management is therefore strongly recommended before initiating medications affecting bone and angiogenesis in cancer patients. A prospective study of 253 patients with prostate cancer receiving bisphosphonates (BPs) found that pretreatment dental care was associated with a 2.59-fold relative risk reduction in necrosis with an 82% decrease in cases of MRONJ reported [8] . Discontinuing antiresorptive therapy in cancer patients prior to dental extractions did not affect outcomes of necrosis in a prospective study of 23 patients [9] . Guidelines for “drug holiday” prior to dental treatment of MRONJ are not supported in current recommendations [2, 3, 10] . Nonetheless, discussion of appropriate management of medication use in MRONJ is continuing. Recent studies have focused on nonsurgical, medical management in conjunction with surgical therapy that is leading to an evolving and increasingly conservative approach to care [11] .

This paper outlines several of these approaches to medical management based on increasing understanding of the pathobiology of MRONJ, including topical or systemic agents (pentoxifylline and alpha-tocopherol [Pent-E], teriparatide, antibiotics, antiseptics, and other miscellaneous topical agents); biophysical therapies (hyperbaric oxygen [HBO], photobiomodulation [PBM], photodynamic therapy [PDT]); and adjunctive treatments with surgical management. We present three stage IV breast cancer (BC) patients (1 patient also had multiple myeloma [MM]) with complex clinical presentation of MRONJ managed at our institute using: (1) a combination of Pent-E, chlorhexidine, and PBM; (2) Augmentin, chlorhexidine, Pent-E, red/infrared light therapy, and teriparatide; and (3) ciprofloxacin, chlorhexidine rinse, Pent-E, and PBM therapy.

Topical or Systemic Agents for MRONJ Management

Pent-E: pentoxifylline was first described for use in osteoradionecrosis (ORN) [12] . The use in ORN leads to the use of pentoxifylline in MRONJ. Improving blood flow, regulation of TGF-β1/BP-signaling, and promotion of osteocyte and connective tissue cell function are potential actions of Pent-E with applicability in prevention and management of MRONJ [4] . In a rat MRONJ model, administering Pent-E before and after dental extraction resulted in 50% reduction in MRONJ and was associated with an increase in osteocytes and increase in blood flow ( p < 0.05) in the wound [13] . The first case series assessing Pent-E for MRONJ was published in 2010 [14] . Six cases were followed for a mean of 10 months with symptom control, and an overall 74% reduction in area of bone exposure was observed. Similar findings were reported in a single case reported in 2014 [15] . A retrospective observational study of 7 patients with metastatic bone disease or MM with MRONJ using Pent-E found all patients had symptom relief. New bone fill of lesions was noted in all patients: two with complete clinical resolution, two were improved, one had no change, and one with 3 lesions had resolution in one site, improvement in one site, and stability in one site [16] . Systematic reviews of Pent-E for MRONJ included observational and case series and showed utility in nonsurgical management of MRONJ. In 2019, three observational studies and two abstracts were included with evidence of subjective and objective improvement in MRONJ [17] . Pain reduction and new bone formation were reported [18] .

Teriparatide: an early report of teriparatide in treatment of MRONJ reported healing in all 6 patients within 2 months of treatment [19] . A randomized trial of teriparatide (20 μg/d) or placebo in 57 MRONJ lesions in 37 patients was performed [20] . The results from this study noted improved rate of resolution of MRONJ, with 45.4% of lesions in patients on teriparatide resolved versus 33.3% in those receiving placebo (OR 0.15 v 0.40; p = 0.013) and reduced bony defects upon resolution (OR 0.81; p = 0.017). Teriparatide with bone morphogenetic protein (BMP)-2 were evaluated in 17 patients [21] . This study noted increased bone formation reported with combination therapy than with BMP alone and compared it to controls.

Antibiotics and antiseptics: topical application of chlorhexidine via oral rinsing is standard in the management of MRONJ with the goal of reducing microbial colonization of exposed bone. When clinical findings of infection, including swelling, tenderness, exudate, and increased pain, are noted, systemic antibiotics are prescribed. Antimicrobial therapy may be required on an ongoing basis, and antibiotic rotation based on culture and sensitivity may be required in long-term management. A prospective trial supported use of antibiotics and antiseptics of 34 consecutive patients with MRONJ and found time-related decrease in area of exposed bone and pain reduction [22] . A recent single center report that employed antimicrobial therapy prior to surgery reported that 88.5% (31 of 35 patients) who had spontaneous loss of sequestrate and healing with medical management [23] .

Miscellaneous topical agents: local application of lactoferrin to sites of bone exposure was reported to enhance repair and improve wound closure following surgical treatment of MRONJ in an open label study [24] . Fluvastatin administered by local injection and by topical application in sites of MRONJ in animal models showed increased rate of healing, reduced necrotic bone, and new bone formation, supporting the potential in future clinical trials [25] .

Biophysical Agents for MRONJ Management

HBO: this approach uses a high-pressure (above ambient atmospheric) chamber with 100% oxygen and has been shown to improve perfusion, improve resilience to infections, and promote tissue healing. The molecular mechanism of HBO is based on the increased partial pressure of oxygen that generates reactive oxygen and reactive nitrogen species [26] . These intermediate chemical species can exert direct antimicrobial actions on infection-causing microbes, promote the resolution of inflammation, and improve tissue healing. While this treatment has shown prominent benefits in necrotizing soft tissue infections and osteomyelitis, it has not been recommended in MRONJ currently [2, 3] . The Cochrane review of 2022 did not support HBO for management of MRONJ [10] .

PBM: the use of low-dose visible and near-infrared light to reduce pain or inflammation and promote tissue healing and regeneration is termed PBM [27] . PBM treatment has the potential to prevent and treat a range of cancer care, and guidelines will be revised in the future [28] . Consistent results with infrared light were reported in a systematic review, with positive effects on bone repair in 75% of reviewed studies [29] . Increased connective tissue, new bone, and stability of implants have been shown with PBM [30–32] . PBM has been shown to reduce tissue inflammation, promote higher blood vessel count, and accelerate bone healing in tooth extraction sites [33] . Increased mineralization and differentiation of mesenchymal stem cells have also been shown with PBM [34] . Acceleration of bone healing with PBM was shown in a systematic review of animal studies following dental extractions [35] . These effects suggest potential for positive effects upon MRONJ. Studies in animal models of implant repair and integration confirm the positive effects of PBM, with evidence of increased bone density, trabecular bone density, and mucosal/epithelial regeneration [36] . PBM using red/infrared light has shown to accelerate periodontal and implant wound healing [37] .

Cellular and molecular aspects of PBM in bone healing: PBM has been shown to promote wound healing by increasing cell proliferation, migration, and differentiation [38, 39] . Increased viability of human adipose stem cells has been reported [40] . PBM has been shown to increase mitochondrial ATP in osteoblasts [41] , as well as enhance expression of osteocalcin, collagen, RUNX-2, vascular endothelial growth factor, bone morphogenic proteins (BMPs), and cyclooxygenase-2 (COX-2) [42] . PBM treatments have been shown to directly activate latent TGF-β1 that has key roles in bone biology [43–45] . Immunohistochemistry and molecular evaluation of bone repair have been included in some studies. Bilateral third molar extractions comparing PBM with no light therapy showed reduced inflammatory cell infiltration, more mature epithelium, and increased myofibroblasts in the extractions on the PBM-treated sites [46] . When combined with platelet-rich fibrin, PBM treatment resulted in increased bone volume and bone surface [47] . In a systematic review that included 37 articles, PBM reported accelerated healing in a review, with only 4 studies not showing improved outcomes [48] . Another systematic review that assessed bone healing in dental care and included 17 studies found that 11 showed improved bone repair while 6 reported no effect [49] . Meta-analysis of 2 RCT of fracture repair with 106 participants showed statistical improvement in physical function, but no difference in imaging was seen regarding healing [50] .

PBM in diabetic models: studies in diabetic animal models with PBM therapy are relevant as diabetes is recognized risk factor for MRONJ [51] . Hyperglycemic animals had significantly less bone regeneration than controls, but with PBM, bone regeneration increased comparable to that in non-diabetic control animals [52] . Significant effects upon healing of skin wounds in diabetic rats were seen with PBM [53] . Wound repair and wound strength increased in infected skin wounds of diabetic rats with PBM. In addition, PBM was shown to decrease CFU microbial counts in the wounds [54] . PBM has shown to accelerate healing in diabetic patient pressure sores with increased granulation tissue at treated sites. Gene expression analysis showed increased vascular endothelial growth factor and TGF-β and decreased TNFα, while IL6 was not affected [55] .

PBM and osteonecrosis: in patients at various stages of MRONJ, the overall success of PBM with complete healing was reported as 96% in a report of 241 patients exposed to antiresorptive or antiangiogenic therapy and patients with bone exposure [56] . Of the 108 patients treated with surgery, antibiotics, and PBM, 96% resolved, with only 1 case progressing. Another case report noted that in an 82-year-old man with BP-related MRONJ, five PBM treatment sessions every 2 days along with antibiotics and curettage reported complete healing within 3 weeks, and resolution was confirmed at 12-month follow-up [57] . Case reports of healing of chronic soft tissue necrosis due to radiation therapy have noted accelerating healing with PBM [58, 59] . A case report of lenvatinib-associated MRONJ in the maxilla was successfully managed with PBM [60] . In Gilsenan et al. [61] , teriparatide did not increase adult osteosarcoma incidence in a 15-year post-marketing surveillance study. The Osteosarcoma Surveillance Study was initiated in the USA in 2003 to monitor for a potential association between the osteoporosis treatment teriparatide and osteosarcoma. Osteosarcoma occurs at a background incidence rate of approximately 2.5 cases per million per year in US adults aged 40 years or older. The prevalence of suspected risk factors for the development of osteosarcoma among the osteosarcoma cohort was 19% for the history of radiation and 4% for the history of Paget’s disease of the bone. These findings showed that the incidence of osteosarcoma associated with teriparatide use during the 15-year surveillance period was no different than would be expected based on the background incidence rate of osteosarcoma.

PDT: the use of low-dose light treatments with an exogenous chromophore (dye or nanoparticle) is termed PDT. While there has been some confusion between the use of PDT and PBM, both are nonsurgical, nonthermal, light-based therapies, but PDT entails higher reactive oxygen species generation with the goal of destroying its target (microbes, tumors, or endothelial cells) [62] . In contrast, PBM treatments only reversibly inhibit or stimulate specific biological responses. PDT following dental surgery in a patient with ORN showed complete healing following treatments post-surgery and continuing twice weekly until repair was noted with no recurrence at 1 year follow-up [63] . PBM and methylene blue may enhance osteoblast biologic activity and cell proliferation that may be relevant in the management of osteonecrosis [64] . The antimicrobial effect of methylene blue and PDT has been shown with decreased microbial counts and reduced biologic activity/viability of Staphylococcal bacteria [65] and potential periodontal pathogens [66] . In a rat model of MRONJ, bone repair 1 month following extraction of a first molar found that PDT reduced osteonecrosis with evidence of decreased apoptosis of osteocytes, reduced mononuclear cells and T lymphocytes, and decreased gamma interferon in the specimen [67] . PDT using 0.1% methylene blue in patients at risk for MRONJ at the time of dental extraction was followed by weekly PBM until mucosal wound healing was assessed in a preventive protocol. No cases of MRONJ occurred in 18 patients following dental extraction. Another 17 patients with MRONJ received PDT until symptoms improved, followed by sequestrectomy and weekly PBM, with all but one case achieving wound closure [68] .

Adjunctive Approaches with Surgical Management for MRONJ

A Cochrane review in 2017 assessed controlled trials of one modality of treatment that included 5 trials. Evidence was insufficient for recommending plasma-rich growth factors for prevention or treatment. Some evidence of benefits of regular 3-month dental evaluation was found to potentially be more effective for reducing incidence of MRONJ [69] . An updated Cochrane review (2022) included 13 controlled trials (1,668 subjects). Lower risk for MRONJ was suggested in patients with regular dental examination and preventive treatment interventions for MRONJ, as well as management did not have adequate data for recommendation for use [10] .

Recent case reports suggest the addition of repair and growth factors may have utility in surgical management of MRONJ. Studies have included platelet-rich fibrin, mesenchymal stem cells, autologous platelet concentrate, and growth factors including bone morphogenic proteins [70–73] . A Cochrane review in 2017 assessed controlled trials of one modality of MRONJ treatment that included 5 trials. Evidence was insufficient for recommending plasma rich growth factors for prevention or treatment. HBO was not found to improve healing of MRONJ compared to standard therapy. An updated Cochrane review (2022) included 13 controlled trials (1,668 subjects). Lower risk for MRONJ was suggested in patients with regular dental examination and preventive treatment interventions for MRONJ, as well as management did not have adequate data for recommendation for use [10] . Growth factors have been discussed in treatment of MRONJ, often in the context of surgical treatment of the lesion. Platelet-rich fibrin appears to promote healing of extraction sites compared to controls ( p < 0.05) in patients previously treated with oral BPs [74] . Concentrated growth factors in surgically treated cases of MRONJ were studied in 28 patients, of whom 19 had complete resolution [72] . However, no differences were seen in placebo versus concentrated growth factor application in surgically treated cases. Growth factors present in human amniotic membrane were assessed in a case-control study of 49 patients of surgical wound healing with no difference in resolution identified [75] . Platelet-rich fibrin was assessed in management of MRONJ in 23 consecutive cases treated with surgical curettage and was reported to promote closure of bone exposure [76] . Surgical management of MRONJ including platelet-rich fibrin with/without bone morphogenic protein 2 (BMP-2) in 55 patients, found better outcomes ( p = 0.03) with combined therapy when assessing lesion resolution. Bacterial colonies in the biopsy specimen were found to be a significant factor in disease resolution ( p = 0.02) [77] .

In this report, we present 3 patients with advanced-stage MRONJ of the maxilla in a clinical setting using combined modality medical therapy, where surgical intervention was avoided and good outcome was achieved. Studies to date have assessed single-modality therapy in a small number of cases to provide guidance for clinical care. In the patients presented here, multiple medical interventions were combined based upon different mechanisms of action, evidence from prior case reports and small clinical trials, and potential synergistic effects in the medical management due to different mechanisms of action in complex cases with oroantral MRONJ (stage 3). In these patients, PBM was provided by a home device (Photonics Therapy Institute, red/infrared (650/810 nm) torch with fiber-optic oral probe tip in pulsed mode. Skin surface application provided 178 mW/s, 10.66 J/cm 2 per minute (15.99 p.J/cm 2 or 3.5 E), and intraoral application with fiber-optic tip delivering 1,066 mW/s, 63.96 J/cm 2 per minute (95.94 p.J/cm 2 or 21 E).

Case Reports

Patient 1

A 68-year-old female with a history of stage IV BC presented for evaluation of upper jaw discomfort. She previously received induction chemotherapy (CT), total mastectomy, and radiotherapy with concurrent CT and has been in sustained remission since 2015. She was maintained on trastuzumab, pertuzumab, and denosumab (120 mg every 4 weeks), which was discontinued upon detection of MRONJ and resumed when full mucosal cover occurred and symptoms resolved. Two dental implants were placed in the maxillary molar region on November 2, 2017, that subsequently failed and were removed, followed by several additional surgical procedures conducted under local anesthesia for removal of bony sequestra in 2019. However, she continued to experience a persisting lesion in the maxillary alveolus and developed sinus symptoms.

She was seen for medical management of MRONJ on November 7, 2019, and started Pent-E, chlorhexidine rinse 0.12% BID, and at-home PBM treatments for involved sites 1 min daily. She was seen monthly for follow-up, and in the office, PBM combined with 1% methylene blue was applied to the exposed bone. Augmentin 250 mg bid was prescribed to be used if swelling/exudate or pain developed. Augmentin was begun, and resistance developed. She was switched to ciprofloxacin based upon culture and sensitivity testing. She confirmed oral/antral communication by liquid exchange and sinus tenderness. On May 11, 2020, a 6 × 8 mm sequestrum was mobilized and digitally removed without surgical intervention, leaving isolated millimeter sites of bleeding, following which clinical symptoms and findings improved. Complete resolution was confirmed at the 6-month follow-up, and at last follow-up, 13 months post-medical management with complete resolution.

Prior to MRONJ treatment (July 22, 2019), positron emission tomography-computed tomography (PET/CT) showed FDG activity in the right upper molar region (SUV 11.2) on 10/16/19 (shown in Fig. 1 a), with a prior image of the area (SUV5.5). She received 8 weeks of teriparatide injection (20 μg daily) from December 15, 2020, to February 9, 2021. After beginning treatment, follow-up PET/CT on June 24, 2020, showed no uptake (shown in Fig. 1 b). The last PET/CT on November 30, 2022, also did not show uptake in the jaw (shown in Fig. 1 c).

Patient 2

A 36-year-old female diagnosed with de novo stage IV BC in March 2019 with metastasis to the brain, bone, liver, and lung developed jaw discomfort. First-line treatment included tamoxifen, trastuzumab, and pertuzumab in June 2019. She received SBRT for brain metastasis in July 2019. She received denosumab 120 mg once and switched to zoledronic acid (4 mg every 6 weeks) from June 2019 to March 2021. On August 25, 2021, she was referred due to painful bone exposure in the lower left jaw and in the upper right molar region. Mild tenderness was present over the left maxillary alveolus and maxillary antrum with extraoral and intraoral palpation. A large area of bone exposure over the left maxillary residual arch was seen. This sequestrum was minimally mobile, suggesting progress in sequestration. Bone exposure and soft tissue inflammation extended to the depth of the vestibule on the buccal aspect of the molar/bicuspid region. The adjacent teeth were highly mobile, and extension of necrosis into the sinus (stage III) was identified. Symptoms of sinusitis were reported. An additional area of exposed bone was present in the right mandible (stage I).

Medical management for necrosis included Augmentin 500 mg BID, chlorhexidine oral rinsing BID, and Pent-E BID. Red/infrared light therapy is delivered daily using a home LED unit. Management continued for 9 months. Teriparatide was started on September 22, 2021, 20 μg daily and completed on November 30, 2021. On December 8, 2021, spontaneous exfoliation of the sequestrum and involved tooth in the mandible occurred. The site had full mucosal cover. MRONJ with large area of bone exposure over the left maxillary residual arch remained. This sequestrum was minimally mobile, suggesting progress in sequestration. SPECT imaging with technetium-99 on August 12, 2020, showed uptake consistent with dental disease in the maxilla and mandible. On November 24, 2020, greatest uptake was seen in the left maxilla and left mandible (shown in Fig. 2 a). She received 8 weeks of teriparatide injections (20 μg daily) from May 24, 2021, to July 19, 2021. CT face/neck with contrast, January 11, 2022, suggested bony sequestra in the left maxilla, with soft tissue thickening of the sinus floor (shown in Fig. 2 b).

The maxillary sequestrum exfoliated on May 4, 2022. Residual mild tenderness at the apical area of the buccal vestibule in the bicuspid/molar region was seen at the last follow-up. There was no tenderness over the antrum. Nine months after diagnosis (May 4, 2022), full mucosal cover of the left residual maxillary alveolus was seen. Alveolar bone loss with rounded contours of residual bone and no tenderness on the palatal surface was noted. There was moderate erythema in the upper vestibule of the buccal aspect of this area with minimal tenderness. There was no exudate and no fistula. The adjacent first bicuspid tooth and second molar tooth were moderately mobile, and recession of the gingival and periodontal tissues of the distal aspect of the bicuspid on the mesial aspect of the second molar and moderate mobility of these teeth were noted.

Patient 3

A 75-year-old female with IgA MM was seen for MRONJ diagnosed in September 2021. She had a history of triple negative BC diagnosed in 2002, was in remission until 2021, when she was diagnosed with DCIS and received local radiation therapy in May 2021, and is now in remission with continued anastrozole. She was diabetic on insulin and metformin and had acute renal insufficiency and anemia secondary to MM and CT. MM therapy included multiple medication protocols and autologous transplant in 2011. She was taking pomalidomide (2 mg every 2 days) due to recent increase in light chains. She had received a total of 10 courses of zoledronic acid, which was discontinued due to dental pain. She was never a tobacco user.

Swelling and pain were reported in the left mandible, and she was aware of rough bone in the maxillary right canine region with swelling and pain extending to the depth of the vestibule. She did not report symptoms of oroantral fistula. She was diagnosed with MRONJ. Medical management included ciprofloxacin, chlorhexidine rinse, Pent-E, and home PBM therapy once daily. She did not tolerate Pent-E due to nausea and discontinued Pent-E. All other treatment continued for 7 months.

On March 30, 2022, she reported spontaneous loss of the lower left first bicuspid as well as loss of bone in the right upper jaw, after which local pain resolved. She had localized tenderness and pressure in the right upper canine region and in the lower left bicuspid region, where the bicuspid tooth was exfoliated before the prior visit with her. Localized tenderness remained at the site. In the upper canine area, minimal swelling and mild tenderness with bone exposure measuring 3 × 4 mm remained.

She continued to use red/infrared LED light twice daily at home and chlorhexidine rinse which was increased to 4 times daily rinsing due to clinical candidiasis. Amoxicillin 250 mg TID × 10 days was prescribed due to secondary infection.

Twelve months following diagnosis (August 3, 2022), minimal bone exposure remained in the maxillary area (2 × 1 mm). The area was not tender, and no pain was reported with palpation over the sinus; mild sensitivity was present immediately over the minor area of bone exposure. In the left lower bicuspid region, a 3 mm-diameter area of bony exposure remained at the depth of the defect of the alveolar bone with evidence of granulation at the site. No exudate was produced upon palpation. The remaining area was covered with mucosa over the edentulous ridge. The adjacent teeth were not mobile, and there was tenderness to percussion of the teeth. Further remodeling of the bone and increased mucosal cover have occurred in the sites of MRONJ. At this visit, MRONJ in the mandible was associated with secondary infection.

A panoramic image of the jaws on September 30, 2021, showed irregularity of bone in the right maxillary bone, with loss of visible sinus floor (shown in Fig. 3 a). PET/CT on November 14, 2021, showed activity in right maxilla (SUV 10.3). Panoramic imaging on August 3, 2022, showed loss of bicuspid lower left, bone loss in the right upper jaw, sinus floor appeared intact, and no visible sinus lining thickening (shown in Fig. 3 b). The CARE Checklist has been completed by the authors for these case reports, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000529502 ).

Discussion

The etiology and pathophysiology of MRONJ are complex and hypothesized to involve inflammation or infection, impaired bone remodeling, and angiogenesis with risk due to impact of bone-modifying agents, antiangiogenic drugs, and some targeted medications. In the position paper of AAOMS, medical management was discussed as non-operative therapy [2] . Imaging was reported as essential with suggestion of three-dimensional imaging best performed using cone-beam CT. Other imaging including nuclear medicine and PET scan imaging can support diagnosis and assess progression or recovery was not discussed. Single photon emission computed tomography (SPECT) was evaluated in 7 patients (three cases of MRONJ, three ORN, and one rheumatoid arthritis compared to normal mandible) and reported the highest uptake demonstrated in cases of MRONJ [78] . SPECT imaging provides evidence of biologic activity in the bone with potential application in MRONJ diagnosis and management. In the patients presented in this report, uptake was seen prior to diagnosis of MRONJ in 2 patients and confirmed at the time of diagnosis in all cases. In all patients, functional imaging improved with medical management, suggesting correlation with bony involvement and repair. As these patients demonstrated, PET/technetium-99 SPECT imaging correlated with clinical diagnosis, findings, symptoms, and in resolution was shown. Consideration should be given to the utility of biological imaging in clinical management and staging of MRONJ.

To date, medical management of MRONJ has been primarily antimicrobial therapy. Developing research demands extension of medical management to include interventions to support bone and mucosal repair. In AAOMS guidelines, Pent-E and teriparatide were mentioned as potential interventions. MASCC/ISOO/ASCO guidelines do not discuss medical management other than antimicrobial therapy and good oral care [3] . Combined medical therapies are not adequately emphasized. Non-operative treatments may be better described as medical management and can be potentially useful in all stages to treat or stabilize early stages of MRONJ. This was not recommended in advanced cases in the prior recommendations. In contrast, our patients suggest that combined medical management should be considered in all cases of MRONJ including stage III, prior to determining if surgical intervention is required. Decisions on management should be patient-specific. MASCC/ISOO/ASCO recommends medical management prior to considering surgical management. Surgical management is described as segmental and marginal resection with or without surgical reconstruction. Primary closure with/without bone repair and growth factors are considered in advancing stages. In patients who failed medical management of MRONJ, surgical management is considered.

Complex surgical intervention may be contraindicated in oncology patients. This has been previously described in ORN, where medical management is recommended. Two cases treated with Pent-E for grade III ORN with pathological fractures and oro-cutaneous fistula were not surgical candidates and showed successful medical management, suggesting this approach was effective in advanced cases [79] . In addition to improving symptoms, medical management in MRONJ may reduce or eliminate the need for eventual surgical interventions. This could result in reduced risks related to surgical management, improved quality of life, and reduced cost of care. This report outlines our experience where combined modality medical therapy led to good outcomes in MRONJ stage III disease of the maxillary dental arch, including a case involving adjacent sinus. The loss of sequestrum with an intact oral-antral barrier had dramatic and positive outcome of management.

We employed combined medical management documented as potential interventions in small studies, with less advanced cases of maxillary MRONJ. It is not possible to determine if a specific intervention was more impactful in the management of our cases, but the good outcomes seen with combined modality management that is well tolerated and without toxicity suggest this synergistic approach may be most appropriate for complex cases of MRONJ. Of the side effects noted, 1 patient experienced nausea with Pent-E, which was discontinued. Teriparatide was used in two cases. Intermittent antibiotics were used in the presence of clinical infection. In one case, antibiotic resistance developed, and culture and sensitivity were necessary to guide continuing antibiotic therapy. In all cases, medical management included PBM treatments and chlorhexidine rinsing. There is robust evidence for the role of PBM in MRONJ management from lab animal studies and human clinical reports.

Much of the literature is based upon case studies of MRONJ, and further study is required, although individual approaches are now being assessed in controlled clinical trials. Continuing studies using each modality are required to better delineate dosing and schedule of therapy. In summary, this report presents clinical nonsurgical management of challenging cases of MRONJ, using combined modality medical/nonsurgical therapy, as a “real world” clinical approach to management, which in these cases did not require complex surgical management for good outcomes. The cases suggest a multimodality care algorithm including Pent-E (when tolerated), teriparatide (20 μg/day × 2 month), chlorhexidine with exposed bone, antibiotics when clinical infection occurs, and PBM. PBM may be delivered by the medical provider and in patients instructed in home use of an LED-based PBM device, with light therapy applied one or two times daily. These patients present “real world” care in complex cases of MRONJ, with successful management not requiring surgery and possible reconstruction. This suggests the need for multidisciplinary medical management with PBM, which should be considered even in advanced cases with sinus involvement.

Acknowledgments

The authors thank the patients and their families for participating in this study.

Statement of Ethics

The study was approved by the City of Hope Internal Review Board under IRB 07047 (effective January 21, 2020, January 10, 2018, and February 13, 2020). All procedures were performed in accordance with the ethical standards of the City of Hope, the National Research Ethics Committee, the 1964 Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice, and later amendments or comparable ethical standards. Written informed consent was obtained from the patients for publication of these case reports and any accompanying images.

Conflict of Interest Statement

Dr. Yuan has contracted research sponsored by Merck, Eisai, Novartis, Puma, Genentech, Celgene, and Pfizer; is a consultant for Pfizer and Gilead; and is on the Speakers Bureau for Merck, Genentech, AstraZeneca, Daiichi Sankyo, and Gilead. The other authors declare that they have no competing interests.

Funding Sources

City of Hope core facilities were supported by the National Cancer Institute of the National Institutes of Health (P30CA033572).

Author Contributions

Conceptualization, supervision, and writing – original draft preparation: J.B.E.; methodology, validation, and writing – review and editing: J.B.E, P.R.A., S.E.Y., and Y.Y.

Funding Statement

City of Hope core facilities were supported by the National Cancer Institute of the National Institutes of Health (P30CA033572).

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.

Supplementary Material

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Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.