Clin Oral Invest DOI 10.1007/s00784-014-1384-1

ORIGINAL ARTICLE

Stage-related treatment concept of medication-related osteonecrosis of the jaw—a case series Petra Rugani & Stephan Acham & Barbara Kirnbauer & Astrid Truschnegg & Barbara Obermayer-Pietsch & Norbert Jakse

Received: 2 June 2014 / Accepted: 2 December 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Objectives There is no general consensus for treatment of medication-related osteonecrosis of the jaw (MRONJ). A stage-related approach that primarily aims to minimize morbidity and preserve function was prospectively evaluated. Patients and methods Treatment goals are stable mucosal closure and absence of clinical symptoms. Patients were enrolled between March 2010 and October 2011. MRONJ lesions were treated either by conservative means or surgically by debridement or resective surgery. Results In total, 38 patients were treated. Six patients were healed by undergoing conservative measures; nine were treated palliatively. Four patients dropped out after surgery in the recall phase. In 17 of 19 patients (89.5 %) surgical treatment was successful. After a 1-year observation period, the success rate was 92 % (23 of 25), including all patients treated as per protocol. Results were presented at the Annual Congress of Austrian Dentists 2013. Petra Rugani and Stephan Acham contributed equally. P. Rugani (*) : S. Acham : B. Kirnbauer : A. Truschnegg : N. Jakse Department of Oral Surgery and Radiology, Medical University of Graz, Graz, Austria e-mail: [email protected] S. Acham e-mail: [email protected] B. Kirnbauer e-mail: [email protected] A. Truschnegg e-mail: [email protected] N. Jakse e-mail: [email protected] B. Obermayer-Pietsch Division of Endocrinology and Nuclear Medicine, Department of Internal Medicine, Medical University Graz, Graz, Austria e-mail: [email protected]

Conclusion In stage-related treatment, conservative means or surgical debridement can be successful at early stages. Extensive resection is solely indicated in cases of extended necrosis. Clinical relevance The number of patients with MRONJ is steadily increasing. Guidelines to deal with this condition are helpful for both clinicians and dental practitioners. Keywords Antiresorptive therapy . Jaws . Medication-related osteonecrosis . Treatment concept . Surgical therapy

Introduction In 2014, the term medication-related osteonecrosis of the jaw (MRONJ) was introduced, replacing the common expression BRONJ (bisphosphonate-related osteonecrosis of the jaw), as this condition can also result from treatment with other antiresorptive (denosumab) and antiangiogenic therapies. The American Association of Oral and Maxillofacial Surgeons (AAOMS) defines MRONJ as a condition of exposed or probable bone in the maxillofacial region without resolution for greater than 8 weeks in patients treated with an antiresorptive and/or an antiangiogenic agent who have not received radiation therapy to the jaws. Five stages are specified [1] (Table 1). A general consensus for treatment of MRONJ has not yet been reached even though several authors and institutions have published proposals. Basically, there are two different options: conservative measures and more or less advanced surgical approaches. In the beginning of MRONJ treatment, the success of surgical therapy was poor. Recurrence of exposed bone, infection, and pain were common. The method relied mainly on experience gained in the treatment of osteoradionecrosis. The fact that bisphosphonates deposit in the whole jaw, making it

Clin Oral Invest Table 1

AAOMS 2014 staging [1]

MRONJ staging At risk category: no apparent necrotic bone in patients who have been treated with either oral or IV bisphosphonates Stage 0: no clinical evidence of necrotic bone, but non-specific clinical findings, radiographic changes and symptoms Stage 1: exposed and necrotic bone, or fistulae that probes to bone, in patients who are asymptomatic and have no evidence of infection Stage 2: exposed and necrotic bone, or fistulae that probes to bone, associated with infection as evidenced by pain and erythema in the region of the exposed bone with or without purulent drainage Stage 3: exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone (i.e. inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla), resulting in pathologic fracture, extra-oral fistula, oral antral/oral nasal communication or osteolysis extending to the inferior border of the mandible of sinus floor

impossible to position the resection margins in unaffected bone, was thought to be a possible reason. Consequently, Marx proposed to focus the therapy not on healing but on controlling MRONJ symptoms and avoiding progression of disease by conservative means [2]. This recommendation was widely adopted [3–8]. Conservative measures are antiseptic mouth rinses, the administration of antiphlogistics and analgetics, and antibiotic and antimycotic therapy. The therapy is aimed at fighting the infection and concomitant inflammation and to prevent its progression into bone. Prophylactic application is also proposed [9]. The surgical approach relies on the aim of reaching stable mucosal closure to prevent recurrent infection. Extent of the resection can vary from simple surgical debridement of necrotic bone to resective surgery of a different dimension. In surgical debridement sequesters and all surrounding necrotic bone are removed, the extent of removal being kept as small as possible. Sharp bony edges are rounded, and persisting sockets may be flattened (saucerization). Wound closure should be tight but tensionless and is done with local flaps. The procedure can be performed under local or general anesthetic, depending on the amount of bone that needs to be removed and on the patient’s general health condition. Resective surgery aims at putting the resection margins into healthy and undoubtedly perfused bone [10]. This is done by marginal resections without loss of mandibular continuity or segmental resections and subsequent reconstruction in the mandible. This radical resection is commonly indicated in advanced cases involving the basal bone or with complications, such as oro-cutaneous fistula or pathologic fracture. In the maxilla, partial maxillectomies are performed. High success rates are reported [10–12]. On the other hand, several authors noted serious complications, such as development of large necrotic bony defects [1, 7, 13, 14]. Radical intervention

may lead to severe impairments in function and esthetics and may therefore compromise the patients’ quality of life. Aim The aim of this study was to prospectively evaluate the effectiveness of a stage-related treatment regime involving surgical treatment of MRONJ (AAOMS classification) in a case series of patients at the Department of Oral Surgery and Radiology. The protocol used strongly relies on personal experience of MRONJ-treating oral surgeons at the department and had been concerted with empirical findings from current literature as valid evidence-based data did not exist at that time [15].

Patients and methods Patients were recruited between March 2010 and October 2011 in the Health Care Centre for MRONJ Patients at the Department of Oral Surgery and Radiology, Dental Clinic of Graz, Austria. Inclusion criterion was the fulfillment of the AAOMS criteria for the definition of MRONJ. In case of planned surgery, general condition had to be sufficient. Subsequently, a history of local radiation therapy was an exclusion criterion. A treatment concept was drawn up on the basis of 245 different sources, such as scientific papers, guidelines, books, and websites. It contains detailed instructions for anamnesis, diagnostics, and therapy of MRONJ and was tested in a pilot case series of five patients [16]. The therapeutic regimen is chosen depending on the stage of MRONJ. Staging relies on the AAOMS positioning paper [1]. Treatment is directed to stable symptom-free condition without exposed jawbone. Treatment concept At-risk patients Patients who are “at risk” are informed and sensitized for MRONJ and referred to a dentist, oral, or maxillofacial surgeon familiar with MRONJ. In periodic appointments, patients are examined for signs of osteonecrosis or risk factors for the development of MRONJ. The time intervals for these clinical and radiological check-ups are set according to each patient’s individual risk profile. Patients with a low MRONJ risk (suffering from primary osteoporosis and with good oral health status) are scheduled for annual appointments, whereas patients carrying a high MRONJ risk (metastatic bone disease, multiple myeloma, or local risk factors) are recalled every 3 to 6 months. Local risk factors are managed by conservative means. If oral surgery is needed, anti-infective and antiinflammatory preventive measures are obligatory according to

Clin Oral Invest

the AAOMS guidelines. Bone exposure and osseous injury are kept as low as possible, and tight, secure primary wound closure is performed.

Stage II Conservative measures are applied pre-operatively for up to 2 weeks to reduce inflammatory symptoms. Surgical debridement as described above is mandatory.

Stage 0 Stage III Conservative methods, such as antiseptic mouth rinses and low-level laser therapy as well as antibiotic, antimycotic, antiphlogistic, and analgetic therapy, are applied. The management of local risk factors is indicated.

Stage I If fistulas or areas of exposed bone are present, they are rinsed with antiseptic fluids. Next, the exposed bone is covered with an adhesive paste (Solcoseryl-Adhäsivpaste®). The patient performs this procedure three times daily; follow-up examinations take place weekly. If there is no healing tendency after 8 weeks, surgical therapy is scheduled. Antibiotic therapy (amoxicillin with clavulanic acid or according to the antibiogram) is administered from 1 day before surgery until sutures are removed 10 days postoperatively. A surgical debridement is applied, if possible under local anesthesia. The extent of removal is as low as possible, but as large as necessary to remove all affected bone. First, a local flap is raised. Bony sequestra and adjacent superficial bone with a typical yellow pumice stone appearance are removed, and bony edges are smoothened using piezosurgery and rotating burs. Finally, bony margins are treated with an Er:YAG laser (Fidelis II, Fotona D. D., Slovenia). If necessary, periosteal releasing incisions are carried out to ensure a tight and tensionless wound closure. To provide secure mucosal coverage, double-layer sutures are used. Pain and inflammation are controlled with antiphlogistics (dexibuprofen). The postoperative regimen includes the recommendation not to wear removable dentures. Follow-up examinations are performed twice a week during the first 14 postoperative days. In the case of postoperative impaired healing, such as dehiscence or inflammation, 3 % hydrogen peroxide and photodynamic therapy by low-level laser irradiation (Helbo Minilaser 2075 F dent [HELBO Photodynamic Systems, Austria], 75 mW, 680 nm, 90 s, 2 mm distance) are applied. Sutures were removed after 10 days. Follow-up examinations take place after 1, 2, 3, 6, and 12 months. After 3 and 12 months, a panoramic X-ray is taken obligatorily. In addition, cone beam computed tomography (CBCT) is performed if pathological findings are suspected. The aim of therapy is to achieve a long-term stable, symptom-free clinical situation by secure mucosal coverage.

In advanced cases, marginal or segmental resections of the jaw under general anesthesia are performed at the department of maxillofacial surgery. Radical surgery is indicated only if likely to improve the patient’s quality of life. Alternatively, for palliative therapy or if the patient refuses surgery, conservative measures are applied to control symptoms and avoid progression of disease. Procedures were in accordance with the Helsinki Declaration of 1975 as revised in 1983. The local ethics committee approved the study protocol (ethical board number 21–255 ex 09/10). Informed consent was obtained from all individual participants included in the study.

Results In the observation period, 111 patients visited the Health Care Centre for MRONJ patients (Table 2). They were aged between 34 and 84 years (mean 62±10.8 years); the vast majority was female (99 patients, 89.2 %). About 80 % suffered from breast cancer (41.4 %) or osteoporosis (39.6 %). A total of 57.7 % had malignant diseases (breast, prostate, renal cell or lung carcinoma, multiple myeloma, cancer of unknown primary (CUP), or combinations). In 78.4 %, the medication was administered intravenously (87 patients). Patients received mostly zoledronic acid (57 patients, 51.4 %); alendronate and ibandronate were administered in 15 patients (13.5 %) each and risedronate in nine patients (8.1 %). One patient received pamidronate (0.9 %), and the rest (14 patients) received different combinations (Table 2). Two patients showed two independent MRONJ lesions. In all, 113 “regions” were therefore distributed to the corresponding management protocol (at-risk or stage 0 situations counted as one “region”) (Fig. 1). A total of 72 patients were categorized at-risk. Corresponding management consisted of performing control examinations or surgical interventions in patients taking bisphosphonates (Table 3). Three patients with MRONJ stage 0 were put on regular recall for control examinations. In 38 patients, frank bone exposure (four patients with fistulas) corresponding to AAOMS stage I–III was detected. Due to an advanced state of the underlying malignant disease, nine patients were referred to palliative care. Five patients

Clin Oral Invest Table 2 Patients Patients Age

Underlying disease

Medication—administration route

Medication—substance

Total Female Youngest Oldest Median Mean Breast cancer Osteoporosis Secondary osteoporosis Multiple myeloma Prostate cancer Renal cell carcinoma Osteoporosis+rheumatoid arthritis Bronchial carcinoma Breast cancer and lung cancer CUP (cancer of unknown primary origin) Chronic polyarthritis Intravenously Orally Orally then intravenously Intravenously then orally Zoledronate Ibandronate Alendronate Risedronate Alendronate then ibandronate Zoledronate then ibandronate Pamidronate Alendronate then zoledronate Zoledronate then pamidronate Alendronate then pamidronate Alendronate then denosumab Zoledronate and sunitinib Zolendronate and thalidomide Ibandronate then pamidronate then zoledronate Risedronate then alendronate then zoledronate Zoledronate and bevacizumab

with MRONJ stage I and one patient with fistulas categorized as stage II were healed by undergoing conservative treatment alone. One stage I patient was healed after additional surgical debridement. Altogether 23 patients (18 female, 78.3 %), aged between 44 and 83 years (mean 67±9.1 years), underwent surgery (22 surgical debridement, one patient resective surgery). The underlying disease was breast cancer or osteoporosis (eight patients each, 34.78 %) in most cases; three patients suffered from prostate cancer, two from multiple myeloma, one from renal cell carcinoma, and one from bronchial carcinoma. A total of 16 lesions were located in the mandible (69.7 %) (Table 4).

111 99 34 84 63 61.65 46 43 1 9 4 2 2 1 1 1 1 80 24 6 1 57 15 15 9 3 2 1 1 1 1 1 1 1 1 1 1

100.0 % 89.2 %

41.4 % 38.7 % 0.9 % 8.1 % 3.6 % 1.8 % 1.8 % 0.9 % 0.9 % 0.9 % 0.9 % 72.1 % 21.6 % 5.4 % 0.9 % 51.4 % 13.5 % 13.5 % 8.1 % 2.7 % 1.8 % 0.9 % 0.9 % 0.9 % 0.9 0.9 0.9 0.9 0.9 0.9 0.9

% % % % % % %

Postoperatively occurring complications were swelling and related pain. Three patients (P01, P09, and P20) showed dehiscence that healed via secondary granulation by undergoing postoperative treatment with photodynamic therapy. Two of these lesions were located in the mandible; one was in the maxilla. A total of 17.39 % (four patients) who had experienced local surgical debridement dropped out due to death (three) or missing recall (one). Two patients who died before the end of the recall phase showed stable mucosal conditions after 6 months (P13) and 9 months (P10), respectively. After an observation period of 1 year, a symptom-free situation including mucosal closure was achieved in 17 of

Clin Oral Invest

Fig. 1 Distribution of the 113 regions to the corresponding management protocol

19 patients who were treated with surgery (success rate 89.5 %) and in six out of six patients who had undergone conservative treatment according to protocol (totaling 23 of 25 patients, 92 %).

In two patients with MRONJ stage II, the procedure was not successful. One developed a dehiscence after 1 month, and one displayed a discharging fistula after almost 12 months. Both had undergone local surgical debridement (Table 3). One

Table 3 MRONJ staging and management

Regions—at risk, 0 or MRONJ lesion

Total

113

100 %

AAOMS staging

At risk 0 I II III Control Surgery needed (i.e. extraction, apical surgery, implant placement…) Conservative Conservative palliative Surgical debridement Resective surgery Minor resective surgery at patient’s request

72 3 6 25 7 32 43

63.7 2.7 5.3 22.1 6.2 28.3 38.0

% % % % % % %

6 8 22 1 1

5.3 7.1 19.5 0.9 0.9

% % % % %

Management

Clin Oral Invest Table 4

Patients with MRONJ and surgical therapy

Patient

m/f

Age

UD

Compound

Time of medication intake

MRONJ stage and localization

Date of surgery

Result

Recall

P01 P02 P03 P04

f f m f

69 65 57 69

SOP BC PC OP

Fosamax® Zometa® Zometa® Actonel®

8 3 1 4

II, 35–38 II, 35–38 II, 38 I, 36

18.10.2010 18.07.2011 17.05.2010 03.05.2010

Success Failure (dehiscence) Success Success

1 1 1 1

P05 P06 P07 P08 P09 P10 P11 P12 P13 P14 P15 P16 P17 P18 P19 P20 P21 P22

f f f m f f m f f f m f f f f f f f

76 59 67 69 74 48 57 64 63 83 66 44 62 68 71 68 66 80

MM BC MM PC BC BC RCC OP BC OP PC LC OP OP OP BC BC BC

Zometa® Zometa® Zometa® Zometa® Zometa® Zometa®, Avastin® Zometa® Bonviva® Zometa®, Aredia® Fosamax® Zometa® Zometa® Zometa® Fosamax® Fosamax® Zometa® Zometa® then Bonviva® Bondronat®

5 years 9 years 5 years 2 years 1 year 2 months 6 months 3 years 3 years 5 years 18 months 2 years 4 years 7 years 5 years 7 months 2 years 5 years

II, 16–17 II, region 27 II, 45–46 III, 16–21 II, 46–47 II, 36 II, 47–48 II, 37–38 II, 47 II, 38 II, 44–45 II, 45–47 II, 33–38 II, 33–35 II, 31–32, 34–35 II, 16–17 II, 13 II, 26

28.06.2010 11.05.2010 10.10.2011 25.04.2012 23.05.2011 14.02.2011 22.08.2011 16.05.2011 23.01.12 02.05.2011 07.03.2011 15.11.2010 30.11.2010 02.05.2011 23.01.2012 17.1.2011 28.02.2011 10.05.2010

No recall Success Success Success Success Died Success Success Died Success Failure (sequester) Died Success Success Success Success Success Success

– 1 1 1 1 9 1 1 6 1 1 – 1 1 1 1 1 1

P23

m

75

OP

Zometa®

6 years

II, 14–16

07.02.2011

Success

1 year

years years year years

year year year year year year year year months year year months year year year year year year year year

m male, f female, UD underlying disease, OP osteoporosis, SOP secondary osteoporosis, BC breast cancer, RCC renal cell carcinoma, PC prostate cancer, LC lung cancer

patient (P15) was successfully treated with resective surgery, and one patient (P02) underwent palliative conservative treatment due to the advanced state of the underlying disease.

Discussion The described stage-related treatment protocol was successfully applied in 23 out of 25 patients (92 %) who were treated according to protocol and in 17 out of 19 patients (89.5 %) who underwent surgery. Nevertheless, due to the relatively low number of patients, larger trials are needed to confirm the reliability of these results. Regarding the patient sample, the high prevalence of MRONJ (20.7 %) in the study collective is remarkable. This is due to a selection bias as patients referred to a specialized clinical department are not an adequate sample. The high percentage of women (almost 90 %) results from a close cooperation with the Department of Obstetrics and Gynecology and to the prevalence of breast cancer (41.4 %) and osteoporosis (39.6 %) as underlying diseases, which affect

mainly women. Most patients received antiresorptive therapy intravenously. This is not exclusively due to the underlying disease but represents the general trend towards the intravenous administration route. A possible reason may be higher patient compliance because of fewer gastrointestinal side effects as well as the simple mode of administration and better dose control. On the whole, published success of MRONJ treatment is rather moderate. Filleul et al. calculated a healing rate of only 35 % in a PubMed research including 2408 cases between 2003 and 2009 (evidence level (EL) Ia) [17]. Scoletta et al. (EL III) and Vescovi et al. (EL IIa) showed that, in general, surgery is more successful than conservative treatment [18, 19]. It is noticeable that success rates have improved over the years. In 2005, Pires et al. succeeded only in three of 11 cases (21 %) (EL III) [20], and Miglorati et al. reported that surgical measures were not effective in most cases (EL III) [7]. A little later, Abu-Id et al. reported that about 33 % of patients needed a second intervention after surgery (EL III) [21], and Zarychansky et al. noted that performed surgical measures may even have worsened the clinical picture (EL III) [22].

Clin Oral Invest

In more recent publications, success rates were considerably higher, mostly exceeding 80 % (Table 5). But still the evidence level remains low, with mostly case reports and only one controlled trial. Due to the poor results in the first reports of surgical BRONJ therapy, the recommendation for symptomatic treatment gained weight [2]. This conservative approach has been and is being adopted again and again [3–8]. Furthermore, many authors categorize surgery in patients with BRONJ as risky and consider it as second choice after conservative measures have failed [1, 2, 5, 6, 9, 18, 23–26]. Conservative treatment options are successful in the treatment of pain and inflammation and often lead to a reduction of the exposed bone. In general, conservative measures may be justified in early stages. Nicolatou-Galitis et al. reached higher healing probability in stages 0 and I (EL IIa) [51]. Furthermore, Van de Wyngaert et al. reported that higher stages of BRONJ had poorer healing rates (EL III) [27]. In the presented study, collectively four patients with fistulas and two further patients with BRONJ stage I healed by undergoing conservative treatment. Nonetheless, if areas of uncovered jawbone remain, they are always at risk of re-infection and recurrence of symptoms. Only on rare occasions does a simple abatement of symptoms after conservative treatment persist [21 (EL III), 22 (EL III), [28] (EL IIa)].

Table 5

Published success rates of MRONJ therapy Success rate (%) Evidence level

Conservative therapy O’Ryan et al. 2009 [46] 10.2 Nicolatou-Galitis 2011[51] 14.9 Vescovi et al. 2012 [19] 27.5 Scoletta et al. 2010 [18] 41.7 Van de Wyngaert et al. 2009 [27] 53 Surgical therapy, surgical debridement Wutzl et al. 2008 [48] 58.5 Scoletta et al. 2010 [18] 76.9 Curi et al. 2011 [33] 80 Vescovi et al. 2012 [19] 80.4 Stanton et al. 2009 [47] 84 Pautke et al. 2011 [48] 85 Wilde et al. 2011 [39] 88 Stockmann et al. 2010 [41] Fleisher et al. 2008 [42] Williamson 2010 [25] Markose et al. 2009 [49] Surgical therapy, resective surgery Carlson und Basile 2009 [11] Seth et al. 2010 [50]

III IIa IIa III III III III III IIa III III III

89 90 100 100

III III III III

92 100

III III

Consequently, surgical measures are often needed to ensure a stable outcome. The premise of the presented therapy protocol was to treat patients with BRONJ lesions individually, according to stage of BRONJ, and to avoid progression without causing considerably high morbidity. Surgical therapy should be more promising in low stages. Vescovi et al. noted a better outcome of limited invasive surgery in early forms, correlating with the progression of disease (EL IIa) [19]. In 2012, Kühl et al. published a systematic review including publications from 2003 to 2009 and found no difference between the conservative and the surgical approach regarding success rates, but acknowledged a built-in bias as surgery was rather performed in more advanced cases of BRONJ [15]. Furthermore, they found out that the group receiving surgical treatment had fewer new cases of BRONJ (3.1 % vs. 8.1 %) and that almost 80 % had a direct benefit related to surgical treatment (successful healing 60 %) (EL IIb). They concluded that surgery seems to be inevitable in most of the cases where complete and successful healing is the aim. Adjuvant treatment options had been introduced. Hyperbaric oxygen has been applied mainly in the therapy of osteoradionecrosis and has also been used in cases of BRONJ (EL Ib) [29]. Freiberger et al. reported a tendency of better mucosal healing in 46 patients, however without statistical significance, and a faster decrease of BRONJ-linked symptoms, such as the size of exposed bone area, swelling, and pain. Nevertheless, the results of this study are not unchallenged. Several other authors disbelieve the evident benefit of hyperbaric oxygen [30–32]. Further adjuvant treatment options are platelet-rich plasma [33, 34] (EL III), ozone therapy [35] (EL III), low-level-laser or photodynamic therapy (EL III) [16, 18, 36], and parathyroid hormone [37]. Scientific evidence that unambiguously supports the benefit of any of these methods is lacking so far. In the presented protocol, photodynamic therapy was used adjuvantly to reduce actual inflammation prior to surgery and in cases of wound healing disorders. By that approach, three patients (P01, P09, and P20) with postoperative dehiscences healed via secondary granulation. The key elements of successful MRONJ therapy have not yet been fully identified. Some factors seem, however, to be essential: Reducing the bacterial burden by conservative measures prior to surgery can be recommended, as it helps avoid healing complications after surgery. Tight wound closure and good postoperative hygiene contribute to avoiding reinfection. Mücke et al. demonstrated an increased risk of recurring BRONJ in cases with bacterial bone infection of the necrotic area (EL IIb) [38]. A possible key factor is removing all necrotic bone [11, 16, 38–40]. Our results indicate that at early stages this can be easily accomplished by surgical debridement. In addition,

Clin Oral Invest

tight wound closure [16, 39–41] can be managed by local flaps. Finally, minimizing invasive procedures reduces postoperative impairment in patients who may already be burdened by their underlying disease. Functional and esthetic rehabilitation after extended resections may also be difficult. Resective surgery is therefore indicated only in advanced cases and if an improvement in quality of life can be expected. If the underlying disease is advanced or general health is severely compromised, palliative therapy by conservative means is indicated. Regarding the removal of all affected bone, the identification of necrotic bone margins may be difficult. Fleisher et al. describe fluorescence-guided resection as a helpful tool to define resection margins [42]. In the present study, the extent of surgical debridement was estimated preoperatively by three-dimensional imaging (computed tomography, cone beam computed tomography, and positron emission tomography) and finally defined according to the intraoperative picture. Bone of yellow pumice stone appearance was removed. If existing, surgical debridement followed demarcation lines. One patient nevertheless developed a sequester almost 1 year after surgery. In that case, a second intervention with a more invasive design was successful. Fig. 2 CBCT scan showing the formation of a sequestrum

Type and progression of the underlying disease as well as related therapeutic measures seem to have an impact [43, 44]. Wutzl et al. showed that surgery is more successful in patients with osteoporosis or multiple myeloma than in those with solid tumors [45]. One patient in this study showed good local conditions and no uncovered bone after surgery but developed dehiscence after 1 month. Induced conservative measures were not successful. The patient suffered from advancing breast cancer, and therefore chemotherapy had to be started again. Routine dental procedures influence the outcome of surgery significantly. In our experience, it is also very important to avoid known risk factors for development of MRONJ after surgery. Even after successful therapy, patients remain at risk of developing further lesions. Therefore, a recall period of at least 1 year is necessary to evaluate the outcome of MRONJ therapy. But even after this period, a recurrence of symptoms is possible. In this study, one patient had a fistula shortly before the 1-year control examination. A performed CBCT scan showed the formation of a sequestrum, and a second intervention had to be performed (Fig. 2). The necrosis probably developed after a trauma of the oral mucosa due to a pressure mark.

Clin Oral Invest

Conclusion Preservation of function and minimization of morbidity are the most important issues in dealing with MRONJ. Therefore, prevention by pre-therapeutic establishment of optimal dental and oral health conditions and ongoing dental supervision after the start of antiresorptive therapy are crucial. If MRONJ develops, the early initiation of therapeutic measures is essential because the condition is likely to be manageable with conservative or minimal invasive means. Therapy should aim at achieving a stable mucosal coverage. If conservative measures are not successful after 8 weeks, surgery is indicated. Resection should be as limited as possible but should include all necrotic bone. In advanced cases of MRONJ, resective surgery is indicated, but only if improvement of patients’ quality of life is conceivable.

11. 12.

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17. Conflict of interest None 18.

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