Clin Oral Invest DOI 10.1007/s00784-013-0979-2

ORIGINAL ARTICLE

Relevance of surgical management of patients affected by bisphosphonate-associated osteonecrosis of the jaws. A prospective clinical and radiological study Philippe Lesclous & Sophie Grabar & Semaan Abi Najm & Jean-Pierre Carrel & Tommaso Lombardi & Jean-Louis Saffar & Jacky Samson

Received: 14 February 2012 / Accepted: 4 April 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Objectives Actually, consensus management of osteonecrosis of the jaws (ONJ) related to nitrogen-containing bisphosphonates (NBPs) is mostly a conservative approach. It does not always control the symptoms and the progression of the disease. The aim of this study was to evaluate the clinical and radiological outcomes of three therapeutic management strategies of established ONJ. Materials and methods Three treatment strategies, i.e., conservative approach, minimal invasive surgery, and extensive surgery were evaluated in 39 ONJ patients treated with NBPs for malignant diseases or osteoporosis. The patients were closely monitored, and the outcome (extension, improvement, P. Lesclous : J.-L. Saffar Laboratoire Biothérapie de l’Organe Dentaire, Faculté de Chirurgie Dentaire, EA2496, Université Paris Descartes, Paris, France P. Lesclous Inserm U 791, Center for Osteoarticular and Dental Tissue Engineering (LIOAD) Skeletal Tissue Engineering and Physiopathology group (STEP), School of Dentistry, University of Nantes, Nantes, France S. Grabar Unité de Biostatistique et Epidémiologie, Hôpital Cochin, Broca, Hôtel Dieu, AP-HP, Paris, Université Paris Descartes, Paris, France S. Abi Najm : J.-P. Carrel : T. Lombardi : J. Samson Division of Stomatology and Oral Surgery, School of Dental Medicine, University of Geneva, Geneva, Switzerland P. Lesclous (*) Faculté de Chirurgie Dentaire de Nantes, 1 place Alexis Ricordeau BP 84215, 44042 Nantes Cedex 1, France e-mail: [email protected]

or healing) of mucosa and bone was clinically and radiographically evaluated on a long-term period (27.05±2.96 months). Results Primary pathology (osteoporosis or malignancies) and clinical severity of ONJ (mild, moderate, severe) were decisive factors. Osteoporotic patients showed more frequently complete mucosa or bone healing (p=0.0128 and p=0.00021, respectively) than malignant patients. Mucosa closure and bone improvement occurred more in mild ONJ patients than in severe ONJ (p=0.0053 and p=0.0319, respectively). Treatment strategy appeared to be a crucial factor for mucosa but not for bone healing. The rate of complete mucosa healing increased after an extensive surgical procedure (p=0.0096). Conclusions A surgical management of patients with ONJ positively influenced the clinical outcome by enhancing mucosa healing. Clinical relevance These results deserve further investigations involving a larger cohort. However, they strongly suggest that the guidelines of management of patients with ONJ related to NBPs have to be reconsidered. Keywords Nitrogen-containing bisphosphonates . Osteonecrosis of the jaws . Surgical management . Clinical follow-up

Introduction Bisphosphonates are drugs efficiently used in the treatment of metabolic (i.e., postmenopausal osteoporosis, Paget's disease, osteogenesis imperfecta) and malignant (i.e., multiple myeloma, bone metastasis of solid tumors, e.g., breast and prostate cancers) bone diseases for their ability in inhibiting bone

Clin Oral Invest

resorption. Among them, nitrogen-containing bisphosphonates (NBPs) are the most potent by suppressing the recruitment and activity of osteoclasts [1]. Osteonecrosis of the jaw (ONJ) associated with NBPs therapy is a detrimental effect first reported in 2003 [2, 3]. ONJ is characterized by an area of exposed bone in the maxillofacial region that does not heal within 8 weeks, in a patient who has no metastasis or radiation therapy in the craniofacial region [4]. Repeated high doses of NBPs administered intravenously to cancer patients are more frequently associated with ONJ [5–7]. In contrast, patients receiving oral NBPs for osteoporosis are less prone to ONJ [8]. Various etiologies have been proposed, and there is currently no consensus on its underlying mechanism [9, 10]. It is generally admitted that this adverse effect targets the jaws because they concentrate NBPs, owing to their high bone turnover compared with other anatomical sites [11], and because bisphosphonates are toxic for osteoclasts [12]. Presently, guidelines recommend mostly a conservative management of the patients affected by ONJ. Infection and pain controls are the primary targets by using long-term antibiotics, antibacterial mouth rinses, pain medication, and periodic superficial debridement of orally exposed necrotic bone. Surgical resection is restricted to the most symptomatic patients or to the patients refractory to a conservative approach [13, 14] that does not always control ONJ symptoms and the progression of the disease. Because many patients do not respond to conservative management, a primary surgical approach becomes a treatment of choice, resulting in positive responses [15–20] that deserve a thorough evaluation based on disease severity, primary pathology, and NBPs mode of administration. However at present, there is an obvious trend towards an early surgical approach in the management of ONJ [21–23]. The aim of this long-term prospective study was to evaluate the clinical and radiological outcomes of three different therapeutic strategies in the management of established ONJ, i.e., conservative approach, minimal invasive surgery, and extensive surgery.

anonymously included in the study that complied with the Declaration of Helsinki. Each patient's detailed medical and dental histories and follow-up data were analyzed. Criteria for diagnosis of bisphosphonate-related osteonecrosis of the jaw were defined according to the ASBMR specifications [4]: – – – –

Ongoing intravenous or oral bisphosphonate therapy No history of maxillofacial radiation therapy Oral exposure of necrotic bone at the maxilla or the mandible for 8 weeks without healing Exclusion by histology of bone metastases of a primary malignant disease and confirmation of bone necrosis

ONJ treatment strategies As described previously [18], ONJ were classified into three types: mild (bone exposure <1 cm2), moderate (1 cm2> bone exposure <2 cm2), and severe (bone exposure >2 cm2). The AAOMS staging system was not used, as some patients of this cohort were recruited before its first publication in 2007 [24] and divided into subgroups according to the size of bone exposure in the oral cavity. Three treatment strategies were used. A first group included eight patients with mild ONJ and more severely affected patients who refused invasive procedures. Patients were treated conservatively with systemic antibiotics, local antiseptics, and oral analgesics if necessary. A second group (n=8) consisting of patients with mild or moderate ONJ had minimal invasive surgery consisting of decortication and flattening of rough necrotic bone, fibrin glue coverage, tension-free primary closure with mucosal tissue, and medical treatment as above. In the third group (n=23), patients with moderate or severe ONJ had a more extensive surgical procedure, including bone resection and curettage of the surrounding bone, plus local and medical treatments as described above. At surgery, the apparently necrotic bone was hardly discernible from the surrounding bone. Follow-up

Patients and methods Patients Most of the patients included in this study were described in a previous report [18]. The first patient of this cohort was diagnosed in December 2003. Since then, each new additional patient diagnosed with ONJ associated with NBPs therapy (i.e., 38 patients) was systematically included in this study. These patients with persistent oral bone exposure, referred by dental practitioners or oncologists to the division of stomatology and oral surgery of the Dental School of Geneva (Switzerland), were treated and followed for periods ranging from 6 months to more than 7 years. The patients were

Whatever the local situation, all the patients continued their bisphosphonate medication and, if necessary, various cancer treatment with adjunctive corticotherapy. Owing to the benefits of the NBPs treatment for the primary pathology, the medical team decided to proceed with the NBP treatment. The patients were monitored every 3–4 months, the first year, and every 6 months afterwards. An orthopantomogram was performed every 6 months. The behavior (extension, improvement, or stabilization) of the mucosa and bone was evaluated clinically and radiographically, respectively. Mucosa stabilization was defined as clinical mucosa closure, mucosa improvement as a decrease in the area of exposed bone, and mucosa spreading as an increase of this

Clin Oral Invest

area. Bone stabilization was defined as radiological complete reossification of the bone defect, bone improvement as a partial reossification, and spreading as an increase in the size of the defect. During the follow-up, the patients were kept under strict dental care monitoring. Sixteen included patients died during the study because of complications of their malignant disease. Statistical analysis Using standard descriptive statistics for continuous variables or tabulations for categorical variables summarized the characteristics of the patients. Statistical analysis was performed using Student t test. The association between the outcome of ONJ and primary pathology, treatment variables, and severity of ONJ were examined using Fisher's exact test. Differences were considered significant at p<0.05. Data are expressed as means ± SEM.

Local ONJ treatment strategies Eight patients (20 %) were conservatively treated, two osteoporotic patients with mild ONJ, four cancer patients with moderate ONJ, and two cancer patients with severe ONJ refusing more invasive procedures. Eight patients had minimal invasive surgery, three patients with mild ONJ (two osteoporotic and one patient with multiple myeloma), four patients with moderate ONJ (one osteoporotic and three cancer patients), and one cancer patient with severe ONJ. The remaining 23 patients (60 %) had a more extensive surgical procedure. Except three osteoporotic patients with moderate ONJ, all of them were patients with malignancies (five with mild, ten with moderate, and five with severe ONJ). In summary, 79.50 % of this cohort received a surgical procedure for the local treatment of ONJ (mini-invasive or extensive procedure) (Table 2). Outcome of ONJ

Results Characteristics of the patients Of the 39 patients, 31 were affected by a malignant primary pathology (13 multiple myelomas, 12 breast cancers, 3 prostate cancers, and 3 other solid tumors). All patients were treated with intravenous NBP (mean duration of the IV treatment before ONJ diagnosis; 33.41±3.3 months, range 9–86). They had previously received various cancer treatments with adjunctive corticotherapy but no maxillofacial radiation therapy. Five were diabetics, and four were active smokers. Six mild, 17 moderate, and all the 8 severe ONJ were recorded in this subgroup. The remaining patients (n=8) were treated for osteoporosis with oral NBP (mean duration of the oral treatment before ONJ diagnosis; 71.62±5.3 months, range 41– 120). In this subgroup, three had corticoid-induced osteoporosis, one was diabetic, and one was an active smoker. Four mild and four moderate ONJ were recorded in this osteoporotic population (Table 1). The female/male sex ratio was 2.25:1. The mean age was 69.6±2.3 years, range 32–89, (females, 68.7±2.7; males, 71.1±4.7). There were no significant differences in age or gender according to the severity of ONJ or to the local treatment strategy. Fifty-four percent of ONJ occurred in the mandible, 43 % in the maxilla, and 3 % in both sites simultaneously. There was no difference in the treatment outcome according to ONJ location. Sites of dentoalveolar surgery (mainly tooth extraction) were involved in 87 % of cases. The interval between surgery and ONJ diagnosis ranged from 2 to 6 months. No obvious etiology was found in edentulous patients that did not wear dentures (13 % of ONJ).

The mean duration of follow-up was 27.05±2.96 months (range 6–84). It was similar in the three subgroups of patients according to ONJ severity, local treatment strategy, and to the primary pathology. Mucosal outcome The primary pathology appeared to be a decisive factor. Most osteoporotic patients (87.50 %) showed a clinical mucosa stabilization compared with patients with malignancies (29.03 %; p=0.0128) (Fig. 1). Mucosa improvement occurred in 12.50 % of the osteoporotic patients versus 45.89 % in the patients with malignant disease (p=0.0128) (Fig. 2). The remaining 25.08 % of the patients with malignant disease had a mucosa spreading. No mucosa spreading was recorded in the osteoporotic patients (Table 3). Mucosa closure occurred in 80 % of mild and 38.10 % of moderate ONJ (Fig. 1). None was recorded in severe ONJ (p=0.0053). Fifty percent of severe ONJ versus 19.05 % of moderate ONJ showed a mucosa spreading (p=0.0053). No mucosa spreading was detected in mild ONJ. In the group of patients subjected to a conservative approach, mucosa stabilization occurred in 25 % of the patients (all treated with oral alendronate), whereas 62.50 % (all treated with IV NBPs) had a mucosa spreading (p=0.0096). In the eight patients subjected to minimal invasive surgery, four showed mucosa stabilization (two treated with oral alendronate and two with IV NBPs), two showed mucosa improvement (both treated with IV NBPs), and two showed mucosa spreading (both treated with IV NBPs). In the 23 patients subjected to a more extensive procedure, mucosa

Clin Oral Invest Table 1 Characteristics of the patients, local ONJ treatment strategy, and follow-up Patient gender, age

Primary pathology

NBP agent, route, duration (months)

ONJ local treatment

Follow-up duration (months)

Clinical issue

Radiological issue

F 63 F 72 F 76 M 76 F 78 M 79 F 72 F 85 F 83 M 70 F 84 M 75 M 53

Pm ost Pm ost Pm ost MM MM Prostate cancer MM Breast cancer Pm ost MM Cort ost MM MM

Alen, PO, 63 Alen, PO, 120 Alen, PO, 120 Pam, IV, 13 Pam, IV, 23 Zol, IV, 5 Zol, IV, 9 Zol, IV, 10 Pam, IV, 24 Alen, PO, 44 Zol, IV, 33 Alen, PO, 55 Pam, IV, 27 Zol, IV, 6 Pam, IV, 51 Zol, IV, 18

Conservative Conservative Mini-invasive Extensive Mini-invasive Extensive Extensive Extensive Mini-invasive Extensive Extensive Conservative Extensive

28 30 36 39 26 13, † 13, † 10, † 58 15 56 72 41

Healing Healing Healing Healing Healing Healing Healing Improvement Healing Improvement Improvement Spreading (s) Healing

Healing Healing Improvement Healing Improvement Improvement Spreading Improvement Healing Spreading Healing Spreading Spreading

F 60 F 59 F 68 M 89 F 32 F 78 F 71 F 69 M 47 F 36 F 57 F 75 F 59 F 70 F 77 F 85 F 78 F 80

Breast cancer Breast cancer MM MM Breast cancer Breast cancer Lung cancer Cort ost MM Cervical cancer Breast cancer Breast cancer Cort ost Breast cancer Pm ost MM Breast cancer Breast cancer

Zol, IV, 20 Pam, IV, 16 Zol, IV, 36 Pam, IV, 34 Pam, IV, 60 Pam, IV, 32 Pam, IV, 29 Zol, IV, 14 Zol, IV, 24 Alen, PO, 41 Zol, IV, 38 Zol, IV, 31 Zol, IV, 18 Zol, IV, 36 Alen, PO, 46 Pam, IV, 5 Zol, IV, 26 Alen, PO, 84 Zol, IV, 13 Pam, IV, 6 Zol, IV, 36 Pam, IV, 1 Zol, IV, 11

Extensive Extensive Extensive Extensive Conservative Extensive Mini-invasive Extensive Mini-invasive Extensive Mini-invasive Conservative Extensive Conservative Mini-invasive Extensive Extensive Extensive

20, † 49 84 19, † 24, † 6, † 30 9 14 6, † 28 11, † 13 39 13 37 14, † 24

Improvement Healing Improvement Healing Spreading Healing Spreading Healing Improvement Improvement Improvement Improvement Healing Spreading (s) Healing Improvement Healing Improvement

Spreading Spreading Spreading Spreading Spreading Spreading Spreading Spreading Spreading Spreading Improvement Improvement Healing Spreading Healing Improvement Improvement Spreading

M 67 M 45 M 69 F 66 F 70 F 78 M 81 M 84

MM MM Prostate cancer Breast cancer Breast cancer Cervical cancer Prostate cancer MM

Pam, IV, 4 Zol, IV, 19 Pam, IV, 78 Zol, IV, 8 Zol, IV, 16 Pam, IV, 60 Pam, IV, 30 Zol, IV, 12 Iban, IV, 5 Zol, IV, 25 Pam, IV, 4 Zol, IV, 29

Extensive Extensive Conservative Conservative Extensive Mini-invasive Extensive Extensive

26, † 15, † 42 12, † 12, † 46 9, † 16, †

Improvement Improvement Spreading (s) Spreading Improvement Spreading Spreading Improvement

Spreading Spreading Spreading Spreading Improvement Spreading Spreading Spreading

The patients are classified according to ONJ severity; mild (light shade), moderate (medium shade), severe (dark shade) F female, M male, MM multiple myeloma, Pm ost postmenopausal osteoporosis, Cort ost Corticosteroid osteoporosis, NBP nitrogen-containing bisphosphonate, Pam pamidronate, Zol zoledronic acid, Alen alendronate, Iban Ibandronate, IV intravenous, PO per os, † dead, Min inv minimal invasive, (s) sequestrum

spreading occurred only in one patient with severe ONJ, receiving IV zoledronic acid, whereas mucosa improvement occurred in 12 patients (Fig. 2) and mucosa stabilization in 10 patients (p=0.00096) (Fig. 1).

Bone outcome Bone behavior was quite different. Spreading was recorded in 71.93 % of patients with malignancies (Fig. 2) and only in

Clin Oral Invest Table 2 Distribution of local ONJ treatment strategies according to ONJ severity Mild ONJ

Moderate ONJ

Severe ONJ

Total

2

4

2

8

Conservative approach Minimal invasive surgery Bone resection

3

4

1

8

5

13

5

23

Total

10

21

8

and spread in 20 % (p=0.0319). Spreading reached 71.43 and 75 % in moderate and severe ONJ (p=0.0319), respectively. No bone stabilization was recorded in severe ONJ. Whatever the local ONJ treatment strategy, the bone outcome did not show any statistical difference.

Discussion

12.50 % of the osteoporotic patients (p=0.00021). In contrast, stabilization occurred in only one patient (3.69 %) with a malignant disease compared with 75 % of the osteoporotic patients (p=0.00021). Noticeably, the three bone sequestra recorded in this study were found in patients with malignancies treated with a conservative approach (Table 4). In mild ONJ, bone stabilized in 40 % of the patients (mostly treated with PO alendronate), improved in 40 %, Fig. 1 Mucosa closure and bone stabilization after surgical management. A 59-year-old woman with breast cancer receiving IV pamidronate (90 mg/month for 16 months) and IV zoledronic acid (4 mg/ month for 36 months) showed a moderate ONJ revealed by the extractions of the right maxillary second premolar and first molar (a). Fifteen days after the surgical procedure, mucosa closure is achieved but a mucosa inflammation is still discernible (b). The postsurgical X-ray showed the bone loss related to the ONJ and the surgical procedure (c). One year later, the bone deterioration did not increase (d). Two years later, the mucosa healing was stable (e), whereas the bone level appeared in a steady state (f)

ONJ has recently emerged as a serious potential adverse effect of NBP therapy, and conservative management of the affected patients is thought to be as an approach of choice [13, 14]. For the first time, we present data evidencing the relevance over time of the surgical management of the defect. It is noteworthy that this outcome was obtained without interrupting NBPs therapy. This medical decision aimed to protect patients from cancer metastasis burden. In fact, considering the high potency of IV NBPs and their long-lasting incorporation in bone, a positive effect of drug cessation or drug holiday was highly questionable. However, our approach is in line with

Clin Oral Invest Fig. 2 Mucosa improvement and bone spreading after surgical management. An 80-year-old woman with breast cancer receiving IV pamidronate (90 mg/month for a month) and IV zoledronic acid (4 mg/month for 11 months) revealed an ONJ after the placement of a dental implant in the left maxillary second premolar region (a). A slight osteolysis around the implant is discernible on the initial X-ray (b). The removal of the dental implant evidenced an ONJ classified as mild (c). The postsurgical X-ray showed the bone loss related to the implant removal and to the bone resection (d). One week after the surgical procedure, mucosa healing was in progress (e). Six months later, the mucosa closure was stable even if a slight inflammation process was discernible (f). At the same time, the bone increased (g). Eighteen months after the surgical procedure, a mucosal operculum appeared (h), whereas the ongoing bone loss prescribed another tooth extraction (i)

observations showing that cessation of IV bisphosphonate therapy has no positive effect on the healing rate of ONJ lesions [20, 25]. The first outstanding result of this study was that the surgical management led more frequently to mucosa improvement or complete stabilization than a conservative approach that in our cohort was more often associated with mucosa spreading. Moreover, the mucosa closure obtained in surgically-managed patients appeared to be stable, although the bone lesions kept on spreading. A majority of patients (79.50 %) were surgically managed; in most of them (90 %), mucosal benefit was obtained on a long-term Table 3 Outcome of mucosal tissue according to the primary pathology, ONJ severity, and local ONJ treatment strategy (n %)

Primary pathology ONJ severity

Local ONJ treatment

period. This is in keeping with other reports of surgically treated patients followed alike [26, 27]. It seems that the primary pathology is of paramount importance in treatment outcome. Indeed, 87.50 % of the osteoporotic patients showed complete mucosa stabilization versus only 23 % of the patients with malignancies. This is in agreement with another study showing a higher treatment success rate in an ONJ population with a high proportion of osteoporotic patients [19]. It must be pointed out that the route of NBPs administration, and thus their bioavailability, was different according to the primary pathology, i.e., PO NBPs for osteoporotic patients and IV NBPs for patients with

Malignant n=31 Osteoporotic n=8 Mild n=10 Moderate n=21 Severe n=8 Conservative n=8 Mini-invasive n=8 Extensive n=23

Healing

Improvement

Spreading

Fisher exact test

29.03 87.50 80.00 38.10 – 25.00 50.00 43.48

45.89 12.50 20.00 42.86 50.00 12.50 25.00 52.17

25.08 – – 19.05 50.00 62.50 25.00 4.35

p=0.0128 p=0.0053

p=0.0096

Clin Oral Invest Table 4 Outcome of bone tissue according to primary pathology, ONJ severity, and local ONJ treatment strategy (n %)

Healing

Improvement

Spreading

Fisher's exact test

Primary pathology

Malignant n=31 Osteoporotic n=8

3.69 75.00

24.38 12.50

71.93 12.50

p=0.00021

ONJ severity

Mild n=10 Moderate n=21 Severe n=8 Conservative n=8 Mini-invasive n=8

40.00 14.29 – 25.00 25.00

40.00 14.29 25.00 12.50 37.50

20.00 71.43 75.00 62.50 37.50

p=0.0319

Extensive n=23

13.04

21.74

65.22

Local ONJ treatment

malignancies. In addition, the time to closure seems to be shorter in osteoporotic patients treated with PO alendronate; in fact, no statistics could be done due to the few mucosa stabilization in patients treated with IV NBPs. Whatever the issue, the bilayer procedure used in our surgical approach, i.e., fibrin glue coverage and tension-free primary closure with mucosal tissue, may provide a safe coverage of the underlying bone and reduce the risk of recurrent infection. The initial clinical extent of ONJ was also a decisive factor in the outcome of the surgical management. Indeed, no mucosa closure occurred in severe ONJ. The mildest the ONJ, the more frequent the mucosa stabilization or the mucosa improvement. The beneficial effect of the surgical management included these patients with stage II ONJ (i.e., exposed necrotic bone associated with infection) that are not the more severe ONJ in AAOMS class [13], as 70 to 80 % of this patient category experienced clinical closure when an adjunctive long-term preoperative antibiotic treatment was instituted [26]. Interestingly, in this cohort, all the bone sequestra were recorded in the conservative approach group treated with IV NBPs for a long time, i.e., 39 months or more. Taken together, these results suggest that the earlier the surgical management, the better the mucosa behavior, although the expert opinions recommended surgical management only in later stages of ONJ [4, 13, 14]. Moreover, this strongly suggests that the mucosa injury is not of primary importance, and that bone but not mucosa lesions are determinant in ONJ onset and progression. This followup study is in agreement with the clinical and histological data presented in our former report [18]. Several studies attempted to identify comorbidity factors possibly associated with ONJ development such as corticosteroid use or various specific cancer chemotherapies. Although corticosteroids are not consistently considered as a risk factor in the literature [28–30] and in the most recent guidelines [31], we performed specific statistics in patients with malignant diseases receiving corticotherapy and in the patients affected by corticosteroid-induced osteoporosis. No difference was found versus other patients of the same subgroup without corticosteroid use (data not shown). Our study did not also show any difference between patients

receiving current chemotherapy in the follow-up period of this study and those without any various cancer treatments during this period (data not shown). Other studies failed also to show such associations [28, 32]. The bone behavior to surgical management appeared quite different than that of the oral mucosa, whatever ONJ clinical severity. In mild ONJ, although the mucosa was stabilized, 20 % of bone defects were spreading. The percentages of bone defect aggravation were much higher in moderate and severe ONJ and quite different from those observed for mucosal tissue. As a matter of fact, 31 % of the patients with bone defect spreading had a clinical mucosa closure. This may be explained by the rate of bisphosphonate binding and incorporation into bone that is directly related to the local bone turnover. Alveolar bone turnover is high [33, 34], and thus likely may incorporate more NBP than other skeletal sites [35]. This high incorporation as well as the heavy mechanical strains applied on these bones may explain that the posterior sectors of the mandible and the maxilla that are exposed to the highest loading forces are more affected [36]. NBPs inhibit the proliferation [37] or promote the apoptosis [38] of oral keratinocytes, fibroblasts, and endothelial cells [39]. Indeed, bone-bound zoledronate can affect adjacent non-bone cells and inhibit their growth [40]. It is thus likely that the local high bone concentrations of NBPs would be toxic for adjacent soft tissues leading to mucosal disruption and subsequent colonization by the oral flora of the exposed bone. This suggests that the surgical elimination of the exposed bone containing high amounts of NBPs could be beneficial for the overlying mucosa by decreasing the direct toxicity of NBPs on mucosa cells. It is noteworthy that mucosa deterioration was mostly recorded in patients submitted to long IV NBPs treatments responsible for a high cumulative dose into bone. The clinical data recorded in this study strongly support the hypothesis that ONJ is primarily an aseptic process that spreads centrifugally both to the depth of the jaw and towards the oral mucosa, and that the colonization of the exposed bone by the oral flora secondarily aggravates the situation. However, one cannot exclude the persistence of a subclinical infectious origin as, even

Clin Oral Invest

when mucosa closure was achieved, osteolysis frequently continued to spread. In conclusion, this study confirms that ONJ is dependent on the drug, dosage, route of administration, and duration of exposure to NBPs [27]. Patients receiving repeated high doses of NBPs were at an increased risk of ONJ. Zoledronic acid is more frequently implicated in ONJ, possibly because of its strong antiresorptive potential [41]. The intravenous route probably results in rapid and strong tissue accumulation [42, 43] and is more deleterious than the oral route. The outcome after the local treatment appeared to be dependent on the drug and the dose so that the patients treated with zoledronic acid having received high cumulative doses had the poorest outcome. Our findings in this patient cohort strongly suggest that an invasive surgical approach of the lesions is more beneficial than a conservative management to stop or slow down the progress of the lesions, and that an early intervention allowing surgical mucosal closure appears to be a treatment of choice. Future research involving a larger cohort is needed to substantiate this early surgical management.

Conflict of interest The authors declare that they have no conflict of interest.

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