Alberto Bedogni

Learning from experience. Proposal of a refined definition and staging system for bisphosphonate-related osteonecrosis of the jaw (BRONJ)

Dear Editor, It is the authors’ belief that the internationally accepted definition of bisphosphonate-related osteonecrosis of the jaws (BRONJ) (Ruggiero et al, 2009) has several limitations that prevent clinicians from being confident with the diagnosis of the disease. Following recognition of the non-exposed BRONJ clinical variant (Lazarovici et al, 2009), we all became aware that the presence of ‘exposed necrotic bone in the oral cavity’, as outlined in the American Association of Oral and Maxillofacial Surgery (AAOMS) case definition, is just one of the possible clinical manifestations of BRONJ and is not found in all BRONJ patients. As ‘bone exposure’ is certainly not the initial sign of BRONJ in most patients and a minimum of 6–8 weeks’ persistence is required to confirm the clinical suspicion, the final diagnosis is usually delayed for several weeks or months. Therefore, to date, it has been almost impossible to study the early phases of BRONJ. This delayed diagnosis can also explain, at least in part, why the disease is often refractory to the medical and surgical treatments commonly used. We believe that clinicians will benefit from a definition of BRONJ that contains only robust information, without considering any definite clinical picture or a binding time-frame (i.e. 6–8 weeks). As qualified members of the Expert Panel of the Italian Society for Maxillofacial Surgery (SICMF) and the Italian Society of Oral Pathology and Medicine (SIPMO) on Bisphosphonate-Related Osteonecrosis of the Jaws, we are submitting to the attention of the scientific community the following definition of BRONJ: ‘bisphosphonate related osteonecrosis of the jaw (BRONJ) is an adverse drug reaction described as the progressive destruction and death of bone that affects the mandible or maxilla of patients exposed to the treatment with nitrogen-containing bisphosphonates, in the absence of a previous radiation treatment’. Along with this new definition of BRONJ, we set up and propose a diagnostic work-up to be used to reach the final diagnosis. Although exposed necrotic bone in the oral cavity still remains the best indicator of BRONJ (Ruggiero et al, 2009), other non-specific signs and symptoms (Table 1) should raise the suspicion of BRONJ, even in a patient with a well-recognized dental or periodontal disease (Fedele et al, 2010). In short, BRONJ should be always investigated in a patient taking nitrogen-containing bisphosphonates (NBP), when one or more clinical signs are present. Because BRONJ is primarily a disease that affects the jawbone, we strongly believe that radiological examination is an important step of the diagnosis. However, as the radiological findings may be characteristic not only of BRONJ (Khan et al, 2008), these findings should always match the clinical picture, in order to progress from the clinical suspicion to the final diagnosis. This is of outmost importance as bone biopsies for histology are still not routinely advised for the risk of worsening the disease process. A schematic approach to the work-up for a diagnosis of BRONJ is proposed (Scheme 1), where computed tomography (CT) currently represents the most useful diagnostic tool because of its widespread use and accessibility for patients (Bianchi et al, 2007). Structural alteration of trabecular bone is a consistent finding of CT scans performed in patients with BRONJ (Table 2) (Arce et al, 2009). CT scans can clearly depict the degree of osteosclerosis of the affected site, visible as the loss of contrast definition between the endosteal cortex and the subjacent medullary bone (i.e. trabecular thickening and/or regional or diffuse osteosclerosis), with respect to the uninvolved bone tissue (Hutchinson et al, 2010). Osteosclerosis seems to characterize the early stages of disease and also precedes the occurrence of frank bone exposure in the oral cavity (Saia et al, 2010), and thus it should be searched for to provide an early diagnosis. Table 1 Non-specific clinical signs associated with bisphosphonate-related osteonecrosis of the jaws (BRONJ) Table 2 Non-specific computed tomography (CT) findings associated with bisphosphonate-related osteonecrosis of the jaws (BRONJ) Scheme 1 Diagnostic work-up for BRONJ. VAS, visual analogic scale Even though magnetic resonance imaging (MRI) provides more detailed information than CT on focal bone marrow alterations (Bisdas et al, 2008), the former could provide non-diagnostic results owing to magnetic artifacts caused by the presence of dental casting alloys (Shafiei et al, 2003) as well as to motion artifacts caused by the prolonged time necessary to scan the head and neck region (Lenz et al, 2000). The majority of BRONJ cases could be diagnosed and staged correctly by the combined use of clinical methods and CT, the latter method currently being more cost-effective and easily accessible than MRI. On the other hand, we believe that MRI should be used to evaluate cases difficult to identify with CT and to establish the real extent of jawbone and soft-tissue involvement in BRONJ patients who are candidates for surgical resection. The staging system of a bone disease that relies on the use of radiologic imaging for its diagnosis should also be based on the common radiologic features of the disease. The current AAOMS staging system (Ruggiero et al, 2009; Migliorati et al, 2011), which assigns patients to different stages of disease on the basis almost exclusively of clinical criteria, fails, in our opinion, to consider this important aspect. In this regard, we set up a combined clinical and radiological staging system with the aim of pooling BRONJ patients in different groups also based on the radiological extent of the disease. The staging system we propose (Table 3) differs from the 2009 AAOMS classification as follows: Table 3 Clinical and radiological staging system of bisphosphonate-related osteonecrosis of the jaws (BRONJ) The absence of Stage 0, so that BRONJ patients with exposed and non-exposed necrotic bone simply represent distinct clinical pictures within the same disease stage. The description of three stages (1–3) based on clinical and CT findings, ‘where Stage 1 includes patients with focal (alveolar bone) osteosclerosis, Stage 2 includes patients with diffuse (alveolar and basal bone) osteosclerosis and Stage 3 includes patients with clinical and radiological signs of advanced and complicated disease. Pain and purulent discharge are no longer used to distinguish between different disease stages. As these symptoms define only asymptomatic (a) and symptomatic (b) forms of BRONJ in patients within the same stage, exclusion of pain and purulent discharge as criteria would limit the ‘ping-pong’ effect (the migration of patients from Stage 1 to Stage 2, and vice versa) that we all experienced when using the AAOMS classification, as a result of the repeated use of antibiotic therapies to treat recurrent bone infections and associated pain. The presence of clinically detectable sequestra is no longer regarded as a sign of complicated disease, as it is for AAOMS Stage 3. In fact, it is a common experience that the spontaneous expulsion or surgical removal of bony sequestra often leads to dramatic, albeit somewhat temporary, clinical improvement, with mucosal epithelialization of the affected site (Ferlito et al, 2011). The definition, work-up and staging system proposed here might, as a whole, provide several practical benefits, in the order: anticipated BRONJ diagnosis and access of patients to therapies; a reduced need for extensive surgical resections with associated long and debilitating postoperative hospitalization; and increased overall efficacy of treatments and patients’ curability. The disadvantage of the additional cost of bone imaging (CT) for the diagnosis would be offset against the overall reduction in treatment costs. When a new disease is found, little is known of its medical features and behavior; this makes it necessary to avoid general definitions that may include potentially healthy patients (resulting in a higher false-positive risk). This also occurred at the start, when the actual BRONJ case definition was adopted. At present, with the growing bulk of research on BRONJ, we believe that it is necessary to enter a new phase where clinicians try to establish the initial stages of the disease process, in order to make an earlier diagnosis and improve treatment effectiveness. Although adjustments and updating will be necessary in the future, the definition, work-up and staging system proposed here could achieve this purpose.

Survivin expression is significantly higher in pN+ oral and oropharyngeal primary squamous cell carcinomas than in pN0 carcinomas

Conclusions. The preliminary results reported here suggest that survivin expression in primary oral and oropharyngeal squamous cell carcinomas (SCCs) may identify patients at risk of disease disseminating to neck lymph nodes. If these results are confirmed in larger series of patients it may imply that elective neck dissection should be considered in clinically N0 patients with oral and oropharyngeal SCCs who show high expression of survivin. Objective. To investigate the expression of survivin, a member of the inhibitor of apoptosis proteins family, in patients with primary oral and oropharyngeal SCCs with and without neck lymph node metastases. Material and methods. We considered 13 consecutive cases of oral and oropharyngeal SCCs with lymph node metastases (pN + ) and 13 cases of pN0 oral and oropharyngeal SCCs. The survivin reactivity of primary SCCs and lymph node metastases was evaluated immunohistochemically. A lesion was considered positive if >9.5% of the tumour cells showed diffuse strong staining. Results. Sporadic groups of normal basal and parabasal epithelial cells showed weak survivin staining. In SCCs, a nuclear reaction predominated. Eight primary pN+ SCCs were survivin-positive (mean expression 34.7%), compared to 5 primary pN0 SCCs (mean expression 12.3%; p=0.017). Statistical analysis disclosed significantly higher survivin expression in primary oral and oropharyngeal SCCs that developed distant non-lymphatic metastases (p=0.012).

Osteonecrosis of the Jaw in Patients with Metastatic Renal Cell Cancer Treated with Bisphosphonates and Targeted Agents: Results of an Italian Multicenter Study and Review of the Literature

Osteonecrosis of the jaw (ONJ) associated with the use of bisphosphonates has been rarely reported in metastatic renal cell cancer (RCC) patients. Since the introduction of combined therapies consisting of nitrogen-containing bisphosphonates (NBPs) and targeted agents, an increasing number of RCC patients were reported to develop ONJ, suggesting that therapeutic angiogenesis suppression might increase the risk of ONJ in NBPs users. We performed a multicenter retrospective study and reviewed literature data to assess the occurrence and to investigate the nature of ONJ in RCC patients taking NBPs and targeted agents. Nine Italian Centers contributed to the data collection. Patients with exposed and nonexposed ONJ were eligible for the study if they had been taking NBPs and were receiving targeted agents at the time of ONJ diagnosis. Forty-four RCC patients were studied. Patients were mostly male (82%), with a median age of 63 years (range, 45-85 years). Zoledronic acid (93%) and sunitinib (80%) were the most frequently used NBP and antiangiogenic agent, respectively. Other agents included Pamidronate, ibandronate, sorafenib, bevacizumab, mammalian target of rapamycin inhibitors. Forty-nine sites of ONJ were encountered, with the mandible being the preferred site of ONJ (52%); both jaws were affected in 5 cases (12%). The most common precipitating event was dental/periodontal infection (34%), followed by tooth extraction (30%). Oral triggers of ONJ were missing in 10 cases (23%). This unexpectedly high number of ONJ cases, in comparison with literature data, suggests that frequency of ONJ in RCC patients might be largely underestimated and suggests a potential role for targeted agents in the incremental risk of ONJ.

Definition and estimation of osteonecrosis of jaw (ONJ), and optimal duration of antiresorptive treatment in bone metastatic cancer patients: supplementary data from the denosumab extension study?

To the Editor, In their recent article, Stopeck et al. [1] concluded that denosumab confirms its known safety profile even after longterm exposure, or after switching to it from zoledronic acid, and that osteonecrosis of jaws (ONJ) rates increased with increasing exposure to antiresorptives, consistent with previous reports. This is based on the open label extension phase of two phase 3 studies in patients with breast and prostate cancer with bone metastases who were randomized to receive denosumab or zoledronic acid (ZA) [2, 3]. The patients were offered open-label denosumab for up to an additional 2 years after the results of the primary analysis, favorable for denosumab on several aspects. Patients initially randomized to denosumab (denosumab/ denosumab group) continued to receive denosumab at 120 mg Q4W whereas patients on ZA were switched to denosumab in the open-label phase (ZA/denosumab group) at 120 mg Q4W starting 4 weeks from their last ZA dose. Patients who declined further therapy in the open-label extension phase, or who did not complete the blinded treatment phase, continued follow-up for survival every 12weeks (Q12W) for up to 2 years after their last dose. We collected data from the text and the tables of the paper published by Stopeck et al. [1] and summarized them in a new table (Table 1). Although authors’ conclusions are quite reassuring both in terms of denosumab safety and efficacy, it is noteworthy that the median exposure of patients to denosumab in the extension phase study is lower than expected, even in the presence of a longer range. The final median exposure of the 318 denosumab/denosumab breast cancer patients is 19.1 months (range 0.1–59.8), not much longer than that registered for the whole cohort of the 1019 breast cancer patient population enrolled in the blinded phase, that was 17.6 months (range 0– 23.7). As far as prostate cancer patients are concerned, the median denosumab exposure was 12.0 months (range 0.1– 67.2) for the 147 denosumab/denosumab patients from the extension study versus 12.0 months (range 0.1–23.3) for the 942 patients enrolled in the original randomized trial. We could not work out from the paper the median denosumab exposure for 318 breast and 147 prostate cancer patients of the extension study denosumab/denosumab population in the previous blinded phase. This appears to us a weakness of the article. Interestingly, the frequency of ONJ cases in the open label extension study appears substantially higher than what is found in the initial blinded phase (ONJ frequency ranging from 1 to 2 %) [2, 3] despite median denosumab exposure was not significantly longer in the former. The crude ONJ figures increased both in denosumab/denosumab groups and in ZA/denosumab populations: ONJ cases were respectively 20/318 (6.3 %) in breast patients and 12/147 (8.2 %) in prostate patients in the denosumab/denosumab group, whereas they were 18/334 (5.4 %) breast patients and 7/118 (5.9 %) prostate patients in the ZA/denosumab group. Such an increase in ONJ frequency highlights the need for longer patients’monitoring and the adoption of nonparametric actuarial estimation (Kaplan-Meier), as done in other studies * Vittorio Fusco vittoriofusco1@tin.it

Regorafenib Also Can Cause Osteonecrosis of the Jaw

Affiliations of authors: Oncology Unit, SS Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy (VF, GN); Department of Surgical, Oncology and Oral Sciences, Sector of Oral Medicine, Palermo University, Palermo, Italy (GC); University of Tennessee Health Science Center, College of Dentistry, Memphis, TN (CM); DH Oncology, Universit a Campus Bio-Medico, Rome, Italy (DS); Department of Neurosciences (DNS), University of Padua, Padua, Italy (AB)

Osteonecrosi dei mascellari associata a bisfosfonati, denosumab e farmaci anti-angiogenetici nei pazienti oncologici e osteoporotici: diagnosi e terapia

Riassunto Obiettivi Fornire un percorso utile alla diagnosi e al trattamento dell’osteonecrosi delle ossa mascellari (solitamente definita ONJ, OsteoNecrosis of the Jaws). Materiali e metodi Gli autori del lavoro, recentemente estensori e collaboratori – su mandato della Societa Italiana di Chirurgia Maxillo-Facciale (SICMF) e della Societa Italiana di Patologia e Medicina Orale (SIPMO), delle Raccomandazioni clinico-terapeutiche sull’osteonecrosi delle ossa mascellari associata a bisfosfonati e sua prevenzione – hanno esaminato le informazioni scientifiche disponibili in merito alla ONJ associata all’assunzione sia di bisfosfonati sia di denosumab e/o anti-angiogenetici, e revisionato l’epidemiologia, i fattori di rischio, la clinica e i criteri diagnostici. Vengono proposti protocolli di prevenzione primaria e secondaria, di management odontoiatrico e terapia della ONJ sia per il paziente oncologico sia per il paziente non oncologico, principalmente osteoporotico. Risultati e conclusioni L’osteonecrosi delle ossa mascellari da bisfosfonati, ma anche, negli ultimi anni, da denosumab e anti-angiogenetici, si puo considerare la piu emergente delle patologie odontoiatriche severe: negli ultimi 10 anni si sono registrati migliaia di casi in letteratura, con importanti implicazioni sulla qualita di vita del paziente. La comunita medica e odontoiatrica ha percepito in questi anni la severita della patologia, ma anche la necessita di darsi regole e ridisegnare il percorso preventivo e assistenziale di tale malattia: in tutte le nazioni industrializzate, e parimenti in Italia, sono state stilate linee guida o raccomandazioni per la prevenzione e cura della ONJ, malattia inizialmente associata solo ai bisfosfonati per via endovenosa in pazienti oncologici, ma poi rilevata, sebbene con frequenza inferiore, anche nei pazienti non oncologici, principalmente osteoporotici, in terapia con bisfosfonati per os.

Learning from experience. Proposal of a refined definition and staging system for BRONJ.

Dear Editor, It is the authors’ belief that the internationally accepted definition of bisphosphonate-related osteonecrosis of the jaws (BRONJ) (Ruggiero et al, 2009) has several limitations that prevent clinicians from being confident with the diagnosis of the disease. Following recognition of the non-exposed BRONJ clinical variant (Lazarovici et al, 2009), we all became aware that the presence of ‘exposed necrotic bone in the oral cavity’, as outlined in the American Association of Oral and Maxillofacial Surgery (AAOMS) case definition, is just one of the possible clinical manifestations of BRONJ and is not found in all BRONJ patients. As ‘bone exposure’ is certainly not the initial sign of BRONJ in most patients and a minimum of 6–8 weeks’ persistence is required to confirm the clinical suspicion, the final diagnosis is usually delayed for several weeks or months. Therefore, to date, it has been almost impossible to study the early phases of BRONJ. This delayed diagnosis can also explain, at least in part, why the disease is often refractory to the medical and surgical treatments commonly used. We believe that clinicians will benefit from a definition of BRONJ that contains only robust information, without considering any definite clinical picture or a binding time-frame (i.e. 6–8 weeks). As qualified members of the Expert Panel of the Italian Society for Maxillofacial Surgery (SICMF) and the Italian Society of Oral Pathology and Medicine (SIPMO) on Bisphosphonate-Related Osteonecrosis of the Jaws, we are submitting to the attention of the scientific community the following definition of BRONJ: ‘bisphosphonate related osteonecrosis of the jaw (BRONJ) is an adverse drug reaction described as the progressive destruction and death of bone that affects the mandible or maxilla of patients exposed to the treatment with nitrogen-containing bisphosphonates, in the absence of a previous radiation treatment’. Along with this new definition of BRONJ, we set up and propose a diagnostic work-up to be used to reach the final diagnosis. Although exposed necrotic bone in the oral cavity still remains the best indicator of BRONJ (Ruggiero et al, 2009), other non-specific signs and symptoms (Table 1) should raise the suspicion of BRONJ, even in a patient with a well-recognized dental or periodontal disease (Fedele et al, 2010). In short, BRONJ should be always investigated in a patient taking nitrogen-containing bisphosphonates (NBP), when one or more clinical signs are present. Because BRONJ is primarily a disease that affects the jawbone, we strongly believe that radiological examination is an important step of the diagnosis. However, as the radiological findings may be characteristic not only of BRONJ (Khan et al, 2008), these findings should always match the clinical picture, in order to progress from the clinical suspicion to the final diagnosis. This is of outmost importance as bone biopsies for histology are still not routinely advised for the risk of worsening the disease process. A schematic approach to the work-up for a diagnosis of BRONJ is proposed (Scheme 1), where computed tomography (CT) currently represents the most useful diagnostic tool because of its widespread use and accessibility for patients (Bianchi et al, 2007). Structural alteration of trabecular bone is a consistent finding of CT scans performed in patients with BRONJ (Table 2) (Arce et al, 2009). CT scans can clearly depict the degree of osteosclerosis of the affected site, visible as the loss of contrast definition between the endosteal cortex and the subjacent medullary bone (i.e. trabecular thickening and/or regional or diffuse osteosclerosis), with respect to the uninvolved bone tissue (Hutchinson et al, 2010). Osteosclerosis seems to characterize the early stages of disease and also precedes the occurrence of frank bone exposure in the oral cavity (Saia et al, 2010), and thus it should be searched for to provide an early diagnosis. Table 1 Non-specific clinical signs associated with bisphosphonate-related osteonecrosis of the jaws (BRONJ) Table 2 Non-specific computed tomography (CT) findings associated with bisphosphonate-related osteonecrosis of the jaws (BRONJ) Scheme 1 Diagnostic work-up for BRONJ. VAS, visual analogic scale Even though magnetic resonance imaging (MRI) provides more detailed information than CT on focal bone marrow alterations (Bisdas et al, 2008), the former could provide non-diagnostic results owing to magnetic artifacts caused by the presence of dental casting alloys (Shafiei et al, 2003) as well as to motion artifacts caused by the prolonged time necessary to scan the head and neck region (Lenz et al, 2000). The majority of BRONJ cases could be diagnosed and staged correctly by the combined use of clinical methods and CT, the latter method currently being more cost-effective and easily accessible than MRI. On the other hand, we believe that MRI should be used to evaluate cases difficult to identify with CT and to establish the real extent of jawbone and soft-tissue involvement in BRONJ patients who are candidates for surgical resection. The staging system of a bone disease that relies on the use of radiologic imaging for its diagnosis should also be based on the common radiologic features of the disease. The current AAOMS staging system (Ruggiero et al, 2009; Migliorati et al, 2011), which assigns patients to different stages of disease on the basis almost exclusively of clinical criteria, fails, in our opinion, to consider this important aspect. In this regard, we set up a combined clinical and radiological staging system with the aim of pooling BRONJ patients in different groups also based on the radiological extent of the disease. The staging system we propose (Table 3) differs from the 2009 AAOMS classification as follows: Table 3 Clinical and radiological staging system of bisphosphonate-related osteonecrosis of the jaws (BRONJ) The absence of Stage 0, so that BRONJ patients with exposed and non-exposed necrotic bone simply represent distinct clinical pictures within the same disease stage. The description of three stages (1–3) based on clinical and CT findings, ‘where Stage 1 includes patients with focal (alveolar bone) osteosclerosis, Stage 2 includes patients with diffuse (alveolar and basal bone) osteosclerosis and Stage 3 includes patients with clinical and radiological signs of advanced and complicated disease. Pain and purulent discharge are no longer used to distinguish between different disease stages. As these symptoms define only asymptomatic (a) and symptomatic (b) forms of BRONJ in patients within the same stage, exclusion of pain and purulent discharge as criteria would limit the ‘ping-pong’ effect (the migration of patients from Stage 1 to Stage 2, and vice versa) that we all experienced when using the AAOMS classification, as a result of the repeated use of antibiotic therapies to treat recurrent bone infections and associated pain. The presence of clinically detectable sequestra is no longer regarded as a sign of complicated disease, as it is for AAOMS Stage 3. In fact, it is a common experience that the spontaneous expulsion or surgical removal of bony sequestra often leads to dramatic, albeit somewhat temporary, clinical improvement, with mucosal epithelialization of the affected site (Ferlito et al, 2011). The definition, work-up and staging system proposed here might, as a whole, provide several practical benefits, in the order: anticipated BRONJ diagnosis and access of patients to therapies; a reduced need for extensive surgical resections with associated long and debilitating postoperative hospitalization; and increased overall efficacy of treatments and patients’ curability. The disadvantage of the additional cost of bone imaging (CT) for the diagnosis would be offset against the overall reduction in treatment costs. When a new disease is found, little is known of its medical features and behavior; this makes it necessary to avoid general definitions that may include potentially healthy patients (resulting in a higher false-positive risk). This also occurred at the start, when the actual BRONJ case definition was adopted. At present, with the growing bulk of research on BRONJ, we believe that it is necessary to enter a new phase where clinicians try to establish the initial stages of the disease process, in order to make an earlier diagnosis and improve treatment effectiveness. Although adjustments and updating will be necessary in the future, the definition, work-up and staging system proposed here could achieve this purpose.

Relaxin-2 expression in oral squamous cell carcinoma.

Background When advanced, oral squamous cell carcinoma (OSCC) may involve adjacent non-epithelial structures, and the prognosis is worse for bone invasion. Human relaxin-2 is a peptide hormone that has recently been associated with cancer. It can induce human osteoclast differentiation and activation, suggesting a role in tumor-driven osteolysis. This study was a preliminary assessment of the prognostic role of relaxin-2 in surgical specimens of OSCC tissue and adjacent but uninvolved mandibular/maxillary bone. Methods Relaxin-2 immunohistochemical expression and reaction intensity were assessed in tumor and uninvolved adjacent mandibular/maxillary bone specimens from 23 operated OSCC patients. Results All OSCC specimens were positive for relaxin-2. The intensity of its reaction in OSCC correlated significantly with the pattern of the tumors invasion front (p = 0.02), being higher with the infiltrative pattern. Mean relaxin-2 immunohistochemical expression was higher in patients whose OSCC recurred after treatment than those experiencing no recurrence (81.3% ± 22.6% vs. 59.5% ± 29.7%, respectively). A significant direct association emerged between relaxin-2 expression in OSCC specimens and recurrence rate (p = 0.049). Conclusions Relaxin-2 expression in OSCC should be further investigated as a potentially useful marker for identifying patients at higher risk of recurrence, who might benefit from closer follow-up and more aggressive adjuvant therapy. In other oncological settings, increasing evidence of relaxin being produced by cancer cells is prompting efforts to synthesize human relaxin-2 analogs capable of acting as antagonists and limiting tumor growth.

Learning from experience. Proposal of a refined definition and staging system for bisphosphonate-related osteonecrosis of the jaw (BRONJ): Letter to the Editor

Dear Editor, It is the authors’ belief that the internationally accepted definition of bisphosphonate-related osteonecrosis of the jaws (BRONJ) (Ruggiero et al, 2009) has several limitations that prevent clinicians from being confident with the diagnosis of the disease. Following recognition of the non-exposed BRONJ clinical variant (Lazarovici et al, 2009), we all became aware that the presence of ‘exposed necrotic bone in the oral cavity’, as outlined in the American Association of Oral and Maxillofacial Surgery (AAOMS) case definition, is just one of the possible clinical manifestations of BRONJ and is not found in all BRONJ patients. As ‘bone exposure’ is certainly not the initial sign of BRONJ in most patients and a minimum of 6–8 weeks’ persistence is required to confirm the clinical suspicion, the final diagnosis is usually delayed for several weeks or months. Therefore, to date, it has been almost impossible to study the early phases of BRONJ. This delayed diagnosis can also explain, at least in part, why the disease is often refractory to the medical and surgical treatments commonly used. We believe that clinicians will benefit from a definition of BRONJ that contains only robust information, without considering any definite clinical picture or a binding time-frame (i.e. 6–8 weeks). As qualified members of the Expert Panel of the Italian Society for Maxillofacial Surgery (SICMF) and the Italian Society of Oral Pathology and Medicine (SIPMO) on Bisphosphonate-Related Osteonecrosis of the Jaws, we are submitting to the attention of the scientific community the following definition of BRONJ: ‘bisphosphonate related osteonecrosis of the jaw (BRONJ) is an adverse drug reaction described as the progressive destruction and death of bone that affects the mandible or maxilla of patients exposed to the treatment with nitrogen-containing bisphosphonates, in the absence of a previous radiation treatment’. Along with this new definition of BRONJ, we set up and propose a diagnostic work-up to be used to reach the final diagnosis. Although exposed necrotic bone in the oral cavity still remains the best indicator of BRONJ (Ruggiero et al, 2009), other non-specific signs and symptoms (Table 1) should raise the suspicion of BRONJ, even in a patient with a well-recognized dental or periodontal disease (Fedele et al, 2010). In short, BRONJ should be always investigated in a patient taking nitrogen-containing bisphosphonates (NBP), when one or more clinical signs are present. Because BRONJ is primarily a disease that affects the jawbone, we strongly believe that radiological examination is an important step of the diagnosis. However, as the radiological findings may be characteristic not only of BRONJ (Khan et al, 2008), these findings should always match the clinical picture, in order to progress from the clinical suspicion to the final diagnosis. This is of outmost importance as bone biopsies for histology are still not routinely advised for the risk of worsening the disease process. A schematic approach to the work-up for a diagnosis of BRONJ is proposed (Scheme 1), where computed tomography (CT) currently represents the most useful diagnostic tool because of its widespread use and accessibility for patients (Bianchi et al, 2007). Structural alteration of trabecular bone is a consistent finding of CT scans performed in patients with BRONJ (Table 2) (Arce et al, 2009). CT scans can clearly depict the degree of osteosclerosis of the affected site, visible as the loss of contrast definition between the endosteal cortex and the subjacent medullary bone (i.e. trabecular thickening and/or regional or diffuse osteosclerosis), with respect to the uninvolved bone tissue (Hutchinson et al, 2010). Osteosclerosis seems to characterize the early stages of disease and also precedes the occurrence of frank bone exposure in the oral cavity (Saia et al, 2010), and thus it should be searched for to provide an early diagnosis. Table 1 Non-specific clinical signs associated with bisphosphonate-related osteonecrosis of the jaws (BRONJ) Table 2 Non-specific computed tomography (CT) findings associated with bisphosphonate-related osteonecrosis of the jaws (BRONJ) Scheme 1 Diagnostic work-up for BRONJ. VAS, visual analogic scale Even though magnetic resonance imaging (MRI) provides more detailed information than CT on focal bone marrow alterations (Bisdas et al, 2008), the former could provide non-diagnostic results owing to magnetic artifacts caused by the presence of dental casting alloys (Shafiei et al, 2003) as well as to motion artifacts caused by the prolonged time necessary to scan the head and neck region (Lenz et al, 2000). The majority of BRONJ cases could be diagnosed and staged correctly by the combined use of clinical methods and CT, the latter method currently being more cost-effective and easily accessible than MRI. On the other hand, we believe that MRI should be used to evaluate cases difficult to identify with CT and to establish the real extent of jawbone and soft-tissue involvement in BRONJ patients who are candidates for surgical resection. The staging system of a bone disease that relies on the use of radiologic imaging for its diagnosis should also be based on the common radiologic features of the disease. The current AAOMS staging system (Ruggiero et al, 2009; Migliorati et al, 2011), which assigns patients to different stages of disease on the basis almost exclusively of clinical criteria, fails, in our opinion, to consider this important aspect. In this regard, we set up a combined clinical and radiological staging system with the aim of pooling BRONJ patients in different groups also based on the radiological extent of the disease. The staging system we propose (Table 3) differs from the 2009 AAOMS classification as follows: Table 3 Clinical and radiological staging system of bisphosphonate-related osteonecrosis of the jaws (BRONJ) The absence of Stage 0, so that BRONJ patients with exposed and non-exposed necrotic bone simply represent distinct clinical pictures within the same disease stage. The description of three stages (1–3) based on clinical and CT findings, ‘where Stage 1 includes patients with focal (alveolar bone) osteosclerosis, Stage 2 includes patients with diffuse (alveolar and basal bone) osteosclerosis and Stage 3 includes patients with clinical and radiological signs of advanced and complicated disease. Pain and purulent discharge are no longer used to distinguish between different disease stages. As these symptoms define only asymptomatic (a) and symptomatic (b) forms of BRONJ in patients within the same stage, exclusion of pain and purulent discharge as criteria would limit the ‘ping-pong’ effect (the migration of patients from Stage 1 to Stage 2, and vice versa) that we all experienced when using the AAOMS classification, as a result of the repeated use of antibiotic therapies to treat recurrent bone infections and associated pain. The presence of clinically detectable sequestra is no longer regarded as a sign of complicated disease, as it is for AAOMS Stage 3. In fact, it is a common experience that the spontaneous expulsion or surgical removal of bony sequestra often leads to dramatic, albeit somewhat temporary, clinical improvement, with mucosal epithelialization of the affected site (Ferlito et al, 2011). The definition, work-up and staging system proposed here might, as a whole, provide several practical benefits, in the order: anticipated BRONJ diagnosis and access of patients to therapies; a reduced need for extensive surgical resections with associated long and debilitating postoperative hospitalization; and increased overall efficacy of treatments and patients’ curability. The disadvantage of the additional cost of bone imaging (CT) for the diagnosis would be offset against the overall reduction in treatment costs. When a new disease is found, little is known of its medical features and behavior; this makes it necessary to avoid general definitions that may include potentially healthy patients (resulting in a higher false-positive risk). This also occurred at the start, when the actual BRONJ case definition was adopted. At present, with the growing bulk of research on BRONJ, we believe that it is necessary to enter a new phase where clinicians try to establish the initial stages of the disease process, in order to make an earlier diagnosis and improve treatment effectiveness. Although adjustments and updating will be necessary in the future, the definition, work-up and staging system proposed here could achieve this purpose.

Exposure to antiresorptive therapy with bisphosphonates does not induce histological changes in human alveolar jawbone

Aim: The identification of specific alterations in the alveolar jawbone of patients treated with nitrogen-containing bisphosphonates (NBP) but without bisphosphonate-related osteonecrosis of the jaw (BRONJ) may help to identify the early steps of BRONJ and to select patients at risk for it. Materials and Methods: We performed a case-control study. Cases were 60 individuals treated with NBP without clinical and radiological signs of BRONJ and requiring surgical tooth extraction. Controls were 60 individuals never treated with NBP and requiring tooth extraction. Cases and controls were matched by sex (same) and age (within 5 years). 18 categorical (basophile reversal lines, osteoblasts, osteoblastic lines, osteocytes, empty osteocytic lacunae, osteoclasts, Howship’s lacunae, vessel dilatation, vascular congestion, arteriolar thickening, intravascular fat globules, calcific fat necrosis, fatty bone marrow, ruptured adipocytes, granular cytoplasm of adipocytes, oil cysts, perivascular fibrosis, diffuse fibrous metaplasia) and 2 ordinal histopathological variables (inflammation and bone maturation) were investigated. Exact univariable and multivariable (correction for gender and age) logistic regression was used to test the association between NBP use and the histopathological variables. Because of multiple comparisons, the critical p-value was set to 0.0025 (0.05/20). Results: Cases and controls did not differ for any study variable except for vascular congestion that was significantly associated with NBP use (multivariable OR = 0.24, exact 95% CI 0.10 to 0.57 for cases vs. controls, p = 0.0006). Conclusions: Use of NBP does not produce specific histological alveolar bone alterations in the absence of overt BRONJ disease.