Giorgia Saia

Bisphosphonate-associated jawbone osteonecrosis: a correlation between imaging techniques and histopathology

OBJECTIVES Recently, jawbone osteonecrosis has been reported as a potential adverse effect of bisphosphonates administration. This paper considers and highlights histopathologic and radiologic features of this condition. STUDY DESIGN Eleven patients, owing to unresponsiveness to conservative treatment and uncontrollable pain, underwent surgical resection of diseased jawbone after extensive hyperbaric oxygen therapy. A thorough clinical, laboratory, and imaging study was performed. Surgical specimens underwent histopathologic and immunohistochemical evaluation. RESULTS Computerized tomography (CT) scans showed increased bone density, periosteal reaction, and bone sequestration in advanced stages. With magnetic resonance imaging (MRI), exposed areas showed a low signal in T1- and T2-weighted and inversion recovery images, which suggests low water content and is histopathologically correlated with paucity in cells and vessels (osteonecrotic pattern). Unexposed diseased bone was characterized by T1 hypointensity and T2 and IR hyperintensity, which suggests high water content and inflammation, associated with hypercellularity, osteogenesis, and hypervascularity (osteomyelitic pattern). CONCLUSIONS Diseased bone extends beyond the limits of the bone exposed in the oral cavity. Histopathologic examination correlated well with CT and MRI, which are the choice for the evaluation of bisphosphonate-associated jawbone osteonecrosis.

Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis.

Surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is controversial. Current recommendations contraindicate aggressive surgery because its results are unpredictable and may trigger disease progression. In this prospective study, we assessed the effectiveness of surgical resection of the jaws in cancer patients with BRONJ. Between June 2004 and July 2009, 30 cancer patients with refractory BRONJ underwent surgical resection of the jaws at our Units. They were followed-up weekly for the first month, at 3-month intervals up to 1 year, and at 6-month intervals up to 2 years. Panoramic radiographs and CT-scan were obtained at 3, 6, 12, 18 and 24 months. Primary outcomes were the 24-month recurrence rate of BRONJ and the 24-month mortality rate. Secondary outcomes were post-operative complications, duration of hospital stay after surgery, time to return to oral diet, and degree of oral pain. The 30 patients had a median age of 66 years and were mostly females (80%). Twenty-eight underwent a single resection and two had both jaws resected, for a total of 32 resected jaws. The cumulative recurrence rate of BRONJ in resected jaws 3.1% and 9.4% at 3 and 6 months, respectively. All the jaws with recurrent BRONJ had osteomyelitis at the margins of bone resection. The cumulative incidence of death was 3%, 12% and 16% at 12, 18 and 24 months. Surgical resection of BRONJ was highly effective, with few post-operative complications and were not associated with long-term mortality.

Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma

We report on the potential association of suspected bisphosphonate-associated osteonecrosis of the jaw (BRONJ) recurrence with the use of the novel antiangiogenic drug sunitinib. A 59 year-old patient affected by metastatic renal cell carcinoma (RCC) and established BRONJ experienced consecutive episodes of painful jaw infection with cutaneous fistula and bone sequestration which occurred during active treatment with sunitinib, improved after discontinuation and antibiotic therapy, then rapidly worsened with resumption of sunitinib. We hypothesize that the potent antiangiogenic activity of sunitinib may amplify the inhibition of bone remodeling exerted by aminobisphosphonates entrapped within the osteonecrotic mineral matrix, antagonize mucosal healing and expose to infections during treatment. This supports the emerging role of soft-tissue damage in the pathogenesis of osteonecrosis of the jaw.

Vascularized fibula flap reconstruction of the mandible in bisphosphonate-related osteonecrosis.

AIMS To point out the feasibility of microsurgical reconstruction of the mandible in patients with bisphosphonate-related osteonecrosis (BRONJ). METHODS Seven patients with extensive mandibular osteonecrosis underwent subtotal mandibulectomy and immediate reconstruction with a free fibula flap. They were six women and one man aged 49-72 years. The mean size of the bone and oral mucosa defects were 18.5 and 22.5 cm(2) respectively. RESULTS The mean time of surgical intervention was 12 h. All flaps survived and the postoperative course was uneventful. Oral feeding was resumed 14 days after surgery in all cases. The donor legs healed without complications. The pathology report confirmed the diagnosis of BRONJ in all patients. Normal bone was detected at the resection margins in six out of seven patients. Patients were followed-up at intervals of 3 months. After a median follow-up time of 23 months, no clinical and radiographic evidence of recurrent BRONJ were detected in six patients. One patient with osteomyelitis at the resection margins had signs of recurrent BRONJ 6 months after surgery. The overall curative rate of the population was 86%. CONCLUSIONS Despite the limited number of patients studied so far, our data show that mandible reconstruction with the fibula flap is feasible and does not influence the natural course of the primary disease in BRONJ-resected patients.

Oral Bisphosphonate–Associated Osteonecrosis of the Jaw After Implant Surgery: A Case Report and Literature Review

This report documents a case of bisphosphonate-related osteonecrosis of the jaw (BRONJ) after dental implant placement in an osteoporotic patient treated with alendronate for 6 years. A 63-year-old patient underwent rehabilitation of the posterior mandible with 2 dental implants in 2006 while taking alendronate to treat osteoporosis. The surgical procedure was uneventful. Both implants integrated well, and in November 2006 the patient wore a fixed partial prosthesis. Alendronate was never discontinued. In June 2008 a painful cheek swelling of the left mandible developed, associated with gingival bleeding. Since then, the patient underwent several courses of antibiotics, without relief of symptoms. In June 2009 the patient was referred to our department. An area of infected and exposed necrotic bone in the left mandible enclosed 1 dental implant. A panoramic radiograph and computed tomography scan showed an increased bone marrow density with peri-implant bone sequestration. The technetium Tc 99m scintigraphy-labeled granulocytes were positive for active bone infection. Bone exposure persisted for 8 weeks, and diagnosis of oral nitrogen-containing bisphosphonate (N-BP)-related osteonecrosis was made. On the basis of a review of the literature, this is the 10th case of BRONJ after implant placement in patients taking oral N-BPs. Despite the low risk of BRONJ occurrence after implant surgery in oral N-BP users, the fate of dental implants in these patients remains uncertain. Therefore patients at risk must be given a full explanation of the potential risks of implant failure and BRONJ development. Because the potential role of infection is still debated, great attention should be paid to the long-term oral hygiene of implant-prosthetic restorations.

Staging of osteonecrosis of the jaw requires computed tomography for accurate definition of the extent of bony disease

Management of osteonecrosis of the jaw associated with antiresorptive agents is challenging, and outcomes are unpredictable. The severity of disease is the main guide to management, and can help to predict prognosis. Most available staging systems for osteonecrosis, including the widely-used American Association of Oral and Maxillofacial Surgeons (AAOMS) system, classify severity on the basis of clinical and radiographic findings. However, clinical inspection and radiography are limited in their ability to identify the extent of necrotic bone disease compared with computed tomography (CT). We have organised a large multicentre retrospective study (known as MISSION) to investigate the agreement between the AAOMS staging system and the extent of osteonecrosis of the jaw (focal compared with diffuse involvement of bone) as detected on CT. We studied 799 patients with detailed clinical phenotyping who had CT images taken. Features of diffuse bone disease were identified on CT within all AAOMS stages (20%, 8%, 48%, and 24% of patients in stages 0, 1, 2, and 3, respectively). Of the patients classified as stage 0, 110/192 (57%) had diffuse disease on CT, and about 1 in 3 with CT evidence of diffuse bone disease was misclassified by the AAOMS system as having stages 0 and 1 osteonecrosis. In addition, more than a third of patients with AAOMS stage 2 (142/405, 35%) had focal bone disease on CT. We conclude that the AAOMS staging system does not correctly identify the extent of bony disease in patients with osteonecrosis of the jaw.

Up to a quarter of patients with osteonecrosis of the jaw associated with antiresorptive agents remain undiagnosed.

Recent data suggest that the traditional definition of bisphosphonate-associated osteonecrosis of the jaw (ONJ) may exclude patients who present with the non-exposed variant of the condition. To test the hypothesis that a proportion of patients with ONJ remain undiagnosed because their symptoms do not conform to the traditional case definition, we did a secondary analysis of data from MISSION (Multicentre study on phenotype, definition and classification of osteonecrosis of the jaws associated with bisphosphonates), a cross-sectional study of a large population of patients with bisphosphonate-associated ONJ who were recruited in 13 European centres. Patients with exposed and non-exposed ONJ were included. The main aim was to quantify the proportion of those who, according to the traditional case definition, would not be diagnosed with ONJ because they had no exposed necrotic bone. Data analysis included descriptive statistics, median regression, and Fishers exact test. A total of 886 consecutive patients were recruited and 799 were studied after data cleaning (removal or correction of inaccurate data). Of these, 607 (76%) were diagnosed according to the traditional definition. Diagnosis in the remaining 192 (24%) could not be adjudicated, as they had several abnormal features relating to the jaws but no visible necrotic bone. The groups were similar for most of the phenotypic variables tested. To our knowledge this is the first study in a large population that shows that use of the traditional definition may result in one quarter of patients remaining undiagnosed. Those not considered to have ONJ had the non-exposed variant. These findings show the importance of adding this description to the traditional case definition.

Deep neck infection with dental origin: analysis of 85 consecutive cases (2000-2006).

Conclusions. Diagnostic work-up should include contrast-enhanced computed tomography (CT) and mandible orthopantogram. When a dental origin of deep neck infection is suspected, the intravenous antibiotic regimen has to be active against gram-positive bacteria, both aerobes and anaerobes. Surgical exploration and drainage may be mandatory at presentation, or in cases not responding to medical therapy within the first 24 h. Objectives. Deep neck infections are still associated with significant morbidity and mortality rates when complications occur. Despite worldwide improvement in dental care and oral hygiene, a significant prevalence of deep neck infections caused by dental infections has been described recently (>40%). Patients and methods. We analysed retrospectively 85 cases of deep neck infection with dental origin out of 206 consecutive cases of deep neck infection diagnosed in our institution between 2000 and 2006. Results. The most frequent dental source was a periapical infection of the first mandibular molar, followed by second and third molar, respectively. Submandibular space infection involvement was diagnosed in 73 of 85 patients (85.9%), masticatory space infection in 28 (32.9%); in 56 patients (65.9%) the infection involved more than one space. Twenty-four patients (28.2%) were treated only with intravenous antibiotic therapy; 61 patients (71.8%) required both medical and surgical procedures.

Bevacizumab-related osteonecrosis of the mandible is a self-limiting disease process.

A female patient with non-small-cell lung cancer presented with a huge area of exposed bone in the mandible following spontaneous teeth loss. She was receiving multimodal chemotherapy containing bevacizumab. No previous treatment with bisphosphonates or comorbid conditions was reported. Pain medications and infection control were offered to the patient who was closely followed up. Initial imaging and histology of bone and surrounding mucosa (8 weeks after bevacizumab cessation) confirmed the clinical suspicion of avascular osteonecrosis of the mandible. Subsequent imaging and histology of bone and gingiva (12 weeks after bevacizumab cessation) revealed the initial sequestration of the mandible with a marked expansion of the mucosal vascular network. Spontaneous bone sequestration eventually occurred few months later, followed by stable and painless mucosal coverage of the mandibular bone. The patient remained disease-free up to 3 years of follow-up.

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.