Giordana Bettini

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.

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.

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.

Osteomalacia: The Missing Link in the Pathogenesis of Bisphosphonate-Related Osteonecrosis of the Jaws?

BACKGROUND Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented adverse event from treatment with nitrogen-containing bisphosphonates (NBPs). During a preliminary histomorphometric study aimed at assessing the rate of bone remodeling in the jaws of patients with surgically resected BRONJ, we found a defect of bone mineralization (unpublished data). We hypothesized that osteomalacia could be a risk factor for BRONJ in patients taking NBPs. Therefore, we looked for static and dynamic histomorphometric evidence of osteomalacia in biopsies from subjects with and without BRONJ. METHODS This case-control study used histomorphometric analysis of bone specimens of patients using NBPs (22 patients with BRONJ and 21 patients without BRONJ) who required oral surgical interventions for the treatment/prevention of osteonecrosis. Patients were given tetracycline hydrochloride according to a standardized protocol before taking bone biopsies from their jaws. Biopsies with evidence of osteomyelitis or necrosis at histology were excluded from the study. Osteomalacia was defined as a mineralization lag time >100 days, a corrected mean osteoid thickness >12.5 mm, and an osteoid volume >10%. RESULTS In all, 77% of patients with BRONJ were osteomalacic compared with 5% of patients without BRONJ, according to histomorphometry. Because osteomalacia was found almost exclusively in NBP users with BRONJ, this is likely to be a generalized process in which the use of NBPs further deteriorates mechanisms of bone repair. CONCLUSIONS Osteomalacia represents a new and previously unreported risk factor for disease development. This finding may contribute to a better understanding of the pathogenesis of this disease and help with the development of strategies to increase the safety of NBP administration.

Soccer-related Facial Fractures: Postoperative Management With Facial Protective Shields

Facial fractures are one of the most common orofacial injury sustained during participation in sporting events. The frequency of maxillofacial lesions varies according to the popularity that each sport has in a particular country. Soccer is the most popular sport in Italy, and it is responsible for a large number of facial traumas. Traumas and fractures in soccer mainly involve the zygomatic and nasal regions and are especially caused by direct contact that takes place mainly when the ball is played with the forehead. In particular, elbow-head and head-head impacts are the most frequent dangerous contacts. Soccer is not a violent sport, and the use of protective helmets is not allowed because it could be dangerous especially when players play the ball with the head. The use of protective facial shields are exclusively permitted to preserve players who underwent surgery for facial fractures. The use of a facial protection mask after a facial fracture treatment has already been reported. This article describes a clinical experience of management of 4 soccer-related facial fractures by means of fabrication of individual facial protective shields.

Chronic oroantral fistula: Combined endoscopic and intraoral approach under local anesthesia

OBJECTIVE To evaluate the outcome of combined surgical treatment of oroantral communications associated with chronic maxillary sinusitis. PATIENTS AND METHODS 8 consecutive patients affected by complicated oroantral fistula were included in the study. The protocol consisted of: clinical, endoscopic and radiological preoperative evaluation (panoramic tomogram and computed tomography); systemic antibiotic and steroid therapy 2 weeks before surgery; one-stage surgical procedure under local anaesthesia consisting in uncinectomy with enlargement of the osteomeatal complex through endoscopic nasal approach associated with the closure of the oroantral communication by means of a mucoperiosteal flap; postoperative antibiotic and cortisone-based therapy. Follow-up consisted of weekly clinical evaluation during the first month, and nasal endoscopy at 3, 8 and 24 weeks after surgery. RESULTS After surgical treatment, all patients were symptom-free and had no endoscopic and radiological evidences of maxillary sinusitis at the 6-month follow-up. No recurrent oroantral fistulas were found. CONCLUSIONS The current prospective study showed that a one-stage, combined endoscopic and intraoral approach under local anaesthesia represents a feasible and minimally invasive procedure for the long-term effective treatment of chronic complicated oroantral communications. Moreover, it represents an easily applicable approach also in outpatient clinics with minor patient discomfort.