Bisphosphonates (BPs) are widely used as bone-stabilizers, but side effects of BP therapy include bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is resistant to therapy. The aim of this study was to evaluate the outcome of maxillary BRONJ involving sinusitis maxillaris. 21 patients presenting with maxillary BRONJ, from 2005 to 2008, were included in the study. In 18 cases BP had been administered for carcinoma and in 3 cases for osteoporosis, with an average exposure time of 47.4 months. 12 patients spontaneously developed BRONJ. The 10 patients diagnosed with stage III BRONJ presented with concomitant sinusitis maxillaris. Despite treatment, there were six recurrences of BRONJ, four of them with additional sinusitis maxillaris. Whether BRONJ occurred spontaneously or after extraction there was no difference in the outcome. Patients with advanced maxillary BRONJ often suffer from sinusitis maxillaris, both of which are frequently resistant to therapy.
Bisphosphonates (BPs) are widely used as bone-stabilizers in the treatment of osseous metastases, osteoporosis, and Paget’s disease due to their ability to inhibit osteoclast activity . Over 20 million BPs are prescribed annually in the USA . Side effects of BP therapy include acute renal failure, gastrointestinal disorders, hypocalcaemia, and bisphosphonate-related osteonecrosis of the jaw (BRONJ) . BRONJ is defined as the presence of exposed, nonvascularized, and necrotic bone tissue in the oral cavity and is frequently combined with inflammation of the surrounding tissue and pain .
Although several studies have quoted the estimated incidence of BRONJ to be 8–12% , the actual frequency is unclear. BRONJ is largely resistant to antibiotics, so its management remains difficult and includes surgical procedures to eradicate the necrotic bone .
The mandible appears to be more frequently affected by BRONJ than the maxilla . Isolated cases of maxillary BRONJ have been described in which a simultaneous sinusitis maxillaris was diagnosed . Sinusitis is characterized by quantitative and qualitative changes in mucus biosynthesis that contribute to sinus disease. Sinusitis can be classified etiologically as rhinogenic (60–80%) or ontogenic (20–40%).
The odontogenic origins of sinusitis may be periapical abscesses or periodontal disease, as well as infections following sinus perforation during tooth extractions or dislocation of foreign bodies after endodontic therapy . Chronic, focal alveolar osteitis or maxillary osteomyelitis can cause irritation and a subsequent sinus infection .
Functional and aesthetic deterioration resulting from maxillary BRONJ, as well as respiratory obstruction and pain due to an associated sinusitis, may compromise the patient’s quality of life. Due to immunosuppression following combined chemotherapy and corticosteroid treatment, sinusitis may spread to adjacent tissues, such as the orbit, the meninges, and the brain, resulting in life-threatening complications. Therefore, early diagnosis and prompt initiation of therapy are essential.
The aim of the present consecutive study was to determine the frequency of maxillary BRONJ, with special attention to coincidental sinusitis maxillaries, and to evaluate possible therapeutic outcomes.
Materials and methods
All patients presenting with BRONJ of the maxilla between January 2005 and July 2008 were evaluated in terms of frequency and therapeutic outcome, with special attention paid to patients with an associated sinusitis maxillaris.
All patients who met the following criteria were included: a history of BP therapy, intraoral lesion (e.g. exposed bone, purulent discharge, or fistulae) that persisted for more than 8 weeks or an extraoral manifestation of swelling or fistulae and no history of radiation therapy to the jaw. One additional patient (No. 3) with pain but intact mucosa was included after radiological confirmation of BRONJ (irregularly shaped radiolucencies). Malignant lesions of the maxillofacial region were considered an exclusion criterion.
All patients were examined clinically (including dental status and tooth sensibility, Fig. 1 ) and radiologically with digital volume tomography (DVT, Fig. 2 ). Using a standardized questionnaire, data were collected on BP therapy, its duration, and the manner of application ( Table 1 ). The anamnesis included questions related to symptoms of sinusitis such as facial pain, purulent nasal discharge and nasal obstruction. When anamnestic and/or clinical indications of sinusitis maxillaris were found, a computed tomography (CT) scan was performed ( Fig. 3 ).
|Patient no.||Sex||Age||Primary diagnosis||Underlying diseases||Oral surgery||Chemo-therapy|
|2||F||55||Breast cancer||Smoking, alcohol abuse||+||+|
|6||M||65||Breast cancer||HT, NIDDM II||−||+|
|9||M||69||Multiple myeloma||HT, hypothyreosis, gastric ulcer||−||+|
|11||F||66||Multiple myeloma||CHF, arrhythmia||−||+ (SCT)|
|12||F||63||Multiple myeloma||HT, renal failure||+||+|
|14||F||76||Multiple myeloma||HT, systemic scleroderma, MI||+||+|
|15||F||67||Multiple myeloma||Pulmonary embolism||+||+|
|19||F||85||Osteoporosis||HT, IDDM II, anaemia, renal failure, dementia||−||−|
|20||F||80||Osteoporosis||HT, CIHD, hypercholesterolaemia, depression||−||−|
|21||F||91||Osteoporosis||AMI, dementia, amaurosis||−||−|
Staging of BRONJ was based on the classification established by R uggiero et al. and the American Association of Oral and Maxillofacial Surgeons (AAOMS) . Stage 0 includes patients with no clinical evidence of necrotic bone, but presenting with non-specific symptoms or clinical and radiographic findings. Stage I includes exposed/necrotic bone in patients who are asymptomatic and have no evidence of infection or patients symptomatic with pain prior to clinical evidence of exposed bone or radiographic changes. Stage II includes patients with exposed/necrotic bone associated with an infection as evidenced by pain and erythema in the region of the exposed bone with or without purulent drainage. Stage III includes patients with exposed/necrotic bone associated with pain, infection, and one or more of the following: a pathologic fracture, an extraoral fistula, or osteolysis extending into the inferior border or sinus floor.
Management and outcome
Management was based on the results of BRONJ staging. All patients received antibiotics (2 g of amoxicillin plus 200 mg of clavulanic acid intravenously (i.v.) every 8 h) in combination with an intraoral chlorhexidine rinse at least 14 days prior to any intervention. In Stage 0 or I cases, surgical intervention was restricted to debridement of soft tissue. In Stage II or III cases, a segmental bone resection under general anaesthesia was performed. In all of the surgically treated cases, histological findings confirmed BRONJ without evidence of malignant infiltration ( Fig. 4 ). Patients with sinusitis were treated with antibiotics according to the protocol given above. If the sinusitis persisted after five days of antibiotic treatment an antrotomy was performed. A follow-up included clinical and radiological examinations every six months with special attention paid to the recurrence of BRONJ and sinusitis maxillaris. In case of recurrence i.v. antibiotics were administrated and a surgical revision was performed.
The length of BP exposure was determined as the period from the first BP application to the initial diagnosis of BRONJ. The data were statistically evaluated using a χ 2 test and Fisher’s exact test using the Statistical Package for the Social Sciences (SPSS Inc, version 12; Chicago, IL, USA). Probabilities of less than 0.05 were accepted as significant.
Ninety-eight patients were diagnosed with BRONJ between January 2005 and July 2008. Of these, 21 suffered from maxillary BRONJ. The average age of these 21 patients was 69 years (range 48–91 years). Five patients with maxillary BRONJ were men (24%) and 16 were women (76%). The baseline characteristics of the 21 patients included in the study are listed in Table 1 . The mean follow-up period was 17.7 months (range 3–37 months). BP treatment was continued during the follow-up period in all of the cases.
Most patients (86%, n = 18) received intravenous BP therapy to treat malignancies, mostly multiple myeloma (38%, n = 8) or breast cancer (29%, n = 6). The other three patients (14%) developed maxillary BRONJ after oral BP therapy for osteoporosis ( Table 1 ). Sixteen patients (76%) underwent chemotherapy. Of the 21 patients with maxillary BRONJ, eleven had at least one of the following risk factors: hypertension (3%, n = 7), vascular disease (24%, n = 5), or diabetes mellitus (10%, n = 2) ( Table 1 ). Twelve patients (57%) had spontaneously developed BRONJ, while nine (43%) underwent a dentoalveolar procedure prior to BRONJ manifestation ( Table 1 ).
Most patients (71%, n = 15) received zoledronate i.v. (Zometa; Novartis, Basel Switzerland), three patients (4%) received ibandronate i.v. (Bondronat; Roche, Basel Switzerland), and three (4%) received alendronate per os (Fosamax; Merck & Co Inc., USA). The duration from the start of the BP administration to the appearance of BRONJ (defined as the time of exposure) was an average of 47.4 months (range 11–120 months). The average exposure time for each individual BP was 48.4 months (range 11–120 months) for zoledronate, 29 months (range 14–58 months) for ibandronate and 60.7 months (range 23–81 months) for alendronate ( Table 2 ).
|No.||Bisphosphonate||Latency (month)||Localization of BRONJ||Staging of BRONJ||Sinusitis||Therapy||Relapse of BRONJ||Relapse of sinusitis|
|1||Zoledronate i.v.||11||27||3||+||AB, S, A||−||−|
|2||Zoledronate i.v.||120||23||2||−||AB, S||+||−|
|4||Zoledronate i.v.||36||15–17||3||+||AB, S, A||−||−|
|5||Zoledronate i.v.||35||15, 21–27||2||−||AB, S||−||−|
|6||Zoledronate i.v.||55||26||2||−||AB, S||−||−|
|7||Zoledronate i.v.||43||22||2||−||AB, S||−||−|
|8||Ibandronate i.v.||58||24–27||3||+||AB, S, A||+||+|
|9||Zoledronate i.v.||45||22||2||−||AB, S||−||−|
|10||Zoledronate i.v.||60||28||2||−||AB, S||+||−|
|11||Zoledronate i.v.||31||16||3||+||AB, S||+||+|
|12||Zoledronate i.v.||95||26–28||3||+||AB, S, A||+||+|
|13||Zoledronate i.v.||31||15, 25||3||+||AB, S, A||+||+|
|14||Zoledronate i.v.||57||25||2||−||AB, S||−||−|
|15||Zoledronate i.v.||60||14||2||−||AB, S||−||−|
|16||Zoledronate i.v.||24||14–16||2||−||AB, S||−||−|
|17||Zoledronate i.v.||23||13–16||3||+||AB, S||−||−|
|18||Ibandronate i.v.||15||17||3||+||AB, S, A||−||−|
|20||Alendronate p.o.||23||23–24||3||+||AB, S, A||−||−|
|21||Alendronate p.o.||81||23||3||+||AB, S, A||−||−|