Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)

Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)

Vivek Thumbigeremath, D.D.S.:

Editor’s Note: Due to scheduling conflicts, the first and second place winning table clinic synopses were not available for this issue of Northwest Dentistry. They will be published in our July-August issue. We congratulate all the participants, and applaud winners Drs. Sandra Shambarger and Joseph Petrino (first place), Drs. John Bogle and Gary Eggleston (second place), and Dr. Vivek Thumbigeremath (third place).




Bisphosphonates (BP) are a valuable class of drugs widely used in the treatment of osteoporosis, Paget’s disease, bone metastasis, and multiple myeloma. BP inhibit osteoclast-mediated bone resorption and thereby significantly reduce the risk of hypercalcemia and vertebral fractures. Recent evidence also suggests that BP have antiangiogenic and antitumor effects,1 creating new opportunities for their use in the treatment of malignant diseases. However, long-term BP therapy is associated with osteonecrosis of the jaw.2, 3

Definition
The American Association of Oral and Maxillofacial Surgeons (AAOMS) defines BRONJ as “exposed bone in the maxillofacial area occurring in the absence of head and neck irradiation and showing no evidence of healing for at least 8 weeks after identification in patients treated with BP therapy.” 4

Incidence/Frequency
To date, more than 900 cases of BRONJ have been reported in the literature. However, the true incidence of BRONJ remains unknown. In one of the largest series reported to date, Hoff et al reported an overall frequency of 0.72 % in cancer patients treated with intravenous BP (1.2% in breast cancer and 2.4% in multiple myeloma patients).5 In contrast, Bamias et al reported a higher incidence of 6.7% (9.9% in multiple myeloma and 2.9% in breast cancer).6 In a multi-center retrospective chart review study, conducted at the University of Minnesota Masonic Cancer Center and Park Nicollet Institute, we noted an overall frequency of 3.1% (4.2% in breast cancer and 7.2% in multiple myeloma) (unpublished data). Therefore, in conclusion, the frequency of BRONJ is highly variable and may range within 0.72% to 10% in cancer patients treated with intravenous BP. In osteoporosis patients receiving oral BP, the estimated incidence of BRONJ is < 1 case per 100,000 person-years of exposure.7

A program was established at the University of Minnesota School of Dentistry to evaluate and manage BRONJ cases referred to the Division of Oral and Maxillofacial Surgery. Furthermore, clinical and basic science studies are underway to determine the epidemiology and pathophysiology of BRONJ. Following is a brief description about our experience in managing 26 BRONJ cases at the University of Minnesota School of Dentistry.

Clinical Features
BRONJ lesions may be asymptomatic or present with pain, swelling, purulent discharge, tooth mobility, and paresthesia. These symptoms can result in reduced ability to eat and speak. The AAOMS categorizes BRONJ patients into stage I, stage II, and stage III according to the clinical signs and symptoms.4 Briefly, patients are classified into Stage I group if they have asymptomatic exposed bone without any evidence of infection. Patients exhibiting exposed necrotic bone with evidence of infection, pain, and erythema, with or without purulence, are classified into Stage II group. Patients are classified into Stage III group if they have exposed necrotic bone with evidence of pain, infection, and one or more of the following: pathologic fracture, oral-cutaneous fistula, or osteolysis extending to the inferior border.

Of the 26 patients, two patients (12.5%) were classified into stage I, 19 patients (73%) into stage II, and five patients (19%) into stage III group. BRONJ was noted more frequently (85%) in the mandible than the maxilla (15%). BRONJ was more common (88%) in the posterior lingual mandible near the mylohyoid ridge. In addition, most patients (61%) developed BRONJ following dentoalveolar surgery such as tooth extraction, while some (30%) developed it without an obvious precipitating event.

Radiographic Features
Radiographic evaluation is often inconclusive for early lesions, whereas advanced cases with extensive bony involvement can appear as poorly defined radiolucent-radiopaque lesions. Therefore, a correlation with the clinical history and previous BP therapy is very essential in diagnosing BRONJ.

Plain radiographs including periapical radiographs and panoramic radiographs serve as an initial screening modality. Computerized tomography and magnetic resonance imaging are effective in precisely determining the extension and characteristics of the lesion, which is of importance in surgical treatment planning. Nuclear bone scans with Tc-99m often show extremely intense uptake in or around the necrotic bone, and has been shown in a small study group to distinguish BRONJ lesions from the tumor infiltration associated with multiple myeloma.8

BRONJ Management
Management was directed toward alleviating pain, reducing lesion size, soft and hard tissue inflammation and/or infection. In most patients, initial treatment was non-surgical and includes antibiotics (penicillin, clindamycin, amoxicillin/clavulanate, and cephalexin), antifungal agents (Fluconazole, Nystatin), and rinsing or irrigating the lesion with an antimicrobial solution (chlorhexidine gluconate). Debridement of the necrotic bone without mucosal elevation was performed at subsequent visits if patients did not respond to initial treatment. Irrespective of the disease stage, loose segments of bony sequestra were removed. Patients were instructed to improve their oral hygiene. Currently, there is no scientific evidence confirming that discontinuation of BP therapy will promote BRONJ healing. Therefore, the decision to continue or discontinue BP should be made by the prescribing physician in consultation with the oral health care providers.

Potential Risk Factors for BRONJ
BRONJ is considered to be a multifactorial complication associated with trauma, advanced cancer, chemotherapy, corticosteroids, dental infection, co-morbid conditions such as diabetes, and lifestyle behaviors like tobacco and alcohol use.

Most BRONJ cases reported to date have been in patients receiving nitrogen-containing BP. This may be related to the increased potency and prolonged half-life of nitrogen-containing BP. Previous studies demonstrate that the cumulative hazard of developing ONJ is significantly higher with zoledronate treatment compared to pamidronate or pamidronate plus zoledronate.5, 6. In consistent with these results, our study noted that most patients who developed BRONJ had received zoledronate only or zoledronate plus pamidronate.

Long-term BP therapy is significantly associated with BRONJ development. Bamias et al reported that no patient who received fewer than 13 BP infusions developed BRONJ in their series of 252 patients.6 In our study, only two of the 26 patients developed BRONJ within eight months of starting BP therapy and after receiving fewer than 10 infusions. In contrast to intravenous BP, patients receiving oral BP required significantly longer duration of exposure (mean, 82.0 months versus 45.8 months) and more drug doses (mean, 322 versus 37.6) to develop BRONJ (P=0.02).

Conclusion
It is important that the dental and medical professionals are aware of this condition. Also, it is critical that the dentists carefully document medical and BP history of every patient. Patients need to be informed about the implications of BP therapy and the risk of BRONJ before undergoing any invasive procedure that involves manipulation of the bone or periosteum. The discontinuation of BP therapy should be discussed with the oncologist, rheumatologist, or the prescribing physician.

Acknowledgment:
I would like to thank Drs. James Hinrichs, Rajaram Gopalakrishnan, David Basi, Arkadiusz Dudek, Mark Herzberg, Ma’Ann Sabino, Bryan Michalowicz, and Pamela Hughes for their continued support and guidance. The research group gratefully acknowledges Dean Patrick Lloyd for his generous support towards the ongoing projects. n

References
1. Ferretti G, Fabi A, Carlini P et al. Zoledronic-acid-induced circulating level modifications of angiogenic factors, metalloproteinases and proinflammatory cytokines in metastatic breast cancer patients. Oncology 2005;69(1):35-43.
2. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. Journal of Oral and Maxillofacial Surgery 2004;62(5):527-34.
3. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63(11):1567-75.
4. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65(3):369-76.
5. Hoff AO, Toth BB, Altundag K et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008;23(6):826-36.
6. Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005;23(34):8580-7.
7. Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. J Am Dent Assoc 2006;137(8):1,144-50.
8. Catalano L, Del Vecchio S, Petruzziello F et al. Sestamibi and FDG-PET scans to support diagnosis of jaw osteonecrosis. Ann Hematol 2007;86(6):415-23.