Bisphosphonate-associated Osteonecrosis (BON)
        Diagnosis of BON
        Management of BON
        Discontinuation of bisphosphonate therapy
        Spontaneous and asymptomatic BON
        Effects on quality of life
        New trends

Bisphosphonate-associated Osteonecrosis (BON)

Osteonecrosis of the mandible and maxilla can result from radiation therapy of the head and neck, chronic corticosteroid therapy, and herpes zoster virus infection in immunocompromised patients. Terminology associated with the lesions is based on the etiologic agent (e.g., radiation osteonecrosis, steroid osteonecrosis, or viral osteonecrosis). The term BON is based on a comparable approach.

BON is an oral complication of bisphosphonate therapy in cancer patients.[1] First reported in 2003,[2,3] BON is defined as the unexpected appearance of exposed necrotic bone anywhere in the oral cavity of an individual who is receiving a bisphosphonate and who has not received radiation therapy to the head and neck. The exposed bone persists for 6 to 8 weeks after standard dental care is provided. It is also possible that symptoms of dental and/or periodontal disease may be present, without visible exposed bone.[4] The occurrence of BON is based on cases reported in the literature, and occurrence ranges between 1% and 10% for patients receiving the intravenous formulation (pamidronate and zoledronic acid) and less than 1% for patients taking oral bisphosphonate.[5,6] The mandible is affected in approximately 68% of cases, the maxilla in about 28% of cases, and both jawbones in approximately 4% of cases.[7] This complication is exclusively seen in the head and neck area.

Bisphosphonates are potent inhibitors of osteoclasts. They are utilized in cancer patients with skeletal metastasis, including breast, prostate, or lung cancer; and in patients with multiple myeloma. They are also used to treat hypercalcemia of malignancy. (Refer to the PDQ summary on Hypercalcemia for more information.) Bisphosphonates reduce the risk for fracture and skeletal pain, improving the quality of life of patients with malignant bone disease.[8] (Refer to the PDQ summary on Pain for more information.)

Diagnosis of BON can be clinically challenging. The two most common clinical presentations are as follows:

• Classical: a cancer patient with skeletal metastasis who is receiving intravenous bisphosphonate therapy and who presents with visible necrotic bone in the oral cavity. The site may be infected and painful; these conditions are the typical reason for referral to a dentist. Pain results from both inflammation of the soft tissues contiguous to the necrotic bone as well as from infection. Other symptoms typically occur in more advanced cases (e.g., paresthesia secondary to local neurologic involvement). Purulent secretion at the exposed area indicates active infection. Radiographic examination may demonstrate typical radiolucent and radiopaque areas associated with a bone sequestrum. Bone trabeculation may present with a “mothlike” appearance, suggesting ongoing bone destruction.



• Less common: a cancer patient receiving intravenous bisphosphonate therapy who complains of pain that mimics periodontal or pulpal pathology. There is no clinically visible exposed necrotic bone, but a draining fistula or purulent secretion from the periodontal sulcus may exist. The involved teeth will typically be symptomatic upon palpation and percussion.

Confirmed BON with exposed bone in the oral cavity should initially be managed conservatively with local debridement and removal of sharp margins of bone. This reduces risk of trauma to the soft tissues, including the tongue. Systemic antibiotics should be administered when active infection with purulent secretion, swelling and inflammation of the surrounding soft tissues, and pain are present. Initial therapy can be implemented with only one antibiotic, but there is no agreement regarding drug of first choice. Options include the following:

• Amoxicillin, 500 mg 4 times a day for at least 14 days.
• Metronidazole, 250 mg 3 times a day for at least 14 days.
• Clindamycin, 300 mg 4 times a day for at least 14 days.
• Augmentin, 500 mg 4 times a day for at least 14 days.

In addition, topical oral therapy can be implemented via 0.12% chlorhexidine mouth rinses twice a day. The need for oral hygiene with meticulous brushing and flossing after meals should be emphasized.[5-10]

The patient should be reevaluated in 2 weeks. Systemic antibiotics can be discontinued when clinical signs and symptoms improve. The local measures should be maintained, however, as part of the routine oral hygiene procedures consisting of brushing and flossing.

In BON cases refractory to therapy, patients may need to be maintained on long-term antibiotic therapy. With these patients, a combination of different antibiotic agents such as penicillin and metronidazole can be considered. Another possibility is to use clindamycin or augmentin in the place of amoxicillin. When the infectious process extends to more critical areas of the head and neck, the patient may need hospitalization and intravenous antibiotic therapy, culminating in the need for extensive surgical resection of the affected areas.[10]

Occasionally, cancer patients complain of oral pain and discomfort, and a definitive diagnosis of BON cannot be made because no clinically exposed bone is evident. In these cases, the most likely clinical diagnosis should be addressed first. Routine clinical pulp testing and procurement of signs and symptoms of periodontal disease (e.g., pocket depths, bone loss, and bleeding on probing) should be performed. Radiographic examination should also be conducted. Although not yet definitively confirmed in the literature, the radiographic finding of sclerosing or absence of the lamina dura of the involved teeth may indicate early presence of BON.[7] Endodontic and periodontal therapy should be performed first. The patient should be advised about the possibility of BON and should be educated about oral hygiene procedures. If dental extraction is indicated, the possibility of subclinical BON should be considered and explained to the patient. Thus, delay or absence of healing postextraction must be considered. Before the invasive procedure is performed, the risk of excessive bleeding and/or infection due to bone marrow suppression must be discussed with the patient’s physician, and proper preventive measures should be formulated.

The use of hyperbaric oxygen therapy (HBO) to treat cases of established BON does not appear to be effective.[7-10] However, evidence indicates that HBO in addition to discontinuation of bisphosphonate therapy may benefit patients with BON.[11] Research in this area is ongoing.

The literature does not support discontinuing bisphosphonate therapy as a means to enhance the healing process. Bisphosphonates accumulate in the patient’s skeleton and could remain active for several years, especially in patients who have been treated with an intravenous bisphosphonate for longer than a year. There is anecdotal evidence that even with discontinuation of zoledronic acid therapy in patients who developed BON, the osteonecrotic process clinically progresses and can extend to contiguous sites. However, discontinuation of bisphosphonate therapy is advocated by some authors, especially when a procedure is planned to treat BON.[5,7] Some clinicians believe that there may be beneficial effects from discontinuation of the drug in patients who will receive surgery to treat the necrotic area, although this belief is not supported by scientific study. It is recommended that such a drug holiday be maintained until clinical evidence of healing is observed.[5] However, controversy surrounds this issue [6] and will only be resolved with scientific investigation. It is advisable to discuss with the patient’s physician whether discontinuing bisphosphonate therapy will not put the patient’s general health status at risk. Obtaining an informed consent from the patient before execution of the proposed drug discontinuation and therapy is important.

Patients may present with asymptomatic exposed necrotic bone anywhere in the oral cavity, although the mylohyoid plate on the posterior mandible is the most frequently affected area. In this case, only local measures and effective oral hygiene will typically be necessary, in addition to periodic patient recall and evaluation.

The number of patients who develop BON is small compared to the large number of people taking bisphosphonates. However, some lesions can progress to large sizes and cause severe changes in the patient’s quality of life.[1,8] Advanced mandibular lesions, for instance, can cause necrosis of the cortical bone, increasing the risk for fractures.[8] Advanced and nonresponsive infections may require hospitalization and intravenous antibiotic therapy.[8] Advanced cases of BON may require extensive jawbone resection.[12] Therefore, this adverse event of bisphosphonate therapy may negatively affect quality of life.

The use of new and potent nitrogen-containing bisphosphonates such as oral ibandronate in Europe is under investigation in the United States. These compounds could have a relative bone resorption capacity similar to that of zoledronic acid.[13] Studies have indicated important safety profiles for such medications [14-16] and cost-effectiveness when compared with zoledronic acid and pamidronate.[17] However, initial reports have demonstrated that these compounds can also induce BON.[6,18]

The discontinuation of tobacco use to favor the healing process has been recommended in other studies.[19] However, the role of tobacco and other comorbidities in the process of BON formation requires further investigation.[7]

References

1. Migliorati CA, Siegel MA, Elting LS: Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 7 (6): 508-14, 2006.  [PUBMED Abstract]
   
   
2. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61 (9): 1115-7, 2003.  [PUBMED Abstract]
   
   
3. Migliorati CA: Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 21 (22): 4253-4, 2003.  [PUBMED Abstract]
   
   
4. American Association of Oral and Maxillofacial Surgeons: Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws. Rosemont, Ill: AAOMS, 2006. Available online. Last accessed August 19, 2008. 
   
   
5. Woo SB, Hellstein JW, Kalmar JR: Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144 (10): 753-61, 2006.  [PUBMED Abstract]
   
   
6. Khosla S, Burr D, Cauley J, et al.: Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22 (10): 1479-91, 2007.  [PUBMED Abstract]
   
   
7. Marx RE, Sawatari Y, Fortin M, et al.: Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63 (11): 1567-75, 2005.  [PUBMED Abstract]
   
   
8. Migliorati CA, Casiglia J, Epstein J, et al.: Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc 136 (12): 1658-68, 2005.  [PUBMED Abstract]
   
   
9. Migliorati CA, Schubert MM, Peterson DE, et al.: Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 104 (1): 83-93, 2005.  [PUBMED Abstract]
   
   
10. Ruggiero SL, Fantasia J, Carlson E: Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102 (4): 433-41, 2006.  [PUBMED Abstract]
    
    
11. Freiberger JJ, Padilla-Burgos R, Chhoeu AH, et al.: Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg 65 (7): 1321-7, 2007.  [PUBMED Abstract]
    
    
12. Chaudhry AN, Ruggiero SL: Osteonecrosis and bisphosphonates in oral and maxillofacial surgery. Oral Maxillofac Surg Clin North Am 19 (2): 199-206, 2007.  [PUBMED Abstract]
    
    
13. Licata AA: Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother 39 (4): 668-77, 2005.  [PUBMED Abstract]
    
    
14. Body JJ, Diel IJ, Lichinitser MR, et al.: Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 14 (9): 1399-405, 2003.  [PUBMED Abstract]
    
    
15. Body JJ, Coleman R, Clezardin P, et al.: International Society of Geriatric Oncology (SIOG) clinical practice recommendations for the use of bisphosphonates in elderly patients. Eur J Cancer 43 (5): 852-8, 2007.  [PUBMED Abstract]
    
    
16. Bergner R, Henrich DM, Hoffmann M, et al.: Renal safety and pharmacokinetics of ibandronate in multiple myeloma patients with or without impaired renal function. J Clin Pharmacol 47 (8): 942-50, 2007.  [PUBMED Abstract]
    
    
17. De Cock E, Hutton J, Canney P, et al.: Cost-effectiveness of oral ibandronate versus IV zoledronic acid or IV pamidronate for bone metastases in patients receiving oral hormonal therapy for breast cancer in the United Kingdom. Clin Ther 27 (8): 1295-310, 2005.  [PUBMED Abstract]
    
    
18. Malden NJ, Pai AY: Oral bisphosphonate associated osteonecrosis of the jaws: three case reports. Br Dent J 203 (2): 93-7, 2007.  [PUBMED Abstract]
    
    
19. Yarom N, Yahalom R, Shoshani Y, et al.: Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int 18 (10): 1363-70, 2007.  [PUBMED Abstract]
    
    

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