Oral Toxicities Not Related to Chemotherapy or Radiation Therapy

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)

Bisphosphonates are potent inhibitors of osteoclasts. They are used in cancer patients with skeletal metastasis, including breast, prostate, or lung cancer; and in patients with multiple myeloma. Bisphosphonates are also used to treat hypercalcemia of malignancy. (Refer to the PDQ summary on Hypercalcemia for more information.) Bisphosphonates reduce the risk of fracture and skeletal pain, improving the quality of life of patients with malignant bone disease.[1] (Refer to the PDQ summary on Pain for more information.)

Bisphosphonate osteonecrosis (BON) is an oral complication of bisphosphonate therapy in cancer patients.[2] First reported in 2003,[3,4] 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 despite the provision of standard dental care. It is also possible that symptoms of dental and/or periodontal disease may be present, without visible exposed bone.[5] 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.[6,7]

A study evaluating the literature until December 2008 found that the prevalence of BON can vary according to study design and the type of bisphosphonate used. For example, studies in which patient evaluation and follow-up are conducted by dental professionals seem to have an overall prevalence of 7.3%, whereas survey studies of large populations of patients have a prevalence of less than 1%. If the prevalence is calculated on the basis of type of bisphosphonate used, the prevalence of cases of BON when a combination of zoledronic acid and pamidronate is used over the course of therapy can be as high as 24.5%.[8] The mandible is affected in approximately 68% of cases, the maxilla in about 28% of cases, and both jawbones in approximately 4% of cases.[9] However, there have been reports of evidence of BON in other parts of the head and neck and skeleton.[10-12]

Osteonecrosis of the jaw (ONJ) incidence, risk factors, and outcomes were assessed in an analysis of three phase III trials in patients who had metastatic bone disease secondary to solid tumors or myeloma and who were receiving antiresorptive therapies.[13] Patients were assigned to receive either subcutaneous injections of denosumab (120 mg) or intravenous administration of zoledronic acid (4 mg) every 4 weeks. Oral examinations were performed at baseline and every 6 months. Oral adverse events were adjudicated by a panel of dental experts. Of 5,723 patients enrolled, 89 (1.6%) were diagnosed with ONJ; 37 received zoledronic acid, and 52 received denosumab. Tooth extraction was reported for two-thirds of patients with ONJ. As of October 2010, ONJ resolved in 36% of patients (29.7% for zoledronic acid and 40.4% for denosumab). A combined analysis of these trials found that ONJ was an infrequent event, management was mostly conservative, and healing occurred in more than one-third of the patients. Bone-targeted therapy may help reduce the rate of ONJ and improve outcomes.[13]

Risk factors for BON include the following:

• Dental extractions.[14][Level of evidence: II][15]
• Ill-fitting dentures.[14]
• Intravenous bisphosphonate (zoledronic acid, denosumab).[14,15][Level of evidence: I][8];[16][Level of evidence: I]
• Time on medication.[8,15]
• Multiple myeloma.[8]

The incidence of BON may be reduced by the implementation of dental preventive measures before bisphosphonate therapy is initiated in solid-tumor patients with bone metastases.[17]

Diagnosis of BON

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 both from inflammation of the soft tissues contiguous to the necrotic bone and 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 moth-eaten appearance, suggesting ongoing bone destruction. Lesions can arise secondary to surgical dental treatments (e.g., dental extractions or periodontal surgery), significant dental infections, or trauma. Alternatively, BON can arise spontaneously, without any detectable trauma or predisposing treatment.

• 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.

• Occasional: a cancer patient who complains of oral pain and discomfort, but a definitive diagnosis of BON cannot be made because no clinically exposed bone is evident. In these patients, the most likely clinical diagnosis should be addressed first. It is important to recognize that zoledronic acid administration can result in bone pain, including to areas of the head and neck and jaws; this possible etiology for jaw symptoms should be considered as additional dental diagnoses are pursued. Routine clinical pulp testing and assessing for 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 the early presence of BON.[9][Level of evidence: III]

  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 as risk for ultimate development of BON. 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.

Management of BON

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 the risk of trauma to soft tissue, 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 a single 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.
• Amoxicillin and clavulanic acid, 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 or tetracycline rinses (62.5 mg/oz) twice a day. The need for oral hygiene with meticulous brushing and flossing after meals should be emphasized.[1,6,7,9,18,19]

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 the combination of amoxicillin and clavulanic acid in 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.[19]

Reports suggest that BON can be successfully managed by surgical resection and primary wound closure, especially in cases refractory to conservative therapy.[20-22] Furthermore, the use of surgical lasers has also been suggested as an alternative for BON patients who do not respond to conservative management.[23]

Use of hyperbaric oxygen therapy (HBO) to treat cases of established BON does not appear to be effective.[1,9,18,19] However, evidence indicates that HBO in addition to discontinuation of bisphosphonate therapy may benefit patients with BON.[24] Definitive evidence is pending while research in this area continues.[25]

Another possible approach involves surgical manipulation and uses bone labeling with tetracycline. In this modality, the patient is treated with a standard dose of tetracycline a few days presurgery. During the surgery, when bone is exposed, the Wood’s lamp is shone over the bone. Necrotic bone does not fluoresce and is removed. The procedure continues until fluorescence is seen, suggesting the presence of vital bone.[26]

Discontinuation of bisphosphonate therapy

The literature does not support discontinuing bisphosphonate therapy to enhance the healing process. Bisphosphonates accumulate in a 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 discontinuing zoledronic acid therapy for patients who develop BON, the osteonecrotic process clinically progresses and can extend to contiguous sites. However, discontinuing bisphosphonate therapy is advocated by some authors, especially when a procedure to treat BON is planned.[6,9]

Some clinicians believe that discontinuing the drug for patients scheduled for surgery to treat the necrotic area may be beneficial, 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.[6] However, controversy surrounds this issue,[7][Level of evidence: IV] and further research is needed.

In summary, a potential drug holiday for patients on bisphosphonates must be considered in the context of presence or absence of osteonecrosis. In view of the lack of scientific evidence from randomized controlled studies, risk and benefits of drug discontinuation must be determined by the prescribing physician. In patients who are being treated with bisphosphonate therapy and who need invasive procedures, there is no scientific information that supports a drug holiday and that this will prevent the development of BON. In patients with osteonecrosis who need invasive procedures, a drug holiday may be beneficial.[27] On the other hand, there is emerging evidence that patients with multiple myeloma and osteonecrosis may be maintained on bisphosphonate therapy without the risk of progression of the osteonecrotic process.[28]

It is advisable to discuss with the patient’s physician whether discontinuing bisphosphonate therapy will not put the patient’s general health at risk. Obtaining an informed consent from the patient before execution of the proposed drug discontinuation and therapy is important.

Spontaneous and asymptomatic BON

Patients may present with asymptomatic exposed necrotic bone anywhere in the oral cavity, although the mylohyoid plate on the posterior mandible and the mandibular tori are the most frequently affected sites. In this case, local measures and effective oral hygiene are important, as is systematic reevaluation of the patient to ensure resolution.

Effects on quality of life

The number of patients who develop BON is small compared with the large number of people who take bisphosphonates. However, some lesions can progress to large sizes and cause severe changes in a patient’s quality of life.[1,2] Advanced mandibular lesions, for instance, can cause necrosis of the cortical bone, increasing the risk of fractures.[1] Advanced and nonresponsive infections may require hospitalization and intravenous antibiotic therapy.[1] Advanced cases of BON may require extensive jawbone resection.[29] Therefore, this adverse effect of bisphosphonate therapy may negatively affect quality of life.

New trends

The discontinuation of tobacco use to favor the healing process has been recommended.[30] (Refer to the PDQ summary on Smoking in Cancer Care for more information.) However, the role of tobacco and other comorbidities in the process of BON formation requires further investigation.[9] Several cases of oral osteonecrosis have been reported with drugs other than bisphosphonates, including the following:[31,32]

• A human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa beta ligand and is under investigation.

• The antiangiogenic drugs being tested in advanced cancer cases, including bevacizumab, sunitinib, and sorafenib.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. Migliorati CA: Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 21 (22): 4253-4, 2003.  [PUBMED Abstract]
   
   
5. American Association of Oral and Maxillofacial Surgeons: Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws. Rosemont, Ill: AAOMS, 2006. Available online. Last accessed February 27, 2013. 
   
   
6. 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]
   
   
7. 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]
   
   
8. Migliorati CA, Woo SB, Hewson I, et al.: A systematic review of bisphosphonate osteonecrosis (BON) in cancer. Support Care Cancer 18 (8): 1099-106, 2010.  [PUBMED Abstract]
   
   
9. 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]
   
   
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12. Longo R, Castellana MA, Gasparini G: Bisphosphonate-related osteonecrosis of the jaw and left thumb. J Clin Oncol 27 (35): e242-3, 2009.  [PUBMED Abstract]
    
    
13. Saad F, Brown JE, Van Poznak C, et al.: Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 23 (5): 1341-7, 2012.  [PUBMED Abstract]
    
    
14. Vahtsevanos K, Kyrgidis A, Verrou E, et al.: Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 27 (32): 5356-62, 2009.  [PUBMED Abstract]
    
    
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16. Stopeck AT, Lipton A, Body JJ, et al.: Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28 (35): 5132-9, 2010.  [PUBMED Abstract]
    
    
17. Ripamonti CI, Maniezzo M, Campa T, et al.: Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 20 (1): 137-45, 2009.  [PUBMED Abstract]
    
    
18. 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]
    
    
19. 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]
    
    
20. Carlson ER, Basile JD: The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67 (5 Suppl): 85-95, 2009.  [PUBMED Abstract]
    
    
21. Stockmann P, Vairaktaris E, Wehrhan F, et al.: Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up. Support Care Cancer 18 (4): 449-60, 2010.  [PUBMED Abstract]
    
    
22. Williamson RA: Surgical management of bisphosphonate induced osteonecrosis of the jaws. Int J Oral Maxillofac Surg 39 (3): 251-5, 2010.  [PUBMED Abstract]
    
    
23. Vescovi P, Manfredi M, Merigo E, et al.: Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers Med Sci 25 (1): 101-13, 2010.  [PUBMED Abstract]
    
    
24. 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]
    
    
25. Freiberger JJ: Utility of hyperbaric oxygen in treatment of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67 (5 Suppl): 96-106, 2009.  [PUBMED Abstract]
    
    
26. Pautke C, Bauer F, Tischer T, et al.: Fluorescence-guided bone resection in bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg 67 (3): 471-6, 2009.  [PUBMED Abstract]
    
    
27. Dickinson M, Prince HM, Kirsa S, et al.: Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment. Intern Med J 39 (5): 304-16, 2009.  [PUBMED Abstract]
    
    
28. Berenson JR, Yellin O, Crowley J, et al.: Prognostic factors and jaw and renal complications among multiple myeloma patients treated with zoledronic acid. Am J Hematol 86 (1): 25-30, 2011.  [PUBMED Abstract]
    
    
29. Chaudhry AN, Ruggiero SL: Osteonecrosis and bisphosphonates in oral and maxillofacial surgery. Oral Maxillofac Surg Clin North Am 19 (2): 199-206, vi, 2007.  [PUBMED Abstract]
    
    
30. 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]
    
    
31. Migliorati CA, Covington JS 3rd: New oncology drugs and osteonecrosis of the jaw (ONJ). J Tenn Dent Assoc 89 (4): 36-8; quiz 38-9, 2009.  [PUBMED Abstract]
    
    
32. Yarom N, Elad S, Madrid C, et al.: Osteonecrosis of the jaws induced by drugs other than bisphosphonates - a call to update terminology in light of new data. Oral Oncol 46 (1): e1, 2010.  [PUBMED Abstract]