Oral Toxicities Not Related to Chemotherapy or Radiation Therapy
Osteonecrosis of the Jaw Associated With Medications (ONJ)
Diagnosis of ONJ
Management of ONJ
Discontinuation of bisphosphonate therapy
Spontaneous and asymptomatic ONJ
Effects on quality of life
Tobacco use and ONJ
Osteonecrosis of the Jaw Associated With Medications (ONJ)
The first reported cases of osteonecrosis of the jaw associated with medications (ONJ) were seen in patients taking bisphosphonates.[1-3] 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. Bisphosphonates reduce the risk of fracture and skeletal pain, improving the quality of life of patients with malignant bone disease. (Refer to the PDQ summary on Pain for more information.)
- Denosumab, a human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL).
- The antiangiogenic drugs being tested in advanced cancer cases, including bevacizumab, sunitinib, and possibly sorafenib.
|Drug Generic (Trade Name)||Manufacturer (Indication)||Class of Drug||Mode of Action||Reported to Cause ONJ?|
|GIST = gastrointestinal stromal tumor; ONJ = osteonecrosis of the jaw associated with medications; RANKL = receptor activator of nuclear factor kappa beta ligand; VEGF = vascular endothelial growth factor.|
|Zoledronic acid (Zometa, Reclast)||Novartis (bone metastasis; bone loss from cancer therapy)||Bisphosphonate (antiresorptive)||Inhibition of osteoclasts||Yes|
|Pamidronate (Aredia)||Novartis||Bisphosphonate (antiresorptive)||Inhibition of osteoclasts||Yes|
|Alendronate (Fosamax)||Merck (bone loss from cancer therapy)||Bisphosphonate (antiresorptive)||Inhibition of osteoclasts||Yes|
|Denosumab (Prolia, XGeva)||Amgen, Inc. (bone metastasis; osteoporosis; bone loss from cancer therapy)||Humanized monoclonal antibody (antiresorptive)||Suppression of bone remodeling by inhibition of RANKL||Yes|
|Bevacizumab (Avastin)||Genentech BioOncology (advanced cancers: metastatic colorectal cancer; nonsquamous non-small cell lung cancer; metastatic breast cancer; glioblastoma; metastatic renal cell carcinoma)||Antiangiogenic||Inhibition of angiogenesis by blocking the action of VEGF||Yes|
|Sunitinib (Sutent)||Pfizer Oncology (advanced renal cell carcinoma; GIST)||Antiangiogenic||Inhibition of angiogenesis by blocking VEGF tyrosine kinase||Yes|
|Sorafenib (Nexavar)||Bayer Health Care Pharmaceuticals (renal cell carcinoma; hepatocellular carcinoma)||Antiangiogenic||Inhibition of angiogenesis by blocking VEGF tyrosine kinase||Yes, when combined with antiresorptives|
With the approval of a new antiresorptive medication, denosumab, a fully humanized monoclonal antibody that targets RANKL and that has indications similar to those of the bisphosphonates, additional reports confirmed that this new drug can also cause ONJ. Subsequently, the introduction of antiangiogenic medications in clinical trials in oncology revealed that these agents can also be associated with ONJ development, either as single drugs or when used in combination with antiresorptives. When antiangiogenics are used in combination with bisphosphonates, the risk of ONJ increases significantly.
Thus, osteonecrosis of the jaw is no longer a problem exclusively associated with the use of bisphosphonates; it is also associated with the use of other drugs such as the monoclonal antibody denosumab and antiangiogenics such as bevacizumab and sorafenib. For this reason, it is proposed that the nomenclature that refers to this pathology be changed to ONJ, meaning osteonecrosis of the jaw that is associated with medications.
ONJ is an oral complication of antiresorptive therapy in cancer patients. First reported in 2003,[1-3] ONJ is defined as the unexpected appearance of exposed necrotic bone anywhere in the oral cavity of an individual who is receiving drugs that have been associated with ONJ (bisphosphonates, denosumab, and antiangiogenics) and who has not received radiation therapy to the head and neck. The exposed bone persists for at least 6 to 8 weeks, despite the provision of standard dental care. It is also possible that symptoms of dental disease, periodontal disease, or both may be present, without visible exposed bone. The occurrence of ONJ is based on cases reported in the literature, and occurrence ranges from between 1% and 10% for patients receiving the intravenous formulation (pamidronate and zoledronic acid) to less than 1% for patients taking oral bisphosphonates.[10,11]
A study evaluating the literature until December 2008 found that the prevalence of ONJ 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 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, then the prevalence of cases of ONJ in which a combination of zoledronic acid and pamidronate is used over the course of therapy can be as high as 24.5%. The mandible is affected in approximately 68% of cases, the maxilla in about 28% of cases, and both jawbones in approximately 4% of cases. However, there have been reports of evidence of ONJ in other parts of the head and neck and skeleton.[14-16]
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. 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.
When denosumab was compared to placebo in a study of men with nonmetastatic, high-risk, castration-resistant prostate cancer in which patients received treatment for at least 24 months, ONJ incidence was 4.6% in patients treated with denosumab; there were no cases of ONJ in the placebo group. Therefore, time on medication can be a factor in the development of ONJ.
Risk factors for ONJ include the following:
- Dental extractions.[Level of evidence: II]
- Ill-fitting dentures.
- Intravenous bisphosphonate (zoledronic acid, denosumab).[19,20][Level of evidence: I];[Level of evidence: I]
- Time on medication.[12,18,20]
- Multiple myeloma.
Diagnosis of ONJ can be clinically challenging. The most common clinical presentations are as follows:
- Classical: a cancer patient with skeletal metastasis who is receiving intravenous bisphosphonate or denosumab 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, ONJ can arise spontaneously, without any detectable trauma or predisposing treatment.
- Less common: a cancer patient receiving intravenous bisphosphonate or denosumab 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 ONJ 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 antiresorptive 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 ONJ.[Level of evidence: III]
Endodontic and periodontal therapy should be performed first. The patient should be advised about the possibility of ONJ and should be educated about oral hygiene procedures. If dental extraction is indicated, the possibility of subclinical ONJ should be considered and explained to the patient. Thus, delay or absence of healing postextraction must be considered as risk for ultimate development of ONJ. 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.
Confirmed ONJ 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.[4,10,11,13,24,25]
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 ONJ 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.
Reports suggest that ONJ can be successfully managed by surgical resection and primary wound closure, especially in cases refractory to conservative therapy.[26-28] The use of radical surgery is increasing, and it appears that the initial paradigm that surgery should not be done in ONJ cases is no longer true. However, patients must be advised that surgery may result in treatment failure and that not all cases are treated successfully. With surgery as a treatment option, clinicians are now performing bone biopsies to confirm ONJ diagnoses. In cancer patients, there is always a possibility of metastatic disease to the jawbones mimicking ONJ; the final diagnosis should be confirmed by histopathological examination. The use of surgical lasers has also been suggested as an alternative for ONJ patients who do not respond to conservative management.
The use of hyperbaric oxygen therapy (HBO) to treat cases of established ONJ does not appear to be effective.[4,13,24,25] However, evidence indicates that HBO in addition to discontinuation of bisphosphonate therapy may benefit patients with ONJ. Definitive evidence is pending while research in this area continues.
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.Table 6. ONJ Staging System
|BRONJ (ONJ) Staging||Treatment Strategies|
|BRONJ = bisphosphonate-related osteonecrosis of the jaw; IV = intravenous; ONJ = osteonecrosis of the jaw associated with medications.|
|At-risk category: No apparent necrotic bone in patients who have been treated with either oral or IV bisphosphonates.||No treatment indicated; patient education.|
|Stage 0: No clinical evidence of necrotic bone, but nonspecific clinical findings and symptoms.||Systemic management, including the use of pain medication and antibiotics.|
|Stage 1: Exposed and necrotic bone in patients who are asymptomatic and have no evidence of infection.||Antibacterial mouth rinse; clinical follow-up on a quarterly basis; patient education and review of indications for continued bisphosphonate therapy.|
|Stage 2: Exposed and necrotic bone associated with infection, as evidenced by pain and erythema in the region of the exposed bone, with or without purulent drainage.||Symptomatic treatment with oral antibiotics; oral antibacterial mouth rinse; pain control; superficial debridement to relieve irritation of soft tissue.|
|Stage 3: Exposed and necrotic bone in patients with pain, infection, and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone (i.e., inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla), resulting in pathologic fracture, extraoral fistula, oral antral/oral nasal communication, or osteolysis extending to the inferior border of the mandible of sinus floor.||Antibacterial mouth rinse; antibiotic therapy and pain control; surgical debridement/resection for longer-term palliation of infection and pain.|
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 ONJ, 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 ONJ is planned.[10,13]
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. However, controversy surrounds this issue,[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 ONJ. In patients with osteonecrosis who need invasive procedures, a drug holiday may be beneficial. 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.
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 ONJ
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 ONJ 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.[4,8] Advanced mandibular lesions, for instance, can cause necrosis of the cortical bone, increasing the risk of fractures. Advanced and nonresponsive infections may require hospitalization and intravenous antibiotic therapy. Advanced cases of ONJ may require extensive jawbone resection. Therefore, this adverse effect of bisphosphonate therapy may negatively affect quality of life.Tobacco use and ONJ
The discontinuation of tobacco use to favor the healing process has been recommended. (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 ONJ formation is still under investigation.References
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