Key points
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Osteonecrosis has a variable presentation related to the type of medication, duration of the medication, and the patient’s concomitant medications and illnesses.
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Oral surgeons need to recognize the various stages, and provide care based on known outcomes.
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Prevention of necrosis is critical by avoiding invasive therapy and providing preemptive care before these drugs are started.
The widespread use of bisphosphonates and other antiresorptive agents as an inhibitor of bone resorption is directly attributable to their efficacy in improving the quality of life for patients with metastatic bone cancer and osteoporosis. As a potent suppressor of osteoclast activity, bisphosphonates slow the remodeling process and increase bone mineral density, thereby reducing the risk of fracture in women with osteopenia and osteoporosis. All bisphosphonates currently approved for osteoporosis treatment have been shown to significantly reduce the risk of osteoporotic fractures. The efficacy of intravenous bisphosphonates in decreasing osteoclast-mediated lysis of bone in disease secondary to multiple myeloma, advanced breast cancer, and other solid tumors has been well established in clinical trials. Therefore, intravenous bisphosphonates are frequently administered to patients with osteolytic metastases on a monthly basis, especially if there is a risk for significant morbidity. Based on clinical practice guidelines established by the American Society of Clinical Oncology, the use of bisphosphonates is considered the standard of care for treatment of (1) moderate to severe hypercalcemia associated with malignancy; and (2) metastatic osteolytic lesions associated with breast cancer and multiple myeloma in conjunction with antineoplastic chemotherapeutic agents. The Food and Drug Administration has broadened the indications for intravenous bisphosphonates to include bone metastases from any solid tumor. In 2005 it was estimated that more than 2.8 million patients with cancer worldwide had received intravenous bisphosphonates since their introduction to the marketplace.
Denosumab (Prolia, Xgeva) is a new antiresorptive agent that exists as a fully humanized antibody against RANK-L. As such, it is a profound inhibitor of osteoclast function and bone remodeling. It is interesting that these agents do not bind to bone and that their effects on bone remodeling are reversible within 6 months of treatment cessation (in contrast to the bisphosphonates). The efficacy of these novel agents in preventing skeletal morbidity in patients with osteoporosis and cancer has been well established. Unfortunately, because these agents are potent inhibitors of bone remodeling, they have also been associated with jaw necrosis in recent case reports.
Screening
Although it was not the case 10 years ago, bisphosphonate-related osteonecrosis of the jaw (BRONJ) is now a well-recognized entity that is associated with several risk factors that have been identified across various disciplines in medicine and dentistry. Multiple risk factors including drug-related issues (potency and duration of exposure), local risk factors (dentoalveolar surgery), local anatomy, concomitant oral and systemic disease, demographic factors, and genetic factors have all been considered for this complication. Three risk factors have remained constant throughout most clinical studies:
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Recent dentoalveolar trauma; this is the most prevalent and consistent risk factor. Patients with a history of inflammatory dental disease (eg, periodontal and dental abscesses) are at a 7-fold increased risk for developing osteonecrosis of the jaw (ONJ).
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The duration of bisphosphonate therapy also appears to be strongly related to the likelihood of developing necrosis, with longer treatment regimens associated with a greater risk of developing disease.
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In addition, the more potent intravenous bisphosphonates that are administered on a monthly schedule, such as zoledronic acid and pamidronate, bind avidly to bone in high concentrations and are significantly more problematic in comparison with other preparations.
As a result of this increased awareness, medical specialists and general dental practitioners are becoming more involved in promoting preventive strategies for their patients at risk, which has created a greater frequency of referrals to oral and maxillofacial surgeons’ offices for pretreatment screenings and risk assessment. These initial screenings can be categorized into 2 broad groups of patients based on the type of antiresorptive treatment that is anticipated. For those patients with osteoporosis or osteopenia who are about to begin oral bisphosphonate therapy there is no immediate concern, based on the fact that these patients assume a relatively small risk only after receiving these medications for longer than 3 years. These patients may proceed with dentoalveolar surgery; however, they should be educated about the risk they will assume if their antiresorptive treatment extends beyond 3 years. One notable exception applies to those patients receiving concomitant chronic long-term steroid therapy whereby the risk of necrosis may arise after a shorter duration of exposure.
For those patients receiving once-yearly dosing of zoledronic acid (Reclast) the risk of developing necrosis seems to be negligible through 3 years of treatment, based on initial studies. However, the risk of necrosis for patients receiving zoledronic acid for longer than 3 years or for those receiving biannual subcutaneous denosumab remains unknown. In assessing these patients it is important to realize that most were receiving oral bisphosphonates before initiating zoledronic acid or denosumab treatments, which must be taken into consideration.
Efforts to assess risk by measuring fluctuations in bone turnover markers (eg, C-terminal telopeptide levels) are problematic and remain controversial. The rationale for this approach is based on the knowledge that markers for bone remodeling will increase within months following withdrawal of oral bisphosphonate medications, thereby suggesting that osteoclast function and bone remodeling is normalizing. However, these markers are a reflection of total bone turnover throughout the entire skeleton and are not specific to the maxilla or mandible, where it is suspected that the bone turnover rate may be more severely depressed from prolonged bisphosphonate exposure. From a more practical perspective, using bone-turnover markers to estimate the level of bone-turnover suppression is only meaningful when compared with baseline, pretreatment levels, which are rarely obtained in clinical practice.
A more promising mode of risk assessment may be present at the gene level. In one study certain genetic irregularities (ie, single-nucleotide polymorphisms) in the cytochrome P450-2C gene were identified in multiple myeloma patients with ONJ. Those patients who were homozygous for the T allele had a 12.7-fold increased risk of developing ONJ.
Patients with cancer who are about to receive monthly treatments with zoledronic acid or denosumab will assume a measurable risk of developing jaw necrosis within a relatively short period. Management strategies similar to osteoradionecrosis prevention protocols should be implemented for such patients. The initiation of monthly intravenous or subcutaneous therapy should be delayed, if possible, until the dental health is optimized. Specifically, nonrestorable teeth and those with a poor prognosis should be extracted before the initiation of therapy. Antiresorptive therapy may begin once there is clinical evidence of bone healing at the surgical sites. Regardless of the clinical scenario, dental prophylaxis, caries control, and conservative restorative dentistry should be continued indefinitely for all patients receiving these medications. The importance of proper dental health maintenance should be underscored for all patients about to receive an antiresorptive agent, so that dentoalveolar surgery (ie, extractions, implants) can be avoided as the risk develops in the future following extended antiresorptive medication exposure.
If antiresorptive potency, duration of exposure, and dentoalveolar surgery are true risk factors for this complication, modification of these clinical variables should translate into a reduction of disease. For those patients who are at risk of developing BRONJ, adherence to risk-reduction protocols have resulted in a decreased incidence of this complication at certain institutions. Implementation of a detailed dental assessment and the avoidance of dentoalveolar surgery during treatment with zoledronic acid resulted in a 5-fold reduction of osteonecrosis. In those instances where BRONJ has developed, instituting stage-specific treatment protocols has resulted in a good level of disease and symptom control in a large majority of cases ( Fig. 1 ). At several institutions, dose-reduction schedules for zoledronic acid in the setting of cancer treatment have been implemented in an effort to reduce the incidence of BRONJ while remaining oncologically effective.
