The task force recognized at the outset that the incidence of ONJ in the general population not exposed to bisphosphonates is unknown. However, the disorder has come to medical attention principally in the setting of bisphosphonate use. Although this association is consistent with a role for bisphosphonates, bisphosphonates have not been proven to be causal. The task force also recognized that quality of the evidence reported in a substantial proportion of case descriptions of patients with ONJ was poor and that many reports were missing important historical or clinical information. The task force recommended that a hierarchy of evidence quality should be established for all future studies reporting cases of ONJ. The overall hierarchy of evidence quality for a case would be based on the quality of seven areas, as indicated in Table 4. Because the incidence of ONJ is very different in patients receiving oral bisphosphonates for osteoporosis or Paget's disease compared with patients receiving high doses of intravenous bisphosphonates for management of malignancy, the literature was examined separately for these two groups of patients. The task force recognized that information on incidence of ONJ is rapidly evolving, that continued surveillance will undoubtedly result in identification and publication of more cases, and that estimates of the frequency of ONJ may change for patients receiving bisphosphonates for both malignant and nonmalignant disease.
Osteoporosis and Paget's disease:
The literature review of bisphosphonate-associated ONJ reports in patients with osteoporosis or Paget's disease is shown in Table 5. The total number of reported cases was 64 after overlapping case reports had been excluded. There were 57 cases that occurred in association with treatment for osteoporosis and 7 cases that occurred in association with treatment of Paget's disease. Of the latter, three were treated with intravenous pamidronate, one with the combination of intravenous pamidronate followed by oral alendronate, and three with oral alendronate. Where it could be ascertained, the dose of bisphosphonate was felt to be unusually high in four of the seven patients.
Table Table 5.. Literature Review of Bisphosphonate-Associated ONJ Reports in Patients With Osteoporosis or Paget's Disease
Of the 57 ONJ cases associated with bisphosphonate therapy for osteoporosis, only 4 were men, but sex was not identified in several cases. Most had been treated with alendronate, two received risedronate, one received a combination of alendronate and risedronate, and two received intravenous pamidronate and/or zoledronic acid. When the site of osteonecrosis was identified, about two thirds of cases occurred in the mandible and most of the remainder occurred in the maxilla, whereas four cases occurred at both sites.
Exposed bone was the most commonly reported clinical presentation. However, it was not invariable. Some reports included the presence of ulcerated mucosa or abscess and fistula formation, but these were less common. Pain was a common finding but was not reported in all cases. A minority of cases had biopsies of the affected jaw, and all biopsies showed necrosis of bone. The duration of bisphosphonate therapy was frequently not included; however, it is noteworthy that the minimum duration of alendronate therapy was 2 yr. Similarly, the duration of the clinical presentation, particularly the duration of exposed bone, was frequently not described.
The task force recommends that there should be a minimal reporting requirement to the respective companies and the Food and Drug Administration (FDA) for future cases of ONJ based on the clinical definition noted above. The task force also recommends that an external agency follow-up and validate FDA drug adverse event report data in detail, both to confirm all reported cases and to accumulate further accurate information on the condition.
The incidence of ONJ in patients receiving bisphosphonates for osteoporosis is not known. Both U.S. pharmaceutical industry (Merck) estimates of the worldwide, cumulative reporting rate of osteonecrosis of the jaw of <1 in 100,000 patient-treatment years, regardless of causality, and the prevalence of <1 in 250,000 in a recent German study are consistent.(2,3) However, data from Australia(2,4) suggest that the incidence could be up to 10-fold higher. In part, these different estimates may be related to under-reporting, different durations of exposure in countries that have adopted bisphosphonates more recently, and/or differing definitions of the disease. The task force fully recognizes that the true incidence of ONJ in patients with osteoporosis may be higher than noted in these estimates because of these potential confounders.
Patients with malignant bone disease are at risk for skeletal-related events, including pathological fracture, metastases requiring surgery or radiation therapy to bone, and spinal cord compromise. They may experience fragility fractures either because of comorbid conditions or because of toxicities of their cancer therapy. Bisphosphonates have been shown to decrease the risk of skeletal complications by approximately one third.(5) In addition, bisphosphonates are clinically important for the treatment of hypercalcemia of malignancy and can reduce cancer induced bone pain. The two bisphosphonates approved by the FDA for use in patients with cancer involving bone are pamidronate and zoledronic acid. Clodronate and ibandronate have been licensed for use in malignant bone disease in other countries. Because of the high frequency of skeletal involvement in advanced cancers, bisphosphonates are routinely prescribed in the practice of medical oncology.(6)
When treating patients with skeletal lesions from cancer, current oncology practice in the United States typically uses either pamidronate, 90 mg, infused over at least 2 h every 3–4 wk, or zoledronic acid, 4 mg, infused over at least 15 min every 3–4 wk.(7–9) With the FDA approval of zoledronic acid in 2001, this agent has gained popularity in clinical practice because of its efficacy in reducing skeletal-related events and the shorter infusion time. The American Society of Clinical Oncology (ASCO) has established guidelines for the use of bisphosphonates in patients with metastatic breast cancer and multiple myeloma.(7,8) The ASCO guidelines suggest that once the bisphosphonate is initiated, it should be continued until there is substantial decline in the patient's clinical condition.(7,8) Because of the lifelong risk of skeletal-related events in patients with metastatic bone disease, the clinical practice in the palliative setting has been to continue bisphosphonate therapy indefinitely.
Bisphosphonate-associated ONJ in patients with malignancy has come to the attention of the medical and dental communities primarily through case reporting, and the number of reported cases has been increasing over the past 3 yr. Most patients in case reports published to date have cancer that involves bone and have been treated with high-potency, nitrogen-containing intravenous bisphosphonates. All bisphosphonates have been associated with cases of ONJ; however, this must be tempered with the acknowledgment of the lack of a consensus definition for ONJ and the unknown incidence of ONJ in the general population. The published literature reviewed by the task force identified <1000 cases. This is consistent with the estimate of 654 cases presented during the Oncology Drug Advisory Committee meeting in March 2005.(10) Although case reporting is a classic means of communicating information on rare conditions, there are limitations to case reports. Presumably, prospective data on bisphosphonate-associated ONJ are limited because of the short amount of time since the condition has come to widespread attention and the low frequency of events.
The recent flurry of case reports began in 2003 in the form of abstracts presented at academic meetings. Ruggiero et al.(11) published the first peer-reviewed report of bisphosphonate-associated ONJ. In this publication, a chart review was performed of patients who presented with a diagnosis of osteonecrosis or osteomyelitis of the jaw and who did not have a history of radiation therapy to the jaw or of neoplasm directly involving the jaw. From February 2001 through June 2003, a total of 63 patients were identified, and their charts were reviewed. Relevant findings included the use of a bisphosphonate (intravenous or oral) in all affected individuals. Therapy included debridement, with some patients requiring a surgical procedure; two patients were treated with hyperbaric oxygen (30 1-h dives) without significant benefit. The clinical observation was made that discontinuing the bisphosphonate did not seem to alter the outcome of bisphosphonate-associated ONJ.
The estimated incidence of bisphosphonate-associated ONJ in patients with malignancy seems to range between 1% and 10%.(4,12–15) The bisphosphonate used and the duration of exposure, which often is correlated with cumulative dose, has been related to risk of bisphosphonate-associated ONJ. Thus, whereas the mean time to onset of bisphosphonate-associated ONJ in individuals receiving zoledronic acid was 18 mo, it was 39–72 mo in patients receiving pamidronate.(13,16) Using insurance claims data, investigators identified an association between patient with cancer receiving intravenous bisphosphonate therapy and oral surgery. Compared with never users, the odds ratio of surgery for intravenous bisphosphonate users was 4.24 (p < 0.05).(17) In a prospective clinical trial performed in Greece of 252 patients with a variety of cancers who had received at least 6 mo of bisphosphonate therapy, the risk of developing bisphosphonate-associated ONJ increased with longer exposure to bisphosphonate therapy and was associated with the bisphosphonate used. For the whole population, the cumulative hazard ranged from >1% at 12 mo to 11% at 4 yr. However, for those who received zoledronic acid alone, the hazard was 1% within the first year but rose to 21% at 3 yr.(18)
Patients with cancer involving the skeleton may be exposed to other medications that compromise oral health, including chemotherapy, glucocorticoids, and antibiotics that may alter the microenvironment of the mouth. Although there are no specific known oral changes associated with the bisphosphonates, those individuals with cancer receiving pamidronate and/or zoledronic acid seem to be the population at greatest risk for bisphosphonate-associated ONJ. The true incidence of bisphosphonate-associated ONJ is unknown, given the difficulty in obtaining accurate assessment of the denominator and the limitations of voluntary case reporting.
Although our present understanding of the risk factors associated with and the pathogenesis of bisphosphonate-associated ONJ is limited, the clinical and patient community has developed an awareness of the condition through the use of guidelines, position papers, and statements generated by the oral and medical academic community, as well as the bone-related national or disease-specific agencies. There are established guidelines for oral health care before initiating chemotherapy.(19,20) Table 6 summarizes risk factors currently felt to predispose to bisphosphonate-associated ONJ(14,21–24); however, the task force recognized that the evidence on risk factors predisposing to ONJ was weak.
Table Table 6.. Risk Factors for Bisphosphonate-Associated ONJ