Written by patient-advocate Musa Mayer: On Friday, March 4, a meeting of the FDA's Oncologic Drugs Advisory Committee (ODAC) considered the condition of osteonecrosis of the jaw (ONJ) as associated with infusional bisphosponates in patients being treated for metastatic bone disease, principally for multiple myeloma and breast cancer, with some data also for prostate cancer. There were presentations from the Office of Drug Safety of the FDA, from researchers and patient advocates, and from the manufacturer of the bisphosphonate Zometa (zoledronic acid), Novartis. According to Dr. Richard Pazdur, Director of Oncology Drug Products, CDER, FDA, he stated purpose of the meeting was to raise public awareness of this problem. Warnings regarding ONJ have already been added to labeling information for both of the drugs in question. Aredia (pamidronate) was approved in 1991, and is indicated for bone metastases from breast cancer and multiple myeloma, and Paget's Disease of the Bone. Studies measured incidence of "skeletal related events," a composite endpoint that includes pathologic fractures, radiation therapy to bone, surgery to bone and spinal cord compression. Zometa (zoledronic acid) was approved in 2001, and is indicated for multiple myeloma, bone metastases from solid tumors (not limited to breast cancer), and hypercalcemia of malignancy, a late-stage complication of bone mets. The lesion type not limited to osteolytic lesions in Zometa, as it had been in Aredia, but also included osteoblastic lesions. The optimal duration of therapy has remained undefined from the various trials, though this is currently being studied. Typical symptoms for ONJ are pain, soft-tissue swelling and infection, loose teeth and exposed bone. The standard advice currently is to avoid elective jaw procedures while undergoing bisphosphonate therapy, and to have routine dental exams and tooth extractions done prior to bisphosphonate therapy. Good communication between dentists, oral surgeons and oncologists is essential. Novartis has produced a patient brochure, available at http://www.us.novartisoncology.com/info/coping/dental_health.jsp The problem of osteonecrosis of the jaw (ONJ), however, remains poorly characterized and understood. In fact, there is not even a ICD-9 code that refers specifically to this kind of osteonecrosis, so that when researchers went looking for incidence, databases could not be searched. Nor is it universally accepted that infusional bisphosphonates are the cause of the disorder. Nevertheless, according to the Office of Drug Safety, ONJ is a rare disorder, not frequently reported prior to 2001, the year of Zometa's approval. In 2002, there were 9 cases reported to the Adverse Event Reporting System (AERS) of FDA, known as MedWatch. 60 cases were reported in 2003, 69 in 2004. As of last month, there have been 610 reported cases, according to FDA's system (more according to Novartis, about which more below). While ONJ may have been under reported in the past, the large recent increase in cases may certainly be related to the wide publicity on this issue. FDA doctors at the meeting referred to ONJ as a "highly plausible safety signal," associated with a high number of instances of a rare event. A profile of patients with ONJ includes the following factors: diagnosis of malignancy; no head and neck radiotherapy; treatment regimen included IV bisphosphonates; high proportion of recent invasive dental procedures; many patients were also receiving chemotherapy and corticosteroids; many patients had signs of local infection including osteomyelitis; and finally, there was no data to suggest that discontinuing therapy reduces incidence of ONJ. The true incidence of ONJ is unknown. This is because the MedWatch reporting system is passive, so many cases will go unreported. There are multiple problems with this system. Reporting bias exists, the quality of cases is variable, there are duplicated cases, and FDA can't reliably estimate incidence rates of events since the numerator is uncertain, and the denominator can only be projected. Since ONJ is a rare event, obtaining a background rate for comparison is difficult. A national registry, if instituted, could provide info, but doing randomized controlled trials would be impossible because of the rarity of the disorder. Dr. Brian Durie, in collaboration with the International Myeloma Foundation, conducted an online survey about osteonecrosis last year that many of you participated in. He presented his findings at the ODAC meeting. In total 904 multiple myeloma patients responded to the survey, and 299 breast cancer patients, with 116 cases of ONJ in myeloma patients, and 36 in the breast cancer patients. A survey of this type is, of course, prone to reporting biases, and only limited conclusions can be drawn. Nevertheless, this survey had the following findings: --overall likelihood of ONJ from time of diagnosis and with length of treatment appears to increase --onset of ONJ may be earlier in Zometa, and more frequent in patients taking Zometa --there was no sign that prednisone, Thalidomide, or dexamethazone increased the incidence of ONJ --the highest incidence appeared in the group of patients switching from Aredia to Zometa --it is likely that Zometa is associated with suspicious findings earlier, after a shorter duration of therapy --70-80% of patients with ONJ had prior dental problems --it is likely that precautions related to dental care may reduce the likelihood of ONJ Dr. Diane Young presented on behalf of Novartis, manufacturer of Zometa and past manufacturer of Aredia, which is now available as a generic drug. She emphasized that ONJ remains poorly understood, adding that there is insufficient evidence to support conclusions about incidence or about the difference between incidence with Aredia vs. Zometa. She expressed concern that perspective not be lost about the significant benefits of these drugs. Bone metastases are a serious consequence of metastatic disease, and these drugs prevent skeletal related events (see above) and hypercalcemia, and are considered standard of care. Dr. Young pointed out that cancer patients are at higher risk of osteonecrosis in general, at a rate about four times higher than general population. Bisphosphonates have been used to TREAT osteonecrosis. The oral cavity is a vulnerable area to infection, hence the propensity for osteonecrosis to attack the jaw. The incidence of osteoradionecrosis, from radiation to the head and neck, is about 8.2%. Novartis believes that ONJ is still a relatively rare side-effect. In reviews of the pivotal trials for their drugs, they found only 6 cases of ONJ in over four thousand patients--but to be fair, if duration of treatment is associated with ONJ incidence, these trials would be unlikely to show many cases, since they are relatively brief in duration. So while Dr. Young said that 875 cases of ONJ have indeed been reported by the end of February, this must be seen in the context of 1.9 million patients treated with Aredia, and a million patients treated with Zometa since these two drugs were approved. In the reported cases, 74% reported at least one other risk factor, and at least 50% of cases report dental extraction. In reported cases of ONJ, 20% recovered or improved, 41% stayed the same, and 8% worsened. The studies draw no conclusion about whether discontinuation makes a difference, but it does appear as if the mean time of onset may be longer for Aredia than for Zometa. Novartis is supporting a retrospective chart review at MD Anderson, encompassing all patients who have received IV bisphosphonates over the last 10 years. 2,500 charts have been reviewed to date. 11 instances of ONJ in 631 breast cancer patients have been found, and 6 cases of ONJ in 148 multiple myeloma patients. In breast cancer, so far an overall rate 1.9% of breast cancer patients with bone mets were affected with ONJ. However this investigation is also hampered by the lack of common definitions, diagnostic criteria, lack of knowledge about natural history of disease, and the absence of a common treatment algorithm. Overall, Dr. Young maintained that the balance of benefit-risk for Zometa and Aredia remains highly favorable. Over 500,000 patients in the USA have metastatic bone disease. Their median survival can be measured in years, not weeks or months. Without bisphosphonates, 10-25% bone mets patients will suffer fractures each year, while 3-5% will suffer from cord compression. The number of skeletal related events are cut by a third to a half in breast cancers through the use of infusional bisphosphonates like Aredia and Zometa. In addition, these drugs decrease bone pain and analgesic use, and prevent deterioration in quality of life. Lesser cases of ONJ will resolve on antibiotics and remain on a bisphosphonate, and more severe cases have improved after drug is withdrawn. Hope this report helps to clarify a little for the many who have been concerned about osteonecrosis of the jaw. By Musa Mayer, author and patient-advocate Remember we are NOT Doctors and have NO medical training. This site is like an Encyclopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.