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Aredia/Zometa and osteonecrosis of the jaws
By Brian G.M. Durie, M.D.
07.25.04

What is osteonecrosis?

  • A rather frightening word which is hard to explain in simple terms

  • A previously rare jaw problem now being observed in a small percentage of myeloma patients taking Aredia and Zometa

  • A condition in which there is pain, swelling and bone damage around the tooth sockets in the jaws. There is bone necrosis or loss of bone which can lead to loose teeth, sharp edges of exposed bone or bone spurs, breaking loose of small bone spicules or dead bone.

  • A patient may notice nothing initially, or may start to experience pain, swelling, numbness or a “heavy jaw feeling” or loosening of a tooth.

How was this problem recognized?

  • A very alert maxillofacial surgeon in Florida (Dr. Robert Marx) became aware that he was seeing more patients with osteonecrosis and reported this in a Letter To The Editor of the Journal of Oral Maxillofacial Surgery in 2003 (1). All the patients had been taking Aredia or Zometa. Eighteen of 36 patients (50%) had multiple myeloma.

  • Dr. Marx and others observed that with more than minor dental surgery there was a risk of very poor healing of the jaw. This sometimes led to infection and a cascade of other problems.

  • The more fundamental finding was the apparent occurrence of jaw osteonecrosis in patients taking bisphosphonates.

A series of questions have emerged: How common is this? Since not all patients develop this problem, what co-factors are important? What are the best treatments? How can this be prevented?

How common is jaw osteonecrosis in myeloma patients?

  • In addition to the report from Florida , there are 2 reports from the New York area (2, 3). Dr. Ruggiero and colleagues have reported 63 total patients, 28 with myeloma over a 3-year span (2001-2003) inclusive. The group at Memorial Sloan Kettering noted 4 myeloma patients with osteonecrosis in their review of bisphosphonate patients. This gives a total of 50 myeloma patients reported in the medical literature.

  • Because of the above reports and concern within the myeloma community, the IMF decided to conduct a web-based survey. The results will be available soon. In the interim, from reports to the IMF hotline, at IMF Patient and Family seminars, and from hematology/oncology groups across the U.S. , patients with osteonecrosis are definitely emerging and requiring treatment.

  • What the true occurrence rate is now and what it may become with ongoing bisphosphonate therapy are both unclear. Thus far, only a small percentage of myeloma patients who are taking bisphosphonates have been affected.

Which patients have developed or will develop osteonecrosis?

  • Certainly, use of Aredia or Zometa is the common factor. Whether or not the likelihood is influenced by the type of bisphosphonate and/or the duration of treatment is not known yet.

  • However, other predisposing factors are possibly important. The IMF survey is attempting to elucidate these potential factors, which include age, radiation therapy to the jaw region, other medications such as steroids or other myeloma therapies, underlying dental problems, tooth removal or local trigger factors such as dental implants or fillings.

What do we know so far about what are the best treatments?

  • Consultation with an oral surgeon or dental oncologist familiar with osteonecrosis is strongly recommended.

  • Management without surgery is recommended as a first step. Minor dental work to reduce sharp edges or remove injured tissue may be required. A protective mouth guard may also be helpful.

  • Antibiotic treatment is recommended if there is infection with specific antibiotics being selected based upon the type of bacterial, fungal and/or viral infection, which is documented. Typical antiobiotics or antimicrobials that may be useful are penicillin, clindamycin or erythromycin; nystatin or fluconazole; acyclovir or valacyclovir. Oral rinses with Peridex® (chlorhexidine gluconate) and/or minocycline hydrochloride (Arestin®) periodontal pockets can also be used.

  • If problems persist and/or if healing is slow, consideration can be given to stopping bisphosphonate therapy for 2-4 months to facilitate recovery. Although study results are lacking, there are anecdotal reports of benefit with brief interruption of Aredia or Zometa treatment.

  • If surgery is absolutely required, interruption of bisphosphonate therapy is strongly recommended. Current data indicate very poor healing with continued bisphosphonates in this setting.

  • Dentures can be worn, but many need adjustment. Placement of dental implants appears to be contra-indicated. Use of hyperbaric oxygen does not appear to be helpful.

  • Obviously, careful monitoring and follow-up are required.

What can be done to prevent the development of osteonecrosis?

  • Be aware of the problem!

  • Maintain excellent mouth hygiene and reduce the risk of infections or injuries by adjusting dentures, avoiding gingival injury with flossing and treating any infections promptly.

  • Avoid tooth extraction and/or any elective jaw surgery if at all possible. Root canal therapy and crowns are safe and may allow preservation of a tooth

  • If there is an opportunity, proceed with careful dental evaluation and any required preventative dental care before starting bisphosphonate therapy.

I hope all of this helps in the understanding of the current situation. The results of the IMF survey will be made available as soon as feasible. Several other investigations are also ongoing.

The scope of this problem, and the impact upon current recommendations for bisphosphonate use, remain to be assessed. There is every reason to hope that with appropriate awareness and early management, serious problems from osteonecrosis can be avoided.

References

  1. Marx RE. Letters To the Editor: Pamidronate (Aredia) and Zoledronate (Zometa) Induced Avascular Necrosis of the Jaws: A Growing Epidemic. J. Oral Maxillofac Surg 2003; 61: 1115-1118.

  1. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the Jaws Associated With the Use of Bisphosphonates: A Review of 63 Cases. J Oral Maxillofac Surg 2004; 62: 527-534.

  1. Estilo CL, Van Poznak CH, Williams T, Evtimovska L, Halpern JL, Tunick SJ, Huryn JM. Abstract 8088: Osteonecrosis of the maxilla and mandible in patients treated with bisphosphonates: A retrospective study. J Clin Onc 2004; 23: 747.