CLINICAL VIGNETTE

Association of Oral Cavity Osteonecrosis with Cancer and
Bisphosphonate Therapy

John Barstis, M. D.

Case Report

A 56-year-old male undergoing therapy for multiple myeloma including zolendronate became aware of right posterior mandible pain after a routine cleaning procedure by a dental hygienist in July 2002. He was evaluated by his dentist for persistence of this pain, and a root canal was performed. The pain did not improve and over the next several months he lost all 3 molars in the right posterior mandible. A referral was made to an oral surgeon, who performed a conservative debridement, but this did not heal and bone remained exposed. In November 2002, he began noting numbness of the right lower lip and face. A computed tomography scan revealed an enlarged masseter muscle with surrounding inflammatory changes. Vicodin taken once or twice a day controlled the pain adequately. Recurrent infections were treated with prolonged courses of amoxicillin and amoxicillin/ clavulanate which were temporarily effective. In September 2003, he was referred to on oral surgeon at the UCLA Dental School, who diag-nosed bisphosphonate-associated osteonecrosis of the mandible. He advised continued intermittent antibi-otics and eventual bone grafting. The patient\'s pain on the right side gradually subsided, but he developed some pain on the left side. No dental procedures have been allowed on the left side of his mouth. He currently feels well, takes no pain medications and is increasingly able to tolerate chewing most foods on the left side. He is currently on no therapy for myeloma and is not on antibiotics.

His past medical history includes diagnosis of multiple myeloma in 1999. Chemotherapy with vincristine, adriamycin and decadron was given followed by an autologous stem cell transplant in 2000. Following that he was placed on medrol (16 mg, every other day) for 6 months, followed by pred-nisone (50 mg, alternating days) for one year. Zolendronate was given monthly from late 2000 to July 2003. Two follow-up bone marrow biopsies have revealed no evidence of residual myeloma.

Discussion

The association of intravenous bisphosphonate
administration to cancer patients and osteonecrosis of the mandible is a recently recognized, but increas-ingly
worrisome finding. Pamidronate (Aredia) and zolendronic acid (Zometa) are estimated to have been
given to 2? million patients since their introduction. 1 Multiple clinical studies have demonstrated their
effectiveness for treatment of hypercalcemia of malignancy. They have also demonstrated benefit to
patients with metastatic bone disease by reduction of bone pain and fracture when compared to placebo or
no bisphosphonate therapy. Some studies have suggested benefit in terms of overall survival as well,
although this is not consistent. 2,3

Bisphosphonates work by inhibiting bone resorption. This has been shown to be due to action on osteo-clasts,
although the exact mechanisms are not fully understood. Furthermore, they have been shown to
have antiangiogenic properties, decreasing endothe-lial cell proliferation and increasing apoptosis. 4 Their
demonstrated clinical benefits and their potential anti-cancer properties make them attractive agents to
oncologists and their patients. It is thus not surprising that they are given to a majority of cancer patients
with bone metastases, and that in the view of most oncologists they have become a standard of care.

Extensive early clinical trials demonstrated that toxicity from these agents was generally mild. It
consisted mainly of potential renal toxicity, and was minimal in other ways. 5,6 With their widespread use,
the occurrence of osteonecrosis of the mandible, and less often the maxilla, has been reported in increasing
numbers of patients receiving these agents. 7,8 Despite the fact that zolendronic acid is at least 100 times
more powerful than pamidronate, the occurrences reported have not predominated with either. It is
controversial whether bisphosphonates are in fact causative, as osteonecrosis of the mandible has been
reported in cancer patients for many years. An analysis of the General Population Research Database
in the United Kingdom showed this condition to be 4 times more common in cancer patients than in the
general population. 1 Furthermore, the use of chemotherapy, high-dose steroids, anemia and radio-therapy
have all been demonstrated to further increase the incidence.

In the last two years more than 100 occurrences of this condition have been reported with bisphospho-nates.
One report by Marx in 2003 included 36 patients receiving either or both of these agents. 9
Approximately 2 out of 3 of these patients had recently received both chemotherapy and high-dose
steroids. 9

The onset of this process is heralded most often by the onset of unexpected pain, often after an invasive
dental procedure. This then is followed by nonhealing at the procedure site. Corrective dental
procedures do not help. The benefit of prolonged antibiotics is uncertain, though they are generally the
main therapeutic intervention. Hyperbaric oxygen does not seem to be of benefit. An unanswered
question is whether bisphosphonates should be continued once osteonecrosis has occurred.

In summary, there is an association of osteonecrosis of the mandible and maxilla with use of biphospho-nates.
Whether there is causation or only correlation is not established. The weight of evidence suggests
that they are contributory to cause in a setting of markedly increased risk due to multiple factors asso-ciated
with cancer. Physicians involved with the care of cancer patients, especially when on bisphospho-nates,
should be aware of this potential condition. Dental procedures should be approached with caution
and only after careful evaluation by a dentist or oral surgeon who is familiar with the risks involved for
these patients. A patient at risk who has these symptoms, or unexplained prolonged mouth pain,
should receive a careful evaluation by a specialist who is familiar with such patients, often an academic
oral surgeon.

REFERENCES

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Combined analysis of two multicenter randomized, placebo controlled studies of pamidronate for palliation of bone pain in men
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