Journal of Clinical Oncology, Vol 21, Issue 22
(November), 2003: 4253-4254
© 2003 American Society for Clinical Oncology
Bisphosphanates and Oral Cavity Avascular Bone Necrosis
Cesar A. Migliorati
NOVA Southeastern University, Fort Lauderdale, FL
To the Editor: Bisphophonates are widely used in the treatment of cancer patients with hypercalcemia of malignancy and bone metastasis.1 Within the last year, we saw five patients who presented with intraoral bone necrosis while taking pamidronate (Aredia; Novartis, East Hanover, NJ) or zoledronic acid (Zometa; Novartis). Three patients had spontaneous bone necrosis of the mylohyoid plate (internal posterior mandible) and two on the molar region after a tooth extraction. The exposed necrotic bone in all cases was infected, and the area was painful. Patients complained of difficulty eating, speaking, and performing oral hygiene. This process has been named drug-induced avascular bone necrosis.2 It presents a difficult clinical management problem. Antibiotics are not effective. Surgical treatment of the bone defect and the use of hyperbaric oxygen have proven to be ineffective. The lesions increase in size, independently of the type of treatment. Patients have to be observed periodically for regional débridement, bone trimming, control of the infectious component, and pain. Although the malignant disease is stabilized, patients have poor quality of life because of the oral complication.
Intraosseous circulation may be altered when intraosseous pressure changes. This is seen in avascular necrosis of the femoral head when pain results from increased bone pressure.3 Bone blood flow may be altered if intraosseous angiosenesis is inhibited.3 Two recent articles4,5 reported the novel antiangiogenic effect of bisphosphonates. It has been demonstrated that these compounds are effective in inhibiting endothelial cells. Zoledronic acid decreases endothelial cell proliferation and induces apoptosis.5 In rats, it can inhibit testosterone-stimulated vascular regrowth in the ventral prostate.5 The precise mechanism of inhibition of bone resorption is not well understood. There may be inhibition of the formation of mature osteoclasts. Internalization of the drug in active osteoclasts disrupts the cytoskeleton and vesicular trafficking, leading to cessation of resorption and induction of apoptosis.4
In addition to the use of bisphosphonates in hypercalcemia of malignancy and metastatic bone disease, antiangiogenesis effect may lead to increased use of these drugs in the treatment of some solid tumors and inflammatory diseases (Paget’s, osteoporosis), in which angiogenic effect plays a role.4
We postulate that bisphophonates may cause oral avascular bone necrosis due to antiangiogenic effect leading to inhibition of osteoclasts. Medical oncologists should consider this possible side effect when treating cancer patients with bisphophonates. Prevention of this complication and identification of individuals at risk should be investigated.
AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 a year from a company for either of the last 2 years: Cesar A. Migliorati, Colgate-Palmolive.
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Fig 1. Bone necrosis of the mandible on a female patient with metastatic breast cancer to bone under treatment with zoledronic acid.
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REFERENCES
1. Zometa (Zoledronic acid for injection): Package insert. Basel, Switzerland, Novartis Pharma AG, 2002
2. Marx RE, Stern D: Oral and Maxillo-Facial Pathology: A Rationale for Diagnosis and Treatment (ed 1). Quintessence, Carol Stream, IL, 2003, pp 36–38
3. Laroche M: Intraosseous circulation from physiology to disease. Joint Bone Spine 69:262–269, 2002[CrossRef][Medline]
4. Wood J, Bonjean K, Ruetz S, et al: Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302:1055–1061, 2002[Abstract/Free Full Text]
5. Fournier P, Boissier S, Filleur S, et al: Bisphophonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 15:6538–6544, 2002
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