Bisphosphonates and Osteonecrosis of the Jaw
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: Jaw osteonecrosis may be a unique adverse effect of bisphosphonate treatment.
Source: Farrugia MC, et al. Osteonecrosis of the mandible or maxilla associated with the use of new generation bisphosphonates. Laryngoscope. 2006;116:115-120.
Twenty-three patients are reported with osteonecrosis of the mandible or maxilla associated with bisphosphonate treatment. Eighteen of the patients were treated with intravenous bisphosphonates for complications associated with malignancies (9 with multiple myeloma, 6 with metastatic breast cancer, 2 with prostate cancer, and 1 with renal cell carcinoma). Four of the patients were receiving oral alendronate for the treatment of osteoporosis and one for Paget's disease. Local debridement, antibiotics, and hyperbaric oxygen could not reverse the necrotic process in a single patient.
Commentary
The total number of reported cases of osteonecrosis associated with bisphosphonate treatment has now reached about 150. No other sites of osteonecrosis have been reported. What have we learned?
Bisphosphonates prevent bone loss by inactivating osteoclasts. The binding of bisphosphonates to bone is characterized by great affinity, and local concentrations in resorption lacunae reach very high levels. The nitrogen side chain in the newer bisphosphonates prevent metabolism, allowing accumulation in bone with persistent effects. This raises the possibility of overdosage with adverse effects.
Bisphosphonate, especially with the potent intravenous agents, has been enthusiastically endorsed by oncologists to treat hypercalcemia with malignancy and bone metastases with multiple myeloma or solid tumors such as prostate, lung, and breast cancers. The oral agents are not as efficacious for this use. However it should be noted that patients receiving bisphosphonate treatment for osteoporosis with no history or evidence of malignancy have experienced jaw osteonecrosis.1
Most, but not all, of the patients developing osteonecrosis have had dental intervention. But even in the absence of dental procedures, the oral cavity is a site of microflora and minor injuries or disease. Even dental implant failures have been reported in patients receiving oral bisphosphonate treatment for osteoporosis. A compromise in the healing ability of bone (inhibition of bone turnover) can lead to a non-healing wound, sequestered osteomyelitis, and necrosis. Bisphosphonates have been demonstrated to exert antiangiographic activity, perhaps by decreasing levels of vascular endothelial growth factor.2 This could be another mechanism contributing to ischemic necrosis.
Most of these cases are detected late and treatment has had limited success. Attention to dental status is essential prior to cancer and bisphosphonate therapy. Dental procedures should be avoided in these patients, and good oral hygiene must be emphasized.
But obviously this dreadful complication has occurred in individuals without cancer and being treated for osteoporosis. Therefore we must direct our attention to duration of bisphosphonate treatment in our patients. The potential risk that has been long recognized is that prolonged exposure to bisphosphonates or excessive dosage would oversuppress bone resorption, thus oversuppressing bone turnover and affecting the biomechanical strength of bone. The mechanism for overdosage can be the unique tight binding of bisphosphonates to bone causing this drug to remain in the body for decades. This is believed to be the explanation for why there is no rapid bone loss after discontinuing bisphosphonate treatment in contrast to the rapid loss that follows the termination of estrogen therapy. Thus, when bone remodeling releases bound bisphosphonate, it is free to be active again, and the result is the endogenous bisphosphonate is added to the administered bisphosphonate, raising dosage exposure. At this time, we don't know the lowest effective dose and the lowest effective duration of exposure.
An increased susceptibility to nonspinal fractures may occur relatively early when bisphosphonate treatment is combined with another antiresorptive treatment, and this should be avoided because no additional benefit on fracture risk has been demonstrated with combined treatment. Bisphosphonate treatment is best reserved for older postmenopausal women. It is not a drug of choice for the prevention of osteoporosis in relatively young postmenopausal women. In all patients being treated with bisphosphonates, it would be wise to consider a time limit for duration of exposure, perhaps 5 years. Patients can be monitored after discontinuing treatment either by bone density measurements or by serial monitoring of the urinary biochemical markers of bone resorption.
References
- Rggiero SL, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004;62:527-534.
- Wood J, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302:1055-1061.
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