Intravenous Bisphosphonate and Facial Bones

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: IV bisphosphonate treatment is associated with an increased risk of inflammation in the bones of the jaw and face.

Source: Wilkinson GS, et al. Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: a population-based analysis. J Natl Cancer Inst. 2007;99:1016-1024.

Wilkinson and colleagues from the University of Texas in Galveston analyzed information from the Surveillance, Epidemiology, and End Results (SEER) databank linked to Medicare claims.1 There, 16,703 cancer patients were identified who were treated with IV bisphosphonates (pamidronate and zoledronic acid) from 1995 to 2003. When 14,349 treated patients were matched with 28,698 controls, the treated group had a 3-fold increased risk of jaw or facial bone surgery (HR = 3.15; CI = 1.86-5.32) and a very large increased risk of osteomyelitis of the jaw (HR = 11.48; CI = 6.49-20.33). The estimated absolute risk equaled 5.48 events per 100 patients over 6 years. In addition, the risk increased with increasing cumulative dose.

Commentary

By now the link between bisphosphonates and jaw osteonecrosis is accepted even though the previous studies contained small numbers. It is acknowledged that this is a relatively rare complication. The mechanism is uncertain beyond the recognition that infection and blood flow changes are involved. It is postulated that compromised healing ability of bone because of inhibition of bone turnover leads to a sequestered osteomyelitis and necrosis. This study is of importance because of its large size, and it confirms the earlier reports. Yet despite its size, the number of cases is not great enough to provide an estimate of the exact relative risk (note the wide confidence intervals indicating imprecision, usually due to small numbers).

Previous studies have suggested that the risk of osteonecrosis of the jaw is greater in patients treated with zoledronic acid compared with pamidronate.2-4 Unfortunately, because of a delay in issuing a separate billing code for zoledronic acid, this question could not be addressed in this large cohort study.

The study also examined a large list of risk factors (such as different types of cancers, the presence of other medical conditions, the use of other drugs) and could find no associations with specific factors.

Awareness of this problem has led to increased attention to oral hygiene and the avoidance of tooth extractions in the high risk population of cancer patients receiving this treatment. The infrequency of this problem does not outweigh the substantial reduction in fractures and the need for irradiation or surgery of bone metastases in treated patients. But there remains the important question of the prevalence of this complication in individuals being treated for osteoporosis or the prevention of bone loss. Patients receiving bisphosphonate treatment for osteoporosis, with no history or evidence of malignancy, have experienced jaw osteonecrosis.4,5 Clinical judgment suggests the following guidelines:

  1. Duration of exposure to bisphosphonate should be limited, avoiding high local dosage secondary to the liberation of tightly bound bisphosphonate combined with on-going treatment. Many clinicians recommend discontinuation after 5 years with resumption of treatment when bone loss is demonstrated.
  2. Avoid combining two anti-resorptive agents (even though there may be a small additional gain in bone density, there is no evidence that an additional benefit on fracture risk is achieved).
  3. Think twice before treating young postmenopausal women with a bisphosphonate.

References

  1. Wilkinson GS, et al. Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: a population-based analysis. J Natl Cancer Inst. 2007;99:1016-1024.
  2. Zervas K, et al. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br J Haematol. 2006;134:620-623.
  3. Durie BGM, et al. Osteonecrosis of the jaw and bisphosphonates. New Engl J Med. 2006;353:99-100.
  4. Farrugia MC, et al. Osteonecrosis of the mandible or maxilla associated with the use of new generation bisphosphonates. Laryngoscope. 2006;116:115-120.
  5. Ruggiero 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.