NEW YORK, NY—Osteonecrosis of the jaw (ONJ) associated with bisphosphonate use was first reported in 2003. Clinicians soon began to worry that the problems seen in some cancer patients treated with these antiresorptive agents would also develop in patients treated with the lower doses used for osteoporosis. A review by John P. Bilezikian, MD, in the November 30 issue of the New England Journal of Medicine suggests that this is unlikely to happen.

According to Dr. Bilezikian, professor of medicine and pharmacology at the College of Physicians and Surgeons at Columbia University, in New York, "[One] in 100,000 patient-years is a reasonable estimate of the incidence of osteonecrosis of the jaw in persons receiving oral nitrogen-containing bisphosphonates for osteoporosis."

Dr. Bilezikian notes that fewer than 50 cases of ONJ have been reported among several million patients treated with oral bisphosphonates for osteoporosis, and that no cases of ONJ were reported among osteoporosis clinical trial patients over more than 60,000 patient-years of exposure to nitrogen-containing bisphosphonates such as oral alendronate (Fosfamax®, Merck), oral risedronate (Actonel®, Proctor & Gamble/sanofi-aventis), and oral or intravenous ibandronate (Boniva®, Roche). He concludes, "The documented benefits of using bisphosphonates for established indications clearly outweigh whatever small risk of osteonecrosis of the jaw might be incurred."

Low Risk – But Some Precautions Advised

Since pre-existing dental problems might increase the risk of ONJ, Dr. Bilezikian informs patients about the risk of ONJ and advises them to see their dentists before beginning intravenous bisphosphonate therapy.

"Routine dental hygiene is important; this point should be emphasized, given that some dentists are reluctant to provide even routine oral health care for patients who are taking bisphosphonates. Such reluctance, however, seems unwarranted," Dr. Bilezikian writes.¹

Bart L. Clarke, MD, agrees. Dr. Clarke, of the Metabolic Bone Disease Core Group, Mayo Clinic and Mayo Foundation, in Rochester, Minnesota, coauthored an American College of Rheumatology briefing paper on bisphosphonate-associated ONJ.²

Dr. Clarke told CIAOMed that for patients being treated with bisphosphonates for osteoporosis, there is likely to be very low risk of ONJ, but that some precautions would be reasonable. "Significant dental problems should be dealt with before beginning bisphosphonates (tooth extractions, root canals, or dental implants)," he said. "There is more debate about stopping bisphosphonates around the time of these procedures, since the drug is in the bone already, and temporarily stopping the drug should have little effect on risk."

What About Long-Duration Bisphophonates?

Most of the cases of ONJ reported in cancer patients were seen in those who received repeated monthly injections of intravenous formulations. This has raised concerns about risks that might be associated with once-monthly or yearly formulations. Dr. Clarke said that the data are reassuring on this point.

"The HORIZON-PFT Trial tested zoledronic acid 5 mg IV once a year in about 7700 women in 29 countries over 3 years. There were three reported cases of jaw osteonecrosis, two of which occurred in the placebo group, one of which was in the zoledronic acid 5 mg treatment group. If the intravenous bisphosphonates are being given to cancer patients at one dose every 3–4 weeks in most cases, and jaw osteonecrosis seems to develop after a mean of 1.5–2 years of roughly monthly dosing, you might anticipate that zoledronic acid 5 mg once a year wouldn't cause many cases of osteonecrosis. It is hard to predict how many years of once-yearly treatment with zoledronic acid 5 mg would be required to induce jaw osteonecrosis," Dr. Clarke said.
 
"Long-duration formulations might over-suppress bone turnover, which could lead to bone microcrack accumulation and eventual increased risk of fracture. To date, this has not been seen with any clinically used bisphosphonate in humans, so the risk remains theoretical," he added.

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