Osteonecrosis of the jaw serious but rare complication

Parenterally administered oral bisphosphonates associated with small risk for complications.

Issue: August 2007

Recent evidence has linked the use of intravenously administered bisphosphonates with osteonecrosis of the jaw, yet no definite relationship between bisphosphonate use and osteonecrosis of the jaw has been established. There are no established guidelines for treating patients with osteonecrosis of the jaw, according to researchers at Duke University.

“Although some investigators have assumed that the primary event in osteonecrosis of the jaw is bony necrosis with osteomyelitis occurring secondarily, it is equally plausible that infection is the inciting event and that changes in the cytokines and bone collagen milieu as a result of bisphosphonate therapy lead to nonhealing and osteonecrosis,” researchers wrote in Endocrine Practice.

In this retrospective study, the researchers reviewed medical records of patients treated at the New York Harbor Health Care System from January 1999 through December 2004. Patients selected for review included those who had a diagnosis that might indicate osteonecrosis of the jaw (n=968) and patients who received treatment with bisphosphonates over the study period (n=983).

“We found that osteonecrosis of the jaw was rare, and it also occurred in people who had not had bisphosphonate therapy,” Helena Guber, MD, assistant professor of internal medicine at New York Harbor Health Care System in Brooklyn, told Endocrine Today.

Records indicated 240 patients were treated with 5 mg, 30 mg or 35 mg of oral risedronate (Actonel, Procter & Gamble) and 5 mg, 10 mg or 35 mg of oral alendronate (Fosamax, Merck). Six hundred patients were treated with 70 mg of oral alendronate; 64 were treated with 30 mg or 90 mg of IV pamidronate (Aredia, Novartis); and 79 were treated with 4 mg of IV zoledronic acid (Zometa, Novartis).

Six-year period

Two patients had bisphosphonate-associated osteonecrosis of the jaw, and two bisphosphonate-naive patients had osteonecrosis of the jaw. The two patients with bisphosphonate-associated osteonecrosis of the jaw received IV bisphosphonates for treatment of multiple myeloma. Thus, during a six-year period, incidence of osteonecrosis of the jaw at the facility was one in 71.5 for patients receiving intensive IV bisphosphonate therapy, according to the researchers.

One patient with bisphosphonate-associated osteonecrosis of the jaw was diagnosed with multiple myeloma in 1994. He was treated with high-dose corticosteroids and irradiation from 1995 to 1996, followed by chemotherapy with melphalan (Alkeran, GlaxoSmithKline), thalidomide (Thalomid, Celgene) and bortezomib (Velcade, Millennium Pharma). In 1995, the patient began monthly infusions of pamidronate; in 2002, physicians changed the regimen to zoledronic acid. In October 2003, the patient underwent a tooth extraction and alveoloplasty. He presented with right-sided jaw pain and earache a year later. Dental examination revealed symptoms suggestive of osteonecrosis of the jaw.

A second patient with bisphosphonate-associated osteonecrosis of the jaw was diagnosed with multiple myeloma and stage D1 prostate cancer in 1995. He was treated with androgen suppression and external beam irradiation. In 2002, there was evidence of rapid progression of multiple myeloma. Therapy included erythropoietin, high-dose corticosteroids and monthly infusions of 90-mg pamidronate. Physicians switched the patient to monthly infusions of 4-mg zoledronic acid in December 2002. In February 2003, the patient underwent extraction of several teeth in preparation for denture placement. Follow-up in August revealed multiple exposures in the anterior maxilla and other signs of osteonecrosis of the jaw.

Physicians diagnosed a patient with osteonecrosis of the jaw who was bisphosphonate-naive with a right maxillary sinus plasmacytoma in 1992. In 2004, he was diagnosed with stage I multiple myeloma. In September 2004, he presented with necrotic bone.

A second patient with osteonecrosis of the jaw, who was bisphosphonate-naive had a history of nasopharyngeal carcinoma. In 2002, he experienced recurrent bouts of facial cellulitis and severe trismus. In 2004, examination revealed signs of osteoradionecrosis.

“Until results from a prospective, randomized, controlled trial confirming causation become available, judicious and proper use of bisphosphonates should be the standard; pretreatment dental care should be encouraged, patients should be educated about dental hygiene, and, if osteonecrosis of the jaw occurs, conservative management seems to be the preferred strategy, at least for now,” the researchers wrote. – by Christen Haigh

For more information:
Murad OM, Arora S, Farag AF, Guber HA. Bisphosphonates and osteonecrosis of the jaw: a retrospective study. Endocrine Practice. 2007;13:232-238.