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Osteonecrosis of the Jaw Associated With Cumulative Dose in Myeloma

TOP - February 2014, Vol 7, No 1

Data from a large population of patients with multiple myeloma receiving zoledronic acid infusions indicate that osteonecrosis of the jaw (ONJ) remains a significant complication, especially for patients who receive it for prolonged periods, investigators from Greece reported at the 2013 American Society of Hematology annual meeting.

“The risk increases with the number of zoledronic acid infusions,” according to Efstathios Kastritis, MD, of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine. “The risk is associated mainly with the cumulative dose.”

Zoledronic acid can reduce skeletal-related events in patients with symptomatic myeloma, and possibly improve survival, but its use increases the risk of ONJ. “Longer exposures and more infusions of zoledronic acid have been associated with a higher incidence of ONJ, and it has been suggested that longer intervals between infusions may reduce the risk; however, this has not been proven,” Kastritis said.

The investigators determined the incidence of ONJ in a prospective study of patients receiving zoledronic acid, specifically looking at dosing and scheduling as potential risk factors. The study included patients who received zoledronic acid and survived at least 6 months after their first infusion.

The relative dose frequency (RDF) was calculated as the average number of weeks between infusions. Time of exposure was calculated from the date of the first infusion until the date of the last infusion. All patients underwent dental evaluations before initiating treatment and were instructed to avoid procedures that predispose to ONJ.

The 266 patients were followed for a median of 36 months; their median survival was 64 months, median number of zoledronic acid infusions was 16, median duration of exposure was 29 months, and median RDF was 7.9 weeks. Half the patients had an RDF of less than 8 weeks.

ONJ developed in 26 (10%) patients. The median time of exposure to zoledronic acid was not significantly associated with risk: 28 months for patients who developed ONJ versus 24 months for those who did not (P = .2). The median number of infusions, however, proved important: 23 infusions for those who developed ONJ compared with 14 for those who did not (P = .004), Kastritis reported.

“Increasing number of zoledronic acid infusions was associated with higher risk of ONJ,” he said. ONJ developed in 2.3% of patients who received less than 10 infusions versus 12% of patients who received 10 to 19 infusions and 15% who received 20 or more (P = .012), he indicated.

The time period in which patients received the drug was not associated with risk. The incidence rate of ONJ for patients who started zoledronic acid before 2008 was 0.31 per 100 person-months compared with 0.26 per 100 person-months for those patients who started it after 2008 (P = .4).

Number of Infusions Most Important

The incidence of ONJ at 3 years was 13.6% for patients with an RDF less than 8 weeks versus 2.6% when the RDF was 8 weeks or longer (P = .018).

“After adjusting for RDF, only the number of infusions remained significant (P = .03) for the development of ONJ,” he said.

The multivariate analysis showed that both the number and frequency of zoledronic acid infusions were associated with a shorter time to ONJ development. More explicitly, the average frequency of infusions in less than 8 weeks was associated with a 15-fold increase in the risk of ONJ, and for every infusion the risk of ONJ increased by 9% (both, P <.001). Cumulative dose, therefore, was the chief risk factor, he concluded.

Prospective studies should determine whether less frequent administration of the drug can reduce the risk of ONJ without compromising its antiresorptive effect, the investigators suggested.


Kastritis E, Terpos E, Melakopoulos I, et al. The cumulative dose but not the frequency of infusions is a risk factor for the development of osteonecrosis of the jaw (ONJ) in myeloma patients who receive zoledronic acid (ZA). Poster presented at: 2013 American Society of Hematology Annual Meeting; December 8, 2013; New Orleans, LA. Abstract 3196.

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