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BOSTON -- Osteonecrosis of the jaw (ONJ) is rare in patients taking the antiresorptive drug denosumab (Prolia), even when invasive dental procedures are performed, according to up to 8 years of data from the FREEDOM and FREEDOM extension studies.

"The clinical significance of these findings is that doctors and patients can be reassured that, even with long-term denosumab therapy, the risk of developing ONJ is very low," said study investigator , from the in Portland.

"For patients with osteoporosis who deserve treatment to reduce fracture risk, concern about ONJ should not prevent them from receiving appropriate, effective osteoporosis treatment."

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study () randomized women ages 60 to 90 years with osteoporosis to receive either 60 mg denosumab (n=3902) or placebo (n=3906) every 6 months for 3 years, explained McClung, who presented the findings at .

At the end of the study, subjects in the placebo arm were given the opportunity to continue or cross over to the active drug for another 7 years in the ongoing FREEDOM extension study ().

Three years into the extension study, patients were asked every 6 months about invasive oral procedures or events (OPE), which have been suggested as risk factors for ONJ.

Of the 3,536 women who agreed to complete the questionnaire, 58% (n=2036) reported no OPEs, and 42% (n=1500) reported OPEs such as root scaling, tooth extraction, dental implants, spontaneous tooth loss, or other invasive procedures involving the jaw.

There were a total of eight adjudicated ONJ cases, seven of which (0.47%) were reported in women with a history of OPEs and one (0.05%) in a woman with no OPE history. "She had dentures and upon removing them exposed bone was seen," said McClung. "She was asymptomatic, but a diagnosis of adjudicated ONJ was made."

Looking at duration of denosumab exposure, the study found that the percentage of patients with OPEs was balanced between those who had been on treatment from the start of the FREEDOM study and those who had crossed over to active treatment for the FREEDOM extension trial (41.8% versus 43.1%).

"This is likely similar to the frequency of OPEs among women of the same age without osteoporosis or without denosumab therapy -- since there is no evidence that denosumab therapy increases the frequency of OPEs," he said

Of the eight ONJ cases, five were in the long-term treatment arm, occurring after 11 doses (n=2), 12 doses (n=2), and 13 doses (n=1) of denosumab, while the three cases in the crossover arm occurred after three, four, and eight doses respectively.

During the extension study, the overall exposure-adjusted incidence of ONJ was 4.2 per 10,000 patient-years.

While OPEs were common on the cohort and appear to be a risk factor for ONJ, "the risk of ONJ in such patients is very low, even among those who underwent OPEs," with the risk remaining much in patients with cancer-related bone diseases receiving high doses of the drug.

"No one knows for sure why the risk of ONJ is so very much higher with zoledronic and denosumab used to treat patients with cancer," he commented. "Certainly the doses used in those patients are higher -- but the patients are also very different: they have cancer, are receiving chemotherapy, and are immunocompromised. It is certainly not as simple as a dose effect."