Background/Purpose: Antiresorptive therapy use is associated with osteonecrosis of the jaw (ONJ), an infrequent but serious adverse event. Positively adjudicated ONJ in the denosumab (DMAb) clinical trial program is rare (between ≥1 and <10 per 10,000). Completion of the 7-year FREEDOM Extension study (EXT) permitted an in-depth assessment of the risk factors and observed invasive oral procedures and events (OPEs; eg, dental implants, tooth extraction, natural tooth loss, scaling/root planing [extensive subgingival cleaning]) in the clinical trial setting.
Methods: In the randomized, placebo-controlled FREEDOM study, women received DMAb 60mg or placebo SC every 6 months for 3 years. Patients who missed ≤1 dose of investigational product and completed the Year-3 visit were eligible to participate in the 7-year open-label EXT to receive DMAb, regardless of original treatment assignment in FREEDOM. Women who reached the EXT Year-3 visit were asked to chronicle their history of invasive OPEs since the start of the EXT through Year 2.5, as well as oral events (including jaw surgery) in the prior 6 months. The oral event questionnaire was then administered every 6 months through the end of the EXT.
Results: During the EXT, the overall ONJ rate was 5.2 per 10,000 patient-years. The majority of women (79%; 3591/4550 patients) participated in the survey. Over the EXT, 1621 (45.1%) reported at least one invasive OPE; the incidence of five individual OPEs were similar between groups (Table). There were 12 confirmed cases of ONJ among women who participated in the survey (11 had OPE and one did not) and one additional case in a woman who did not complete the survey. ONJ incidence was 0.7% (11/1621 patients) in women reporting invasive OPEs and 0.05% (1/1970 patients) in women reporting no invasive OPEs. Of the 12 ONJ cases with survey results, one outcome was unknown due to consent withdrawn, one was ongoing at the end of study, and 10 resolved with treatment.
Conclusion: Nearly all cases of ONJ observed in this study occurred after a reported invasive OPE, yet while invasive OPEs were common in this group of DMAb-treated women with postmenopausal osteoporosis, ONJ incidence was low. The actual number of invasive OPEs may be underestimated due to limited capture of OPEs in medical charts and possible recall bias in patients with events that occurred in the first 2.5 years of the EXT. ONJ is an adverse event of interest that continues to be monitored in DMAb pharmacovigilance activities.

Table: Invasive OPEs during the EXT for patients who completed at least one oral event questionnaire