Risk Reduction of Non-vertebral Fractures with Intravenous Ibandronate: Post-hoc Analysis from DIVA

Objective: In the BONE study (3 years' duration), daily oral ibandronate 2.5 mg reduced vertebral fracture risk by 62% (vs. placebo; p = 0.0001). In the DIVA study (2 years' duration), i.v. ibandronate 2 mg every 2 months (q2mo) or 3 mg every 3 months (q3mo) was superior to daily oral ibandronate in terms of BMD gains (p < 0.001) and normalisation of bone turnover markers, suggesting potential antifracture efficacy with the licensed i.v. regimen (3 mg q3mo). To evaluate this, a post-hoc analysis of non-vertebral fracture incidence was performed using DIVA study individual patient data.

Methods: Both i.v. doses had the same annual cumulative exposure (ACE) - 12 mg. Therefore, data for these two regimens were pooled. This higher dose was compared with 2.5 mg daily oral ibandronate (ACE 5.5 mg) to maintain trial randomisation. Osteoporotic non-vertebral fractures were captured as a secondary endpoint. Time-to-event analysis was conducted using Kaplan-Meier methodology; hazard ratios (HRs) were derived from a Cox model with adjustments for clinical fracture, age and BMD. The DIVA trial was not primarily designed to assess fracture efficacy.

Results: The rate of non-vertebral fractures was significantly reduced when ibandronate ACE 12 mg (3 mg q3mo and 2 mg q2mo i.v.) was compared with ACE 5.5 mg (2.5 mg daily oral). The non-vertebral fracture incidence was 3.1% versus 4.8%, respectively, representing a 43% relative risk reduction with i.v. ibandronate (p = 0.0489; adjusted HR 0.569 [95% confidence interval: 0.324, 0.997]). Time to non-vertebral fracture was also extended for high- versus low-dose ibandronate (p = 0.048).

Conclusions: A significant effect on non-vertebral fracture risk reduction was seen when high i.v. ibandronate doses were compared with a lower oral dose. This post-hoc analysis indicates greater antifracture efficacy for the licensed quarterly i.v. regimen versus daily oral dosing.