Risk reduction of non-vertebral fractures with intravenous ibandronate: post-hoc analysis from DIVA

Abstract

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.

Key words::

• Bisphosphonates
• Bone fractures
• Ibandronate
• intravenous
• Postmenopausal osteoporosis

Transparency

Declaration of funding

This analysis was funded by an unrestricted research grant from F. Hoffman-La Roche Ltd. The authors would like to thank F. Hoffman-La Roche Ltd and GlaxoSmithKline for supplying the individual patient data used in the analysis, and emphasise that the analysis was completed without influence from either company.

Declaration of financial/other relationships

P.S. has disclosed that he has no relevant financial relationships. A.C. has disclosed receiving research sponsorship from Hoffman La Roche and GlaxoSmithKline for this study and research grants in the past from Hoffman La Roche. J.D.A. has disclosed receiving research grants from Amgen, Eli Lilly, GSK, Merck & Co., Novartis, Pfizer, Procter & Gamble, Sanofi-Aventis, Roche, Wyeth and Bristol-Myers Squibb and acting as a consultant and/or serving on the speakers bureau for Amgen, AstraZeneca, Eli Lilly, GSK, Merck & Co., Novartis, Nycomed, Pfizer, Procter & Gamble, Roche, Sanofi-Aventis, Servier, Wyeth and Bristol-Myers Squibb.

Peer reviewers may receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed that he is the recipient of sponsorship and/or research grant funding from GlaxoSmithKline Servier, Merck Sharpe & Dohme, Thermex and Rottapharm and is a consultant/advisor to GlaxoSmithKline, Servier, Galapagos and Rottapharm. Peer Reviewer 2 has disclosed that he/she has been the recipient of grant/research support from Amgen, Eli Lilly, GSK, Novartis, Pfizer, Procter & Gamble, Roche, Sanofi-Aventis, Wyeth; that he is on the speakers bureau and the advisory board for Eli Lilly, Novartis, Roche/GSK; that he is on the advisory board for Amgen, Upsher-Smith and Wyeth; and that he is a direct stockholder in Procter & Gamble and Teva.

Acknowledgements

The authors would also like to acknowledge medical writing assistance provided by Michael Barton and Dr Louise Profit, Gardiner Caldwell Communications in the preparation of this manuscript, financial support for which was provided by F. Hoffmann-La Roche and GlaxoSmithKline. Individual patient data for all studies were provided by the sponsor. All statistical analyses were performed at the University of Ottawa by an independent, external expert group.

Data were previously presented as a poster at the 35th European Symposium on Calcified Tissues, Barcelona, Spain, May 2008.