Results from the Oral IBandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE) study showed a significant (p=0.0001) 62% reduction in the risk of vertebral fractures in women with postmenopausal osteoporosis treated with oral ibandronate, either as 2.5 mg daily or as 20 mg every other day for 12 doses every 3 months [Chesnut CH et al. Bone Miner Res 2004]. Although the study was not powered to evaluate the outcome in non-vertebral fractures, a significant (p=0.013) relative risk reduction for non-vertebral fractures of 69% was seen in a subgroup of high risk patients (mean femoral neck bone mineral density (BMD) T-score ≤3).

This meta-analysis was conducted to assess the efficacy of high vs low doses of ibandronate on non-vertebral factures. All randomized-controlled trials of ibandronate were reviewed and variable definitions of high vs low doses were explored. A time to event analysis was conducted comparing high annual cumulative exposure (ACE) with low ACE with 2-year data taken from two equivalent non-inferiority trials [Reginster JY et al. Ann Rheum Dis 2006; Emkey R et al. Arthritis Rheum 2005]. Hazard ratios, derived from a Cox model, were adjusted for clinical fracture, age, BMD, and study. ACE was based on an oral bioavailability of 0.6% and IV bioavailability of 100%.

A reduced non-vertebral fracture rate was seen when comparing combined high doses equivalent to an ACE of ≥10.8 mg with a low ACE of 5.5 mg (HR 0.620; relative risk reduction: 38%; 95% CI 0.40–0.97; p=0.04). Similar treatment effects were seen when high doses (ACE ≥10.8 mg) were compared with medium doses equivalent to an ACE of 5.5–7.2 mg. There was a dose-response effect with increasing ACE (7.2–12 mg) compared with ACE 5.5 mg. Adjustment for covariates in the analysis had a minimal effect.

A significant effect on non-vertebral fracture risk reduction was seen when combining trials using high ibandronate doses equivalent to an ACE of ≥10.8 mg versus a low ACE of 5.5 mg, and also with ACE ≥10.8 mg versus ACE ≤7.2 mg.

The treatment effect was dose-dependent. Higher doses of ibandronate significantly increase bone mineral density at the spine and hip, and reduce the risk of non-vertebral fractures more effectively than lower doses.