14 CLINICAL STUDIES

14.1 Treatment of Postmenopausal Osteoporosis

Once-Monthly Dosing

The effectiveness and safety of ibandronate once-monthly were demonstrated in a randomized, double-blind, multinational, noninferiority trial in 1,602 women aged 54 to 81 years, who were on average 18 years postmenopause, and had L2-L4 lumbar spine BMD T-score below -2.5 SD at baseline. The main outcome measure was the comparison of the percentage change from baseline in lumbar spine BMD after one year of treatment with once-monthly ibandronate (100 mg, 150 mg) to daily ibandronate (2.5 mg). All patients received 400 IU vitamin D and 500 mg calcium supplementation per day.

Ibandronate 150 mg once-monthly (n = 327) was shown to be noninferior to ibandronate 2.5 mg daily (n = 318) in lumbar spine BMD in a one-year, double-blind, multicenter study of women with postmenopausal osteoporosis. In the primary efficacy analysis (per-protocol population), the mean increases from baseline in lumbar spine BMD at one year were 3.86% (95% CI: 3.40%, 4.32%) in the 2.5 mg daily group and 4.85% (95% CI: 4.41%, 5.29%) in the 150 mg once-monthly group; the mean difference between 2.5 mg daily and 150 mg once-monthly was 0.99% (95% CI: 0.38%, 1.60%), which was statistically significant (p = 0.002). The results of the intent-to-treat analysis were consistent with the primary efficacy analysis. The 150 mg once-monthly group also had consistently higher BMD increases at the other skeletal sites compared to the 2.5 mg daily group.

Daily Dosing

The effectiveness and safety of ibandronate were demonstrated in a randomized, double-blind, placebo-controlled, multinational study (Treatment Study) of 2,946 women aged 55 to 80 years, who were on average 21 years postmenopause, who had lumbar spine BMD 2 to 5 SD below the premenopausal mean (T-score) in at least one vertebra [L1-L4], and who had 1 to 4 prevalent vertebral fractures. Ibandronate was evaluated at oral doses of 2.5 mg daily and 20 mg intermittently. The main outcome measure was the occurrence of new radiographically diagnosed vertebral fractures after 3 years of treatment. The diagnosis of an incident vertebral fracture was based on both qualitative diagnosis by the radiologist and quantitative morphometric criterion. The morphometric criterion required the dual occurrence of two events: a relative height ratio or relative height reduction in a vertebral body of at least 20%, together with at least a 4 mm absolute decrease in height. All women received 400 IU vitamin D and 500 mg calcium supplementation per day.

Effect on Fracture Incidence

Ibandronate 2.5 mg daily significantly reduced the incidence of new vertebral (primary efficacy measure) and of new and worsening vertebral fractures. Over the course of the 3-year study, the risk for vertebral fracture was 9.6% in the placebo-treated women and 4.7% in the women treated with ibandronate 2.5 mg (p < 0.001) (see Table 2).

Ibandronate 2.5 mg daily did not reduce the incidence of nonvertebral fractures (secondary efficacy measure). There was a similar number of nonvertebral osteoporotic fractures at 3 years reported in women treated with ibandronate 2.5 mg daily [9.1%, (95% CI: 7.1%, 11.1%)] and placebo [8.2%, (95% CI: 6.3%, 10.2%)]. The two treatment groups were also similar with regard to the number of fractures reported at the individual nonvertebral sites: pelvis, femur, wrist, forearm, rib, and hip.

Bone Mineral Density (BMD)

Ibandronate significantly increased BMD at the lumbar spine and hip relative to treatment with placebo. In the 3-year osteoporosis treatment study, ibandronate 2.5 mg daily produced increases in lumbar spine BMD that were progressive over 3 years of treatment and were statistically significant relative to placebo at 6 months and at all later time points. Lumbar spine BMD increased by 6.4% after 3 years of treatment with 2.5 mg daily ibandronate compared with 1.4% in the placebo group. Table 3 displays the significant increases in BMD seen at the lumbar spine, total hip, femoral neck, and trochanter compared to placebo.