Objective: The DIVA (Dosing IntraVenous Administration) study compared the efficacy and tolerability of an extended-interval i.v. ibandronate injection with daily oral ibandronate. Oral bisphosphonates, are the current standard of care for osteoporosis, but some patients have difficulties with oral administration. This limits the population in which bisphosphonates can be used and would be addressed by the additional availability of an efficacious i.v. bisphosphonate preparation. Ibandronate, a potent, nitrogen-containing bisphosphonate can be given orally or by rapid i.v. injection (15-30 seconds), with extended dosing intervals. Methods: DIVA is an ongoing, double-blind, phase III, non-inferiority study, comparing the efficacy and tolerability of the first extended-interval i.v. ibandronate injection regimens (2mg, every two months or 3mg, every three months) with a proven 2.5mg daily oral ibandronate regimen (52% vertebral fracture risk reduction at 3 years) in women with postmenopausal osteoporosis (PMO). A total of 1,395 women (aged 55-80 years; ≥5 years since menopause) with PMO (lumbar spine [L2–L4] bone mineral density [BMD] T-score <-2.5) were randomized to treatment. Participants also received daily calcium (500mg) and vitamin D (400IU). The primary endpoint was mean percentage change from baseline in lumbar spine BMD after 1 year. Secondary endpoints were: mean percentage changes from baseline in proximal femur (total hip, trochanter and femoral neck) BMD and serum CTx; and the proportion of patients responding to i.v. ibandronate treatment (predefined as increases in lumbar spine BMD and/or total hip BMD above baseline at year 1). Safety parameters were continuously monitored throughout the study. Results: After 1 year, substantial increases in lumbar spine BMD were observed in all treatment arms, with significantly greater increases seen in the i.v. arm compared to the daily arm. Increases observed were 5.1%, 4.8% and 3.8% in the 2mg/2mo, 3mg/3mo and 2.5mg daily arms, respectively. Non-inferiority (1% margin) and superiority (p<0.001) to the 2.5mg daily regimen was demonstrated for both i.v. regimens. Substantial and comparable increases in hip BMD (all sites) were also observed with the i.v. regimens, which were greater than those seen with the 2.5mg daily regimen. Similar and substantial decreases in serum CTx were observed across all treatment arms. Both i.v. regimens were well tolerated and the incidence of adverse events was similar to the daily regimen. Importantly, the overall incidence of renal adverse events (e.g. nephrolithiasis, urinary incontinence, renal impairment) was low (≤3%) and comparable across i.v. and daily oral arms. The incidence of influenza-like illness was also low (0.6% daily; 3.2 and 3.3% for 2mg and 3mg i.v., respectively) and not associated with increased withdrawals. Conclusions: This study demonstrates that rapid i.v. ibandronate injections, 2mg (every 2 months) and 3mg (every three months), provide superior efficacy (in terms of percentage change in BMD) to a 2.5mg daily oral regimen with proven antifracture efficacy. These injection regimens are also well tolerated and do not show the renal adverse event issues typical of i.v. administration. Extended-interval i.v. ibandronate injections therefore offer an effective, safe and convenient alternative to oral bisphosphonates, which may be of particular benefit for patients who cannot tolerate oral bisphosphonates.
Faculty Member's Name: Michael A. Bolognese, M.D.
Grants/Research Support: Aventis, Pfizer, Lilly, Wyeth
Consultant: Procter and Gamble, Lilly
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