While initial preclinical studies provide an important starting point for dose selection, they may not provide adequate information to identify the optimal dosage for an extended treatment regimen. Determining the best dose for use in an extended dosing regimen requires ongoing development, illustrated best with the bisphosphonate, ibandronate. As mandated for regulatory purposes, the daily oral regimen of ibandronate was proven effective in significantly reducing the rate of new vertebral fractures assessed prospectively, and nonvertebral fractures in a high-risk population, assessed retrospectively. Extended dosing regimens, namely monthly and quarterly intravenous formulations, were developed subsequently to improve the convenience and enhance persistence, while maintaining or increasing efficacy. The continuing and progressive evolution of data led to the understanding that extension of drug-free interval requires higher annual cumulative skeletal exposures (ACE), which were not simply numerical multipliers of the interval and daily dose. For ibandronate, this led to dose selection for the oral monthly 150 mg (ACE 10.8 mg) and intravenous quarterly 3 mg (ACE 12 mg) formulations that proved superior in increasing bone mineral density (BMD) compared with oral daily 2.5 mg (ACE 5.5 mg) ibandronate. Pooling data from clinical trials with high ACE regimens (monthly and quarterly) led to the evolution of statistical evidence for a reduction in clinical and nonvertebral fractures with ibandronate. The ibandronate story should serve as an important future paradigm for bisphosphonate development.