Despite compelling preclinical data, only anecdotal reports have shown that zoledronic acid (ZOMETA, Zol) exerts an anti-multiple myeloma (MM) effect in humans.We postulate that this could be related to the dose-intensity of Zol, since anti-MM effects were clearly observed in mice given a dose equivalent of 8.0 mg (8.0 EQmg) weekly; but not in humans who received only 4.0 mg monthly.We describe 3 patients, who were treated with 2-to 3-fold higher dose-intensity of Zol who demonstrated brisk clinical improvements.When the equivalent dose of Zol was normalized to the patients body surface area, the maximum EQmg rate of Zol administered was between 11.4 EQmgrnax and 12.0 EQmgmax per 28 days.Since the potency of Zol is measured by the degree of inhibition of differentiation of osteoclast precursors (pOC) (i.e.monocytes) to osteoclasts (OC) in vitro, we next investigated whether high-dose rate Zol had an in vivo inhibitory effect on this renewable pOC pool.We demonstrate that there was a linear relationship between the absolute monoeyte count (AMCO) and the stage of MM at presentation.