Recent clinical trials in osteoporotic patients show that cyclical etidronate therapy can increase vertebral bone mass and reduce the incidence of vertebral fractures. Stress generated potentials, which are theorized to participate in a negative feedback arrangement regulating bone and which are electrokinetic in origin, can be characterized in vitro by the zeta potential, a measure of electrical surface charge. Thus, the possible effects of etidronate and oophorectomy on the zeta potential of bone were investigated with respect to bone remodeling, pathophysiology, and osteoporosis. Thirty-two oophorectomized and 48 sham oophorectomized rats received subcutaneous etidronate or saline. The zeta potential magnitude of the control group (sham oophorectomized, vehicle only) increased 23.6% from age 6 to 10 months, a period of bone growth. After 6 weeks of etidronate treatment, which decreased bone turnover, the zeta potential magnitude was decreased 14.9% (0.59 mV) compared with that of controls. Decreased zeta potential magnitudes with etidronate treatment also were observed in sham oophorectomized groups at 16 weeks and in oophorectomized groups at 6 and 16 weeks, but the differences were not statistically significant. A large bolus of etidronate had no effect. The zeta potential of bone is a dynamic quantity that may correlate with bone growth or bone turnover. Whether it exerts a causative effect or is a marker remains unknown.