Soy isoflavone preparations, such as purified genistein and a soy extract (Novasoy), were reported previously to exert beneficial effects on bones. Our purpose in this study was to compare the effects of genistein and Novasoy on 3-dimensional trabecular bone parameters and the expression of bone-specific genes in ovariectomized (OVX) mice. The sham-operated mice were fed the control diet and OVX mice were fed diets containing genistein or Novasoy or the control diet, with or without 17beta-estradiol treatment, for 5 wk. Trabecular bone parameters of tibias were measured by microcomputed tomography and gene expression was assayed by real-time PCR. Consumption of diets containing genistein or Novasoy partially prevented the ovariectomy-induced increase in body weight but did not alter the uterus weight of the OVX mice. Novasoy, but not purified genistein, significantly preserved trabecular bone mass, bone volume, and trabecular bone separation in the proximal tibial metaphysis. Purified genistein decreased mRNA expression of receptor activator of nuclear factor-kappaB ligand (RANKL), carbonic anhydrase II, and cathepsin K and enhanced the ratio of osteoprotegrin:RANKL mRNA expression in the tibial head of the OVX mice. In contrast, the diet containing Novasoy suppressed the OVX-induced increase in serum alkaline phosphatase but did not alter bone-specific gene expression of tibia. Our study demonstrated that a soy extract containing a similar level of genistein in the form of Novasoy is more effective than purified genistein in improving tibial trabecular bone quality in OVX mice, but the mechanism of action might be distinct from that of genistein.