OBJECTIVE: This study investigated the effect of alpha-ketoglutarate sodium salt (AKG) and ipriflavone (IP) treatment on the mineralization of the tibia in male rats during the development and after the establishment of osteopenia. DESIGN: One hundred and twenty eight male rats were randomly selected and submitted to either sham-operation (SHO) or orchidectomy (ORX), after which each group were then randomly divided between the two experiments. In Experiment-1, treatment with AKG or/and IP started after a 7-day recovery period, whereas in Experiment-2, the experimental protocol proceeded after a 60-day period of osteopenia establishment. AKG was then administered as an experimental drinking, at a concentration of 1.0 mol/l. As a control, a placebo solution was administered. IP at 50 mg/kg b.w., and physiological saline - PhS (as a control for IP) were applied daily via gavage. MEASUREMENTS: After 60 days of experimental treatment, in both experiments, the rats were sacrificed, their body weight recorded, while blood serum (Osteocalcin, CTX) and isolated tibia (weight, length, pQCT, DXA, 3-point bending test) were stored for further analysis. RESULTS AND CONCLUSIONS: Our results show that during the development of osteopenia, AKG and IP when applied exclusively, counteracts osteopenia development, whereas their usage after the establishment of osteopenia, significantly limits the development of bone disorders. Furthermore, combined treatment of AKG and IP exceeded the effects of their sole usage. In addition, during the development of osteopenia, AKG and IP not only inhibited bone resorption, but markedly stimulated the formation of bone tissue. Finally, after the development of osteopenia, combined treatment with AKG and IP protected the bone tissue against orchidectomy-induced bone loss.