Abstract The aim of this investigation was to compare the effects of sodium fluoride (NaF) and parathyroid hormone (PTH) on ash density and strength in an osteopenic rat model. The study comprised 66 female virgin rats divided into the following 11 groups, each comprising six animals: baseline controls; baseline ovariectomized (ovx); intact controls (5 and 16 weeks), ovx controls (5 and 16 weeks); ovx-treated with PTH (0.02 mg/kg per day, 5 and 16 weeks); ovx treated with NaF (10 mg/kg per day, 5 and 16 weeks); ovx-treated with NaF (1.0 mg/kg per day, 16 weeks). Ovariectomy was performed at 12 weeks of age, 14 weeks prior to start of treatment. Ash density, bone fluoride content, and biomechanical analyses were performed on femoral cortical bone, the right femoral neck, and the sixth lumbar vertebral body. ovx had no effect on cortical bone, whereas the femoral neck displayed a significantly lower bone strength in ovx baseline animals compared with intact baseline rats ( p < 0.05). Vertebral ash density was found to be significantly decreased in ovx rats after 5 and 16 weeks ( p < 0.05). Treatment with fluoride had little effect on the osteopenic rat skeleton. Cortical ash density was significantly lower than ovx and intact groups in the high-dose-treated rats after 5 ( p < 0.01) but not after 16 weeks. High doses of fluoride for 16 weeks induced a significant increase in maximum load and normalized strength in cortical bone when compared with intact animals ( p < 0.05), but not at the other bone sites. Cortical bone strength was not different from the ovx animals at either timepoint. In fluoride-treated animals, femoral neck bone strength, vertebral body bone strength, bone quality, and ash density were found to be at about ovx levels and, in the vertebral body, significantly lower than intact animals ( p < 0.05, p < 0.01). In contrast, treatment with PTH increased ash density, bone strength, and bone quality to above ovx levels ( p < 0.01), and above the level of the intact animals also, although significant values were reached for cortical bone strength only ( p < 0.01). Additionally, biomechanical competence and ash density measurements were significantly higher in PTH-treated rats compared with fluoride-treated rats. In conclusion, this study has shown that PTH has a highly anabolic effect and is capable of effectively restoring ovx-induced loss of bone mass and biomechanical competence. In addition, in this osteopenic rat model, PTH proved much more advantageous than treatment with fluoride, which failed to restore the ovx-induced loss of bone strength.