The purpose of this study was to determine whether PTH has anabolic effects on cortical bone in aged ovariectomized (OVX) rats treated during the late stages of estrogen depletion. Groups of OVX rats were untreated for 1 year posto-variectomy followed by treatment for 10 weeks with vehicle, estrogen, the bisphosphonate risedronate (NE-58095), calcitonin (CT), PTH, PTH + estrogen, PTH + NE-58095 or PTH + CT. A group of sham-operated control rats was treated with vehicle alone. Cross-sections of the tibial diaphysis immediately proximal to the tibiofibular junction were subjected to quantitative bone histomorphometry. In comparison to vehicle-treated control rats, the following structural changes were detected in cortical bone of vehicle-treated OVX rats: increased cortical bone tissue area, increased bone marrow area and a significant decrease in cortical width. Indices of endocortical bone formation were also significantly increased in vehicle-treated OVX rats relative to vehicle-treated control rats. Treatment with the antiresorptive agents estrogen, NE-58095 or CT prevented the decrease in cortical width in OVX rats, but failed to increase cortical bone area. In comparison to vehicle treatment of OVX rats, estrogen and CT decreased both periosteal and endocortical bone formation, whereas NE-58095 decreased endocortical, but not periosteal, bone formation. In contrast, treatment of OVX rats with PTH alone increased cortical bone area and width as well as decreased bone marrow area compared to vehicle treatment of OVX rats. The PTH-induced increase in cortical bone mass was associated with a marked increase in periosteal and endocortical bone formation. Concurrent treatment of OVX rats with PTH + estrogen, PTH + NE-58095 or PTH + CT did not have a greater anabolic effect on cortical bone than treatment with PTH alone. The results indicate that PTH, in contrast to estrogen, NE-58095 and CT, stimulates cortical bone formation and augments cortical bone mass in the tibial diaphysis of aged OVX rats. Therefore, cortical bone of aged OVX rats retains its ability to respond anabolically to PTH even during the late stages of estrogen depletion.