I ntermittent administration of PTH has been found to be an effective anabolic agent in cancellous bone. We have reported previously that combined treatment with PTH and estrogen in estrogen-deficient rats was beneficial in correcting established osteopenia. To determine if the beneficial effects of PTH therapy can be preserved by estrogen alone and whether PTH therapy can be effective in treating osteopenic subjects stabilized with estrogen, we have undertaken a "crossover" study in the rat model of estrogen-deficiency induced osteopenia. Six-month-old female rats were ovariectomized and after 5 wk treated for 8 wk with vehicle, 30 micrograms/kg per day of rPTH(1-34) plus 15 micrograms/kg per day of 17 beta-estradiol or 17 beta-estradiol alone. One group from each treatment regimen was then sacrificed and for an additional 8 weeks the remaining rats were (a) maintained on their previous treatment; (b) "crossed over" to their reciprocal treatment; or (c) administered vehicle only. At the end of this second 8-wk treatment period all rats were sacrificed. Bone mineral density of the distal femur, histomorphometric measurements of the proximal tibia and mechanical testing of the distal femur and selected vertebral bodies were performed. Our results demonstrated that (a) the gains in bone mass, trabecular connectivity and mechanical strength induced by PTH can be maintained by estrogen alone, but are reversed when both agents are withdrawn; and (b) rats with established osteopenia, maintained on estrogen treatment alone, can derive the full beneficial effects from the addition of PTH to the treatment at a later date. These data indicate that combined and/or sequential use of antiresorptive and anabolic agents may be a promising approach to the treatment of osteoporosis.