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To evaluate the potential use of a combination of parathyroid hormone (PTH) and estrogen as therapy for osteoporosis, we examined the effects of combined and separate administration of low-dose PTH and estradiol in ovariectomized rats with established osteopenia. Ovariectomized rats were untreated for 5 weeks after surgery and then injected s.c. with vehicle (Ovx + V), 1-34 hPTH (2.5 micrograms/kg/day) (Ovx + P), 17 beta-estradiol (50 micrograms/kg/day) (Ovx + E), or a combination of these (Ovx + P + E), for a further 4 weeks. We found no differences in serum calcium, tubular reabsorption of phosphate, or 25OHD. 1,25(OH)2D levels were significantly higher in Ovx + P and lower in Ovx + E, when compared with Ovx + V. Though there was no change in bone mineral density (BMD) in the diaphysis region of femurs, reduction of BMD in the distal region of the femurs in Ovx + V was reversed in Ovx + E and Ovx + P + E. Compared with Ovx + V, Ovx + P and Ovx + P + E had significantly higher cancellous bone volume (Cn-BV/TV) whereas Ovx + E showed a nonsignificant increase. When indices of bone turnover were examined, PTH alone showed a small but not significant improvement in bone formation rate (BFR). Increased osteoclast surface (OCS), as the result of ovariectomy, was inhibited in Ovx + E and Ovx + P + E. Estrogen alone (Ovx + E) severely inhibited BFR, but co-administration of PTH and estrogen (Ovx + P + E) showed an impressive reversal of such inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)