Intermittent administration of parathyroid hormone (PTH) peptides increases bone density in animal and human models of osteoporosis. In vitro studies have demonstrated that PTH analogs lacking the first two amino acids can stimulate cell proliferation in certain cell systems, whereas fragments with an intact N terminus can be antimitogenic. We have tested whether the truncated PTH(3-38) fragment may be a better "anabolic analog" than PTH(1-38) by monitoring bone density and biomechanical properties of the femur in 6-month-old ovariectomized (OVX) rats. Either PTH fragment was administered subcutaneously (8 micrograms/100 g of body weight) 5 days/week, for 4 weeks, starting 1 week after surgery. During the entire study, untreated OVX rats lost 12.1 +/- 4.4% of their initial bone density. PTH(1-38) reversed the initial bone loss, leading to complete restoration of presurgery values after 4 weeks of treatment. Conversely, administration of PTH(3-38) resulted in 13.2 +/- 5.8% bone loss, while continuous estrogen infusion (10 micrograms/kg/day) prevented bone loss but did not reverse it. Sham-operated animals also experienced significant bone loss in the vehicle and PTH(3-38)-treated groups (-4.5 +/- 6.7%, and -7.6 +/- 2.8%, respectively), whereas a significant gain in bone density (+4.4 +/- 5.6%) was observed in the rats treated with PTH(1-38). A bone quality factor (index of strain energy loss) and the impact strength (resistance to fracture) were 25% and 44% lower in femurs explanted from OVX animals treated with either vehicle or PTH(3-38), compared with sham-operated animals. On the contrary, no difference was observed between OVX and control animals after treatment with PTH(1-38), indicating a preservation of the capacity to withstand mechanical stress. Thus, PTH(1-38) counteracts estrogen-dependent loss of mineral density and bone biomechanical properties and increases bone density in estrogen-replete animals. An intact N terminus sequence is necessary for this anabolic action of PTH.