Prostaglandin E(1) (PGE(1)) causes skeletal hypertrophy, a Phenomenon noted when it is administered for several weeks to maintain ductus arteriosus patency in neonates with congenital heart disease. This effect, a dose-dependent and reversible hyperostosis, was described radiologically as bone within bone, but skeletal histopathology was not studied. We compared postmortem gross, radiological, and histological bone findings for untreated controls and term gestation infants after 4, 27, and 56 days of continuous 0.1-0.2 mu g/kg/min PGE(1). Bone was not significantly different from controls after 4 days of PGE(1). Radiographs were negative after 27 days, but femoral colter showed early periosteal osteoblast proliferation. At 56 days of PGE(1), there was severe, radiologically apparent neocortex formation in tubular, rib and scapular bones. Corresponding sections of femoral shaft revealed distinctive histopathology with thickened periosteum and fibrocartilage-like tissue covering an exuberant neocortex of closely aligned, gracile, woven bone trabeculae. Paratrabecular stroma contained ectatic capillaries orthogonally oriented to the periosteum, suggesting that a vascular reaction to PGE(1) is important in the observed effect. The native cortex was partially resolved; because it is stress shielded by the neocortex and no inflammation was present, this was interpreted as a secondary effect. We conclude that PGE(1)-associated paracortical bone hypertrophy is distinct from inflammatory processes and that its early stage may not be apparent radiologically. Moreover, the time course of PGE(1)-induced osteoblast proliferation and mineralization suggests that experimental use for 4-8 weeks may benefit conditions such as united fractures.