Fischer 344 rats (60/sex/group) were given daily subcutaneou s injections of recombinan t human parathyroi d hormone (PTH)(1-34) for 2 years at doses of 0, 5, 30, or 75 l g/kg. Treatment caused substantial increases in bone mass consistent with the known pharmacologi c effects of once-daily administration. As determined by quantitative computed tomography (QCT) and histomorphometr y, bone mass was markedly increased. Substantial new bone formation resulted in a large decrease in marrow space accompanie d by altered bone architecture. Bone proliferative lesions were observed in all PTH(1-34)-treated groups. Osteosarcoma occurred in 3, 21, and 31 male rats and in 4, 12, and 23 female rats in the 5-, 30-, and 75-l g/kg treatment groups, respectively. Focal osteoblast hyperplasia, osteoma, and osteoblastoma were much less frequent. Although the speci c cellular or molecular mechanisms responsible for the rat bone tumors have not been fully elucidated, the data suggest that these lesions resulted from the long duration of treatment and the exaggerated pharmacologi c response of the rat skeleton to daily treatment with PTH(1-34). Important differences between the rat study and clinical use in adult humans suggest that the increased incidence of bone neoplasia in rats treated for 2 years is likely not predictive of an increased risk of bone cancer in skeletally mature adult humans being given PTH(1-34) for a limited period of time in the treatment of osteoporosis.

A long-term study was conducted in female F344 rats to determine the relative importance of dose, treatment duration, and age at initiation of treatment on the incidence of teriparatide [rhPTH[1-34)]-induced bone proliferative lesions. Treatment groups consisted of different combinations of dose (0, 5, or 30 microg/kg/d), treatment duration (6, 20, or 24 months) and age at initiation of treatment (2 or 6 months of age). The primary endpoints were the incidence of bone neoplasms and effects on bone mass and structure as evaluated by quantitative computed tomography and histomorphometery. Significant increases in the incidence of bone tumors (osteoma, osteoblastoma, and osteosarcoma) occurred in rats treated with 30 microg/kg for 20 or 24 months. No neoplasms were found when the 5 microg/kg treatment was initiated at 6 months of age and continued for either 6 or 20 months (up to 70% of life span). This treatment regimen defined a "no-effect" dose for neoplasm formation that nevertheless resulted in substantial increases in bone mass. These results demonstrate that treatment duration and administered dose are the most important factors in the teriparatide-induced bone tumors in rats.

The International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice is a global project that is publishing criteria for both proliferative and nonproliferative changes in laboratory animals. This paper presents a set of general suggestions for terminology across systems. These suggestions include the use of diagnostic versus descriptive terms, modifiers, combination terms, and grading systems; and the use of thresholds, synonyms, and terminology for some processes that are common to several organ systems. The purpose of this paper is to help the reader understand some of the basic principles underlying the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice process.

OVX monkeys treated for 18 months with 1 or 5 g/kg/d teriparatide [PTH (1-34)] had significantly stronger proximal femora relative to ovariectomized controls. Teriparatide enhancement of cortical area, cortical width, and trabecular bone volume seemed to more than compensate for the dosedependent increase in cortical porosity. Beneficial effects of teriparatide treatment on the proximal femur persisted beyond the treatment period and may extend to the marrow. Introduction:We conducted a detailed quantitative analysis of the effects of teriparatide on the proximal femur of ovariectomized monkeys. Teriparatide increased bone mass, enhanced structural architecture, and strengthened the hip, despite increasing cortical porosity. Materials and Methods: Monkeys were treated with vehicle (sham or OVX controls), 1 g/kg/day teriparatide [parathyroid hormone (1-34); PTH1], or 5 g/kg/day teriparatide (PTH5) for 18 months or for 12 months followed by 6 months of treatment withdrawal (PTH1W and PTH5W, respectively). Excised proximal femora were analyzed by CT, conventional histomorphometry, and biomechanics. Results and Conclusions:The femoral neck showed significant reduction in trabecular bone volume (BV/TV) for OVX compared with sham, whereas PTH1 BV/TV was restored to sham levels and PTH5 BV/TV was greater than sham and OVX. The withdrawal groups had BV/TVs intermediate between sham and OVX. PTH1 had trabecular number (Tb.N) greater than OVX, and PTH5 Tb.N was greater than sham and OVX. The withdrawal groups had Tb.Ns intermediate between sham and OVX. No differences between groups were observed for trabecular orientation or trabecular thickness. Teriparatide dose-dependently increased bone formation rate and activation frequency in the femoral neck. Cellular composition analyses suggested a tendency of ovariectomy to increase adiposity of marrow by 100%, whereas PTH tended to reduce adipocyte number and increase osteoblast number compared with OVX. Analyses of the cortex showed dose-dependent elevation of cortical porosity, which was consistent with enhanced bone turnover with treatment. Cortical porosity was reduced after withdrawal of teriparatide, because PTH1W cortical porosity was lower than OVX, whereas PTH5W cortical porosity was intermediate between sham and OVX. Increased cortical porosity did not weaken the proximal femora. Biomechanics showed that ovariectomy weakened proximal femora compared with sham, but PTH1, PTH5, and PTH1W were stronger than OVX and not different from sham. PTH5W strength was intermediate between sham and OVX. Therefore, teriparatide had beneficial effects on the proximal femur, despite increasing cortical porosity. Cortical porosity did not adversely affect the mechanical integrity of the proximal femora, because enhanced cortical area and trabecular bone volume more than compensated for the porosity. Much of the beneficial effects of teriparatide were retained after 6 months withdrawal from treatment. PTH effects on the femoral neck were not limited to bone but may include i...

Abstract.Haemophilus parasuis is a common cause of polyserositis and polyarthritis in swine. Little is known about the mucosal and systemic sites of replication and lesions which follow an aerosol exposure to H. parasuis. In this experiment 5-week-old cesarean-derived, colostrum-deprived (CDCD) pigs were inoculated intranasally with an inoculum containing 2 x 10 9 colony-forming units of H. parasuis. Two principals and one control pig were necropsied at 12, 36, 84, and 108 hours postinoculation (PI) and samples obtained for bacteriologic culture and microscopic examination. Inoculated pigs developed clinical signs of inappetence, reluctance to move, lameness, and a serous nasal discharge. Macroscopic findings included a fibrinous polyserositis and polyarthritis 36 hours PI which became progressively more severe at 84 and 108 hours PI. No lung lesions were grossly visible. Microscopic lesions included a mild purulent rhinitis at each post inoculation interval and fibrinous to fibrinopurulent synovitis and serositis at 36, 84, and 108 hours PI. A focal suppurative bronchopneumonia was observed in one pig examined at 36 hours PI. The nasal cavity and trachea were the only mucosal sites from which H. parasuis was reisolated. Haemophilus parasuis was isolated from the blood and systemic sites at 36, 84, and 108 hours PI. Findings presented indicate that intranasal inoculation of 5-weekold CDCD pigs with H. parasuis results in clinical signs and lesions of polyserositis and polyarthritis typical of field cases and is a useful model for the study of H. parasuis pathogenesis. The results also suggest that H. parasuis initially colonizes the nasal mucosa.