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 pathology report is written to convey information concerning the pathologic findings in a study. This type of report must be complete, accurate and communicate the relative importance of various findings in a study. The overall quality of the report is determined by three Quality Indicators: thoroughness, accuracy, and consistency. Thoroughness is the identification of every lesion present in a particular organ or tissue, including spontaneous background lesions. Experienced pathologists familiar with background lesions may disregard certain types of lesions or establish a threshold or a severity above which background lesions are diagnosed. Accuracy is the ability to make, and precisely communicate, correct diagnoses. Nomenclature of lesions is a matter of definition and experienced pathologists generally agree as to what terms are to be used. Consistency is the uniform use of a specific term to record a defined lesion and implies that the same diagnostic criteria are being followed for each type of diagnosis. The relative severity of nonneoplastic lesions can be recorded either semiquantitatively or quantitatively. Semiquantitative analysis involves the application of defined severity grades or ranges for specific lesions. Quantitative analysis (counts and measurements) can be performed manually or electronically, utilizing image analysis and stereological techniques to provide numerical values. When both qualitative and quantitative parameters are applied in preparation of a pathology report, the recorded pathology findings can be interpreted and put into perspective. The use of this approach assures a reader that the pathology report meets the highest standards.

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 INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the female reproductive tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. There is also a section on normal cyclical changes observed in the ovary, uterus, cervix and vagina to compare normal physiological changes with pathological lesions. A widely accepted and utilized international harmonization of nomenclature for female reproductive tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

No abstract