Response to letter of Vahle et al.

several important points that deserve comment. The primary objective of our paper was to report the results of a standard two-year rat carcinogenicity study conducted with recombinant full-length human PTH (1-84) to comply with international regulatory guidelines. Dr. Vahle et al. are correct that our study did not directly compare the carcinogenic potential of PTH (1-84) and PTH (1-34), that is, teriparatide. Although scientifically intriguing, such a side-by-side comparison would be unprecedented in such studies. Additionally, interpretation of the results would remain problematic because we would have had to test a synthetic PTH (1-34) as comparator and not the recombinant peptide used by Vahle et al. As clearly described in our report, we designed the PTH (1-84) study to mirror as closely as possible that of teriparatide. However, one additional key element not used by Vahle et al. was incorporated into the PTH (1-84) study. Whole-body radiographs allowed detection of bone tumors at sites not routinely sampled at necropsy because such tumors often originate in the endosteum and remain undetected unless they have breached the periosteum. This key element increased the sensitivity to detect bone tumors and increased confidence in the study results. Thus, despite the detection of additional tumors with this procedure, fewer tumors were still observed with PTH (1-84) than with teriparatide. The initial report by Vahle et al. (Toxicol Pathol 30: 312–321, 2002) did an excellent job of establishing diagnostic criteria to categorize hyperplastic, benign, and malignant proliferative findings in bones and greatly facilitated the classification of skeletal changes induced by PTH (1-84). Thus, we are confident that very similar criteria were used for the bone tumors in our study. Importantly, this concept was supported by our pathology assessment validated by peer review, which noted a similar incidence, skeletal distribution, and histological appearance of other bone tumors (osteoblastoma and osteoma) with the mid and high doses of PTH (1-84) and teriparatide. We believe that our report contains sufficient information for the reader to understand that there exists the potential for differences in animals and pathological interpretation. noted that the pharmacodynamic effects on bone of the two peptides are critical in interpreting the results. In vivo studies that have directly compared the effects of PTH (1-84) and teriparatide in bone are unusual, but when they have been performed, teri-paratide tends to be an equivalent or slightly more potent ana-bolic agent in rats. PTH (1-84) did not increase bone …