Millions of patients in the United States take l-thyroxine for treatment of hypothyroidism or suppression of goiters or thyroid nodules. Our recent clinical studies suggest that l-thyroxine in doses sufficient to suppress TSH may result in excessive bone resorption. In the rat there are two enzymes that convert T4 to T3. The pituitary type 2 enzyme is more effective at converting T4 to T3 than the type 1 enzyme present in liver and kidney. Since tissue T3 receptor occupancy is correlated with thyroid hormone effect it is possible that a given dose of l-thyroxine would result in higher pituitary T3 receptor occupancy and suppression of serum TSH at a time when peripheral tissues T3 receptors were unsaturated. Little information is available regarding the relative effects of the two thyroid hormones, T4 and T3, on bone. In one study, T4 and T3 were equipotent in causing bone resorption in organ culture. The relative effects or T4 and T3 on bone may have important implications for optimizing the type of thyroid hormone preparation administered to patients for replacement or suppressive therapy. The goals of this project are to use the hypothyroid rat and mouse to simultaneously characterize the effects of different combinations of T4 and T3 on bone resorption and pituitary TSH suppression, and to characterize the nature of T4 to T3 conversion in bone. These different models will be used. For in vivo studies, young rats, extensively prelabeled with 45Ca or 3H- tetracycline in utero and during the neonatal period, will receive different concentrations of thyroid hormones; bone resorption and pituitary TSH subunit mRNA concentrations will be determined in the same animals. This will determine whether serum TSH concentration is a useful index to monitor the effects of thyroid hormone on bone, and whether some thyroid hormone preparations have less effect on bone resorption than other preparations. For in vitro bone resorption studies, Ca prelabeled neonatal mouse calvaria will be used in organ culture to determine the direct effects of thyroid hormone on bone, as well as the interaction of thyroid hormones with other known mediators of bone resorption. The kinetics of T4 to T3 conversion in bone will be studied in calvaria organ culture, as well as in cell culture utilizing several human and rat osteosarcoma cell lines. This information will be useful in comparing the efficacy of different thyroid hormone preparations for TSH suppression with their potential adverse effects upon bone mineral concentration.
