HORMONAL REGULATION OF BONE GROWTH IN VIVO

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Supraphysiologic doses of PTH and 1,25(OH)2D3 have been used to attempt reversal of bone loss in patients with osteoporosis, a metabolic bone disease primarily affecting older people. Little is known of how these hormones regulate bone cell activity to increase bone mass. The main aim of this research is to study regulation of bone formation by calcium regulating hormones in intact animals. We have established protocols on rats, 4-6 wks old, to increase bone growth by normocalcemic doses of hPTH 1-34 given for 12 days, and to impair mineralization and stimulate matrix formation by hypercalcemic doses of 1,25(OH)2D3 given for 18 days. We have developed methods to measure the changes in bone mass (Ca, Hyp, dry wt.) of distal femurs and the changes in bone appositional rate and forming surfaces and in mineralization rate in rat tibia metaphysis and diaphysis. To study the localized effect of hormones on bone formation in vivo, we are developing a new method of intra-arterial hormone infusion of a femur in mature rabbits, using Alzet osmotic minipumps. Changes in serum Ca, Pi, alkaline phosphatase, urea nitrogen and creatinine and in systemic growth are tested for correlation with the changes in bone. Data will be evaluated by univariate and multivariate statistical analysis. These methods will be used to determine the early effects of anabolic doses of hPTH 1-34 on bone formation and resorption; to determine if the increase in bone mass can be correlated with increased bone apposition rate and/or forming surfaces; to determine if an anabolic effect on bone can also be induced by local infusion of hPTH into the femoral arterial circulation so that local bone growth factors can be investigated and to determine if the synergistic effect of combined PTH and 1,25(OH)2D3 on bone growth can be reproduced in an animal model using older female rats. We will continue our studies of the impairment of mineralization by 1,25(OH)2D3 to determine if the undermineralized matrix will mineralize when no longer exposed to 1,25(OH)2D3 and if 25(OH)D3 or 24,25(OH)2D3, in combination with 1,25(OH)2D3, will either stimulate mineralization of the affected matrix or inhibit the 1,25(OH)2D3-induced response.