GLUCOCORTICOIDS ALTER THE BIRTH & DEATH OF OSTEOBLASTS

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The adverse effects of hypercortisolism on bone have been recognized for over 60 years, but the precise cellular and molecular basis of these changes is still unclear and effective therapy has remained elusive. A cardinal feature of glucocorticoid-induced osteoporosis is decreased bone formation. In addition, patients receiving long-term glucocorticoid therapy sometimes develop collapse of the femoral head (osteonecrosis). Decreased bone formation and in situ death of isolated segments of the proximal femur suggest that glucocorticoid excess may alter the birth and death of bone cells. In preliminary studies leading to this application, it has been established that (1) the male Swiss Webster mouse is a valid and informative model of glucocorticoid-induced bone disease, not confounded by weight loss or sex-steroid deficiency, (2) many of the effects of chronic glucocorticoid administration on bone can be explained by decreased birth of osteoblast precursors and increased apoptosis of mature osteoblasts and osteocytes both in mice and in humans, and (3) decreased osteoblast apoptosis, rather than increased osteoblastogenesis, is the mechanism by which the intermittent administration of parathyroid hormone (PTH) stimulates bone formation - an effect that may be used to investigate the impact of glucocorticoid-induced apoptosis. To test the hypothesis that the adverse skeletal impact of glucocorticoid excess is due to a profound decrease in the birth of new osteoblast precursors in the bone marrow and an increase in apoptosis of mature osteoblasts and osteocytes, we propose to establish the temporal relationships between the changes in bone cell progenitor numbers, histomorphometry and densitometry in a murine model of long-term glucocorticoid excess. In the mouse and in archival specimens of whole femoral heads resected from patients, we will elucidate the molecular mechanisms and extent of glucocorticoid-induced apoptosis of osteoblasts and osteocytes, the correlation with the dose and duration of treatment and the relationship to osteonecrosis. The hypothesis will be further tested by intervention in the murine model with (a) alendronate, an antiresorptive agent; (b) PTH, an anabolic and anti-apoptotic agent; and (c) PTH and alendronate given concurrently to determine the efficacy of these regimens to maintain osteoblast numbers and prevent bone loss.