INHIBITION OF OSTEOBLASTOGENESIS AND PROMOTION OF APOPTOSIS OF OSTEOBLASTS AND OSTEOCYTES BY GLUCOCORTICOIDS - POTENTIAL MECHANISMS OF THEIR DELETERIOUS EFFECTS ON BONE

Glucocorticoid-induced bone disease is characterized by decreased bone formation and in situ death of isolated segments of bone (osteonecros is) suggesting that glucocorticoid excess, the third most common cause of osteoporosis, may affect the birth or death rate of bone cells, th us reducing their numbers. To test this hypothesis, we administered pr ednisolone to 7-mo-old mice for 27 d and found decreased bone density, serum osteocalcin, and cancellous bone area along with trabecular nar rowing. These changes were accompanied by diminished bone formation an d turnover, as determined by histomorphometric analysis of tetracyclin e-labeled vertebrae, and impaired osteoblastogenesis and osteoclastoge nesis, as determined by ex vivo bone marrow cell cultures. In addition , the mice exhibited a threefold increase in osteoblast apoptosis in v ertebrae and showed apoptosis in 28% of the osteocytes in metaphyseal cortical bone. As in mice, an increase in osteoblast and osteocyte apo ptosis was documented in patients with glucocorticoid-induced osteopor osis. Decreased production of osteoclasts explains the reduction in bo ne turnover, whereas decreased production and apoptosis of osteoblasts would account for the decline in bone formation and trabecular width. Furthermore, accumulation of apoptotic osteocytes may contribute to o steonecrosis, These findings provide evidence that glucocorticoid-indu ced bone disease arises from changes in the numbers of bone cells.