Regional trabecular bone matrix degeneration and osteocyte death in femoraof glucocorticoid-treated rabbits

Glucocorticoids at pharmacological concentrations cause osteoporosis and as eptic necrosis, particularly in the proximal femur. Several mechanisms have been proposed, but the primary events are not clear. We studied changes in the bone structure and cellular activity in femora of glucocorticoid-treat ed rabbits before the occurrence of fracture or collapse. In rabbits treate d 28 days with 4 mu mol/kg day of methylprednisolone acetate, changes in th e cortical bone were minor. However, metabolic labeling showed that bone fo rmation was virtually absent in the subarticular trabecular bone, and scann ing electron microscopy showed resorption of 50-80% of the trabecular surfa ce. Thus, reduction in bone synthesis and increased resorption were involve d in bone loss. Vascular changes, which have been hypothesized to mediate g lucocorticoid damage, were not seen, but histological changes suggested tha t trabecular bone was damaged. Matrix integrity was examined using laser sc anning confocal microscopy to detect passive tetracycline adsorption. In tr eated animals, but not controls, tetracycline was adsorbed, in a novel lame llar pattern, in 50-200 mum regions extending deep into trabeculae. This sh owed that the matrix, which is normally impervious, was exposed at these si tes. TUNEL assays showed that matrix damage correlated with cell death in t he subarticular trabecular bone of treated animals. The pattern of cell dea th involving cohorts of osteoblasts and osteocytes comprised up to half of the bone volume in affected regions and is consistent with an apoptotic mec hanism. Small numbers of TUNEL-labeled osteoblasts, but no osteocytes, were detected in control hone. We conclude that exposure of hone matrix permeab ility and that regional cell death consistent with apoptosis is an early ev ent in glucocorticoid-induced bone damage.