THE DEATH OF OSTEOCYTES VIA APOPTOSIS ACCOMPANIES ESTROGEN WITHDRAWALIN HUMAN BONE

Estrogen withdrawal in women leads initially to rapid bone loss caused by increased numbers or activity of osteoclasts. We previously have n oted apoptosis of lacunar osteocytes associated with conditions of hig h bone turnover. Therefore, in this study, we investigated whether the increased bone loss associated with GnRH analogue (GnRH-a)-induced es trogen withdrawal affects osteocyte viability in situ in a way that wo uld be directly contrary to the effect of estrogens on osteoclast viab ility. Transiliac biopsies were obtained from six premenopausal women, between 30-45 yr old, diagnosed as having endometriosis. Biopsies wer e taken before and after 24 weeks of GnRH-a therapy. Biopsies were sna p-frozen and cryostat sectioned. Osteocyte viability, determined by th e presence of lactate dehydrogenase (LDH) activity, was reduced in all but one subject after treatment. Furthermore, in every subject, the p roportion of osteocytes showing evidence of DNA fragmentation typical of apoptosis increased, as demonstrated using in situ DNA nick transla tion (P = 0.008). Gel electrophoresis of extracted DNA and morphologic al studies of chromatin condensation and nuclear fragmentation confirm ed that changes typical of apoptosis were affecting the osteocytes. It was concluded that GnRH-a therapy caused a higher prevalence of dead osteocytes in iliac bone, probably caused by the increase in the obser ved proportion of osteocytes showing apoptotic changes. The capacity o f bone to repair microdamage and to modulate the effects of mechanical strain is currently believed to be dependent on osteocyte viability. Our findings have therefore revealed a possible mechanism whereby estr ogen deficiency could lead to increased bone fragility with or without an accompanying net bone loss.