Skeletal maintenance during normal bone remodeling requires balance between the number of mature osteoclasts and osteoblasts that implement the remodeling process. Such balance is determined by the frequency of division of the appropriate precursors and the life span of their progeny, reflecting the timing of death by apoptosis (34
). The results of the present short-term studies demonstrate that 10 days of glucocorticoid administration increases osteoclast numbers despite decreased osteoclast production, most likely by decreasing osteoclast apoptosis. This effect is temporally linked with loss of BMD. Moreover, our results indicate that glucocorticoids antagonize the proapoptotic effect of bisphosphonates on osteoclasts. The mechanism underlying this antagonism involves inhibition of alendronate-induced activation of caspase-3, the major effector caspase activated in osteoclasts undergoing apoptosis following exposure to nitrogen-containing bisphosphonates (35
). In addition, we have shown that alendronate stimulates activation of caspase-8 and caspase-9 and that this activation is also antagonized by dexamethasone. Furthermore, the inhibitory effect of dexamethasone is mediated by the glucocorticoid receptor as revealed by full blockade of the inhibition with RU 486.
At any time during the excavation of an erosion bay, the number of resident osteoclasts depends both on the number initially assembled on the activated bone surface and on the number that have so far escaped death by apoptosis. Each osteoclast has only a temporary existence, and continuing bone resorption requires the uninterrupted arrival of new preosteoclasts from the circulation (36
). Based on dynamic histomorphometry of the murine vertebral secondary spongiosa, we calculated that the mean active life span of an osteoblast on cancellous bone is about 12 days (20
). In humans, the ratio of the life span of an osteoclast to that of an osteoblast is 21 days/90 days (36
). From these calculations, we estimate that the mean active life span of a murine osteoclast is about 3 days. This estimate is consistent with our conclusion that an increase in the number of cancellous osteoclasts after 10 days of glucocorticoid administration, despite a reduction in osteoclastogenesis, could only result from prolongation of osteoclast life span. Our estimate may have a higher margin of error than would be ideal, but the increase in cancellous osteoclast numbers in spite of decreased production of osteoclast progenitors after 10 days of glucocorticoid administration strongly indicates an increase in osteoclast life span. Our observations are also consistent with our earlier findings of a doubling of the osteoclast perimeter by day 7 of glucocorticoid administration (20
). By day 10, these events, although beginning to wane, still result in a greater than 20-fold increase in the ratio of osteoclasts to osteoblasts and in loss of BMD (Figure ).
We have found previously that administration of alendronate with prednisolone prevented loss of BMD after 8 weeks (18
). In the present experiment, 10 days of alendronate did not prevent glucocorticoid-induced loss of BMD or decrease the number of cancellous osteoclasts, but it did protect osteoblasts from glucocorticoid-induced apoptosis. These findings are consistent with the evidence obtained in the rat that even though hydrocortisone and dexamethasone inhibit osteoclast recruitment, they stimulate bone resorption by existing osteoclastic cells (37
). Furthermore, corticosterone has been shown to cause a transient increase in osteoclast number and bone resorption in cultures of fetal rat parietal bones (38
If the initial increase in bone resorption is due to prolongation of osteoclast life span, which is refractory to bisphosphonates, how do these agents prevent bone loss and reduce bone turnover in glucocorticoid-treated patients? In most clinical studies, the earliest measurements are made at 3–6 months after initiation of treatment (11
), so that very early bone loss could have escaped detection. Nevertheless, the mechanism of the bone protection requires explanation. The impact of the antiapoptotic effect of glucocorticoids on osteoclasts might wane with time because of the fall in osteoclastogenesis. Eventually the proapoptotic effect of bisphosphonates may become more important. According to this scenario, bone turnover is already reduced in glucocorticoid-treated patients, but further reduction by bisphosphonates would contribute to the bone-sparing effect (11
). However, we propose that the most important effect is the prolongation of osteoblast life span by bisphosphonates, so that even if total body bone formation remained depressed, focal bone formation relative to resorption could be increased.
In conclusion, the demonstration that glucocorticoids prevent osteoclast apoptosis in vitro and in vivo and that this protection cannot be thwarted by bisphosphonate treatment explains the early increase in bone resorption. Glucocorticoids increase osteoclast life span and bisphosphonates decrease it; in the short-term, the glucocorticoid effect outweighs that of the bisphosphonate, but in the long term the balance may be reversed as the decimated osteoclastogenesis fails to supply new osteoclasts. The long-term beneficial effects of bisphosphonates on bone mass may be at least partly due to postponing apoptosis and thus prolonging osteoblast life span.