SIMULTANEOUS BLOCK OF INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR IS REQUIRED TO COMPLETELY PREVENT BONE LOSS IN THE EARLY POSTOVARIECTOMY PERIOD

Considerable evidence supports the hypothesis that estrogen prevents b one loss by blocking the production of cytokines in bone or bone marro w. However, controversy remains on the role of candidate factors, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF). As IL -1 and TNF have many additive and/or synergistic effects in hone, we t ested the hypothesis that the simultaneous block of IL-1 and TNF is re quired to prevent the initial phase of rapid bone loss that follows ov ariectomy (ovx). To this aim, rats were ovariectomized and treated for 2 weeks with either IL-1 receptor antagonist (IL-1ra), an inhibitor o f IL-1, or TNF-binding protein (TNFbp), an inhibitor TNF. Ovx increase d bone marrow cell secretion of IL-1 and TNF and decreased the bone de nsity of the distal femur, as measured by dual energy x-ray absorptiom etry. Ovx-induced bone loss was decreased by both IL-1ra and TNFbp and completely prevented by simultaneous treatment with IL-1-1ra and TMFb p. Combined treatment with IL-1ra and TNFbp decreased urinary pyridino line cross-links, a marker of bone resorption that reflects osteoclast number and osteoclast activity, whereas treatment with either inhibit or alone was less effective. Both IL-1ra and TNFbp decreased the numbe r of osteoclasts on the endocortical surfaces and stimulated bone form ation, but the two inhibitors had no additive effects on these indexes , suggesting that inhibition of osteoclastogenesis and stimulation of bone formation do not account for the additive bone-sparing effects of IL-1ra and TNFbp. These inhibitors had no effect in sham-operated rat s, indicating that they specifically blocked estrogen-dependent events . In conclusion, these data indicate that in the early post-ovx period , IL-1 and TNF play a critical causal role in inducing bone loss and d o so by stimulating bone resorption and inhibiting bone formation.