PATHOGENESIS OF OSTEOPOROSIS IN OLDER WOMEN

骨质疏松症是老年妇女的主要健康问题。虽然所有绝经后妇女都缺乏雌激素，但只有一些人会患上骨质疏松症；许多绝经后妇女有很高的骨转换率和骨质流失。我们发现，绝经后的老年妇女骨量和骨转换率的变化范围很广，而根据血清和尿液生化指标的估计，骨转换的增加与骨量的减少和骨质流失的增加有关。此外，我们已经证明，雌激素在这一人群中显著抑制骨吸收，雌激素降低活组织标本中骨转换的形态学指标激活频率的作用与骨吸收生化标志物的基线水平呈负相关。我们计划检验关于细胞因子在骨质疏松发病机制中的作用的两个相关假设。首先，老年雌激素缺乏妇女的骨转换和骨量的变化是由于局部细胞因子产生的差异。虽然有几种细胞因子与绝经后骨质疏松症有关，但我们将重点关注白介素-1系统，包括白介素-1（、白介素-1）、白介素-1受体拮抗剂、白介素-1受体1和白介素-1受体2。我们假设老年妇女的高骨转换和低骨量与IL-1活性呈正相关。第二个假设是雌激素调节骨中局部细胞因子的产生，骨中局部细胞因子产生的差异解释了对雌激素反应的变异性。我们假设，目前使用雌激素的老年妇女在基线时停用雌激素时IL-1活性会增加，重新引入雌激素时IL-1活性会降低，并且变化的幅度将与骨转换和骨量的变化相关。

Osteoporosis is a major health concern for older women. Although all postmenopausal women are estrogen-deficient, only some develop osteoporosis; many postmenopausal women have high rates of bone turnover and bone loss. We have found that older postmenopausal women have a wide range of bone mass and rates of bone turnover and that increased turnover, as estimated by serum and urine biochemical markers, is associated with lower bone mass and greater rates of bone loss. In addition, we have shown that estrogen markedly inhibits bone resorption in this population and that the effect of estrogen to decrease activation frequency, a morphologic indicator of bone turnover in biopsy specimens, is inversely correlated with baseline levels of biochemical markers of bone resorption. We plan to test two related hypotheses regarding the role of cytokines in the pathogenesis of osteoporosis. The first is that the variability in bone turnover and bone mass seen in older estrogen-deficient women is due to differences in local cytokine production. Although several cytokines have been implicated in postmenopausal osteoporosis, we will focus on the interleukin-1 system, including interleukin-1(, interleukin-1(, interleukin-1 receptor antagonist, interleukin-1 receptor 1, and interleukin-1 receptor 2. We hypothesize that high bone turnover and low bone mass will be positively correlated with IL-1 activity in older women. The second hypothesis is that estrogen modulates local cytokine production in bone and that differences in local cytokine production in bone explain the variability in response to estrogen. We hypothesize that IL-1 activity will increase when estrogen is withdrawn from older women who are current estrogen users at baseline and that IL-1 activity will decrease when estrogen is re-introduced and that the magnitude of the changes will be correlated with changes on bone turnover and bone mass.