Histomorphometry and biochemical markers of bone turnover have shown that, although osteoclast activity is increased in multiple myeloma (MM), mostly through the receptor activator of nuclear factor-kappaB ligand/osteoprotegerin axis, the key element in vivo to determine the presence or absence of osteolytic lesions resides on the presence and activity of osteoblasts. The loss of bone observed in MM is the result of an uncoupling of bone formation and bone resorption. Bortezomib is a first-in-class proteasome inhibitor developed as an antineoplastic agent with marked activity in relapsed/refractory MM. Response to bortezomib has been related to a significant increase in alkaline phosphatase (ALP). Increased ALP in patients responding to bortezomib was associated with a parallel increase in bone-specific ALP and parathyroid hormone, suggesting that response to bortezomib in MM is closely associated with osteoblastic activation. Variation in markers of osteoblastic activation (such as ALP) have also predicted response and response duration in patients with myeloma treated with bortezomib (P < 0.0001). This clinical observation has been confirmed in an experimental mouse model for primary human myeloma. The consequences of increased bone anabolism on myeloma growth need to be closely evaluated in prospective trials.

译文

骨转换的组织形态计量学和生化标志物表明,尽管破骨细胞活性在多发性骨髓瘤 (MM) 中增加,但主要是通过核因子-kappaB配体/骨保护素轴的受体激活剂,体内确定是否存在溶骨性病变的关键因素在于成骨细胞的存在和活性。在MM中观察到的骨丢失是骨形成和骨吸收解偶联的结果。硼替佐米是一流的蛋白酶体抑制剂,被开发为抗肿瘤药,在复发/难治性MM中具有显着活性。对硼替佐米的反应与碱性磷酸酶 (ALP) 的显着增加有关。对硼替佐米有反应的患者的ALP增加与骨特异性ALP和甲状旁腺激素的平行增加有关,这表明MM对硼替佐米的反应与成骨细胞激活密切相关。成骨细胞活化标志物 (如ALP) 的变化也预测了用硼替佐米治疗的骨髓瘤患者的反应和反应持续时间 (P <0.0001)。此临床观察已在原发性人类骨髓瘤的实验小鼠模型中得到证实。需要在前瞻性试验中仔细评估骨合成代谢增加对骨髓瘤生长的影响。

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