Bortezomib (Btz) is a proteasome inhibitor approved by the FDA to treat multiple myeloma. It also increases bone volume by promoting osteoblast differentiation and inhibiting osteoclastogenesis in mice. However, Btz has severe systemic adverse effects, which would limit its use as a bone anabolic agent. Here, we designed and synthesized a bone-targeted form of Btz by conjugating it to a bisphosphonate (BP) with no antiresorptive activity. We report that BP-Btz inhibited osteoclast formation and bone resorption and stimulated osteoblast differentiation in vitro similar to Btz. In vivo, BP-Btz increased bone volume more effectively than Btz in three mouse models: untreated wild-type mice, mice with ovariectomy, and aged mice with tibial factures. Importantly, BP-Btz had significantly less systemic side effects than Btz, including less thymic cell death, sympathetic nerve damage, and thrombocytopenia, and it improved survival rates in aged mice. Thus, BP-Btz represents a novel anabolic agent to treat conditions, such as postmenopausal and age-related bone loss. Bone targeting is an attractive approach to repurpose approved drugs to treat skeletal diseases. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

中文翻译：

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将硼替佐米靶向骨骼可增加其骨骼合成代谢活性并减少小鼠的全身不良反应。

硼替佐米（Btz）是 FDA 批准用于治疗多发性骨髓瘤的蛋白酶体抑制剂。它还通过促进小鼠成骨细胞分化和抑制破骨细胞生成来增加骨量。然而，Btz 具有严重的全身不良反应，这将限制其作为骨合成代谢剂的用途。在这里，我们通过将 Btz 与不具有抗再吸收活性的双膦酸盐 (BP) 缀合，设计并合成了一种骨靶向形式的 Btz。我们报道，与 Btz 类似，BP-Btz 在体外抑制破骨细胞形成和骨吸收并刺激成骨细胞分化。在体内，BP-Btz 在三种小鼠模型中比 Btz 更有效地增加骨量：未经治疗的野生型小鼠、卵巢切除小鼠和患有胫骨骨折的老年小鼠。重要的是，BP-Btz 的全身副作用明显少于 Btz，包括较少的胸腺细胞死亡、交感神经损伤和血小板减少，并且提高了老年小鼠的存活率。因此，BP-Btz 代表了一种新型合成代谢药物，用于治疗绝经后和与年龄相关的骨质流失等疾病。骨靶向是重新利用已批准药物治疗骨骼疾病的一种有吸引力的方法。© 2019 美国骨与矿物质研究学会。© 2019 美国骨与矿物质研究学会。