The skeleton is affected by numerous primary and metastatic solid and hematopoietic malignant tumors, which can cause localized sites of osteolysis or osteosclerosis that can weaken bones and increase the risk of fractures in affected patients. Chemotherapeutic drugs can eliminate some tumors in bones or reduce their volume and skeletal-related events, but adverse effects on non-target organs can significantly limit the amount of drug that can be administered to patients. In these circumstances, it may be impossible to deliver therapeutic drug concentrations to tumor sites in bones. One attractive mechanism to approach this challenge is to conjugate drugs to bisphosphonates, which can target them to bone where they can be released at diseased sites. Multiple attempts have been made to do this since the 1990s with limited degrees of success. Here, we review the results of pre-clinical and clinical studies made to target FDA-approved drugs and other antineoplastic small molecules to bone to treat diseases affecting the skeleton, including osteoporosis, metastatic bone disease, multiple myeloma and osteosarcoma. Results to date are encouraging and indicate that drug efficacy can be increased and side effects reduced using these approaches. Despite these successes, challenges remain: no drugs have gone beyond small phase 2 clinical trials, and major pharmaceutical companies have shown little interest in the approach to repurpose any of their drugs or to embrace the technology. Nevertheless, interest shown by smaller biotechnology companies in the technology suggests that bone-targeting of drugs with bisphosphonates has a viable future.

中文翻译：

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使用双膦酸盐将抗癌剂靶向骨骼

骨骼受到许多原发性和转移性实体和造血系统恶性肿瘤的影响，这些肿瘤会导致局部骨溶解或骨硬化，从而削弱骨骼并增加受影响患者骨折的风险。化疗药物可以消除骨骼中的一些肿瘤或减少其体积和骨骼相关事件，但对非靶器官的不良反应会显着限制可以给予患者的药物量。在这些情况下，可能无法将治疗药物浓度输送到骨骼中的肿瘤部位。应对这一挑战的一个有吸引力的机制是将药物与双膦酸盐结合，这可以将它们靶向骨骼，在那里它们可以在患病部位释放。自 1990 年代以来，已经进行了多次尝试，但成功率有限。这里，我们回顾了临床前和临床研究的结果，这些研究旨在将 FDA 批准的药物和其他抗肿瘤小分子靶向骨骼，以治疗影响骨骼的疾病，包括骨质疏松症、转移性骨病、多发性骨髓瘤和骨肉瘤。迄今为止的结果令人鼓舞，表明使用这些方法可以提高药物疗效并减少副作用。尽管取得了这些成功，挑战依然存在：没有药物超越了小型 2 期临床试验，大型制药公司对重新利用其任何药物或接受该技术的方法几乎没有兴趣。尽管如此，小型生物技术公司对该技术表现出的兴趣表明，双膦酸盐药物的骨靶向具有可行的未来。