Coleman R E
Department of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Whitham Road, Sheffield, S10 2SJ, UK.
Breast Cancer. 2000;7(4):361-9. doi: 10.1007/BF02966406.
Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcaemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Pamidronate (Aredia(TM)) is the most widely evaluated bisphosphonate and is recommended for most patients with multiple myeloma or breast cancer with bone metastases. Current research aims include the evaluation of new potent bisphosphonates such as zoledronic acid (Zometa(TM)). It is hoped that this compound is not only more convenient and easier to administer but also more effective in inhibiting skeletal morbidity. Zometa may also have some direct anticancer activity. Preclinical studies with Zometa have demonstrated its potential in malignant bone disease. Clinical studies in treatment of hypercalcemia of malignancy have been completed, as have Phase I and II trials in patients with cancer and pre-existing bone metastases. Three randomized, double-blind, controlled Phase III trials are now ongoing to establish the efficacy and safety of Zometa in treatment of bone metastases in patients with osteolytic and osteoblastic lesions. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signalling mechanisms involved in cancer induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and their use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anti-cancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.
转移性骨病是肿瘤细胞与骨细胞之间多种相互作用的结果。这会导致正常骨代谢紊乱，在大多数（即便不是全部）肿瘤类型中都可见破骨细胞活性增加，这为治疗提供了一个合理的靶点。多发性骨髓瘤、乳腺癌和前列腺癌中转移性骨病的临床病程相对较长，患者在数年时间里会相继出现骨骼并发症。这些并发症包括骨痛、骨折、高钙血症和脊髓压迫，所有这些都会严重损害患者的生活质量。外照射放疗以及全身内分泌和细胞毒性治疗是晚期癌症治疗的主要手段。然而，现在很清楚，双膦酸盐提供了一种额外的治疗策略，可减轻骨受累的症状和并发症。帕米膦酸（阿可达）是评估最广泛的双膦酸盐，推荐用于大多数患有骨转移的多发性骨髓瘤或乳腺癌患者。当前的研究目标包括评估新的强效双膦酸盐，如唑来膦酸（择泰）。人们希望这种化合物不仅更方便、更易于给药，而且在抑制骨骼病变方面更有效。唑来膦酸可能还具有一些直接的抗癌活性。对唑来膦酸的临床前研究已证明其在恶性骨病中的潜力。治疗恶性肿瘤高钙血症的临床研究已经完成，针对患有癌症和已有骨转移的患者的I期和II期试验也已完成。目前正在进行三项随机、双盲、对照的III期试验，以确定唑来膦酸治疗溶骨性和成骨性病变患者骨转移的疗效和安全性。此外，基于我们对癌症诱导的骨病所涉及的细胞信号传导机制的深入了解，已开发出诸如骨保护素等新的特异性分子。这些强效分子现已进入临床试验阶段。正在进行的研究旨在确定转移性骨病中双膦酸盐的最佳给药途径、剂量、给药方案和类型，以及它们在癌症患者骨质疏松症预防和治疗中的应用。体外研究显示的直接抗癌活性以及早期乳腺癌中一些有前景的临床数据，引发了人们对双膦酸盐可能用于辅助抑制骨转移发展的极大兴趣。
