Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh EH4 2XU, UK.
Bone. 2020 Sep;138:115465. doi: 10.1016/j.bone.2020.115465. Epub 2020 Jun 5.
The first clinical use of bisphosphonates was in Paget's disease of bone (PDB) when disodium etidronate was found to be effective at suppressing metabolic activity of the disease. Subsequently, PDB became a testing ground for many bisphosphonates using changes in alkaline phosphatase (ALP) as the primary outcome measure in clinical trials. Bisphosphonates are now considered to be the treatment of choice for PDB since they are highly effective at suppressing the elevations in bone turnover that are characteristic of the disease. Short term studies have shown that treatment with alendronate and risedronate can promote formation of lamellar bone in affected sites and improve x-ray appearances in some patients. Bisphosphonates have also been shown to improve bone pain in PDB and within the bisphosphonates, zoledronic acid (ZA) is most likely to give a favourable pain response. Many patients with PDB do not have pain however, even when there is increased metabolic activity and more research is needed to find out why this is the case. The effects of bisphosphonates on complications of PDB such as deformity, pathological fractures and deafness have not been adequately studied since most clinical trials have been short term and have not collected information on these important outcomes. The PRISM and PRISM-EZ studies investigated the long-term effects of bisphosphonates in patients with established PDB using a treat-to-target approach and showed that intensive bisphosphonate therapy aimed at normalising ALP was no more effective than symptom directed treatment with bisphosphonates at preventing complications of PDB. The Zoledronate in the Prevention of Paget's Disease (ZiPP) trial, which is currently in progress, seeks to determine whether early intervention with this potent bisphosphonate might be effective in preventing disease progression. Should the ZiPP study yield positive results, genetic testing coupled to prophylactic bisphosphonate therapy might represent a new indication for these highly effective inhibitors of bone resorption in future years.
双膦酸盐的首次临床应用是在佩吉特氏病（PDB）中，当时发现依替膦酸钠可有效抑制该疾病的代谢活性。随后，PDB 成为许多双膦酸盐的试验场，使用碱性磷酸酶（ALP）的变化作为临床试验的主要终点。由于双膦酸盐在抑制疾病特征性的骨转换升高方面非常有效，因此现在被认为是 PDB 的首选治疗方法。短期研究表明，用阿伦膦酸盐和利塞膦酸盐治疗可以促进受影响部位板层骨的形成，并改善一些患者的 X 光表现。双膦酸盐还可改善 PDB 的骨痛，在双膦酸盐中，唑来膦酸（ZA）最有可能产生有利的止痛反应。然而，许多 PDB 患者没有疼痛，即使存在代谢活动增加，仍需要更多的研究来了解为什么会这样。双膦酸盐对 PDB 的并发症如畸形、病理性骨折和耳聋的影响尚未得到充分研究，因为大多数临床试验都是短期的，并且没有收集这些重要结局的信息。PRISM 和 PRISM-EZ 研究使用靶向治疗方法调查了已确诊 PDB 患者使用双膦酸盐的长期效果，结果表明，旨在使 ALP 正常化的强化双膦酸盐治疗并不比针对双膦酸盐的症状导向治疗更能预防 PDB 的并发症。正在进行的唑来膦酸预防 Paget 氏病（ZiPP）试验旨在确定这种有效的双膦酸盐早期干预是否可有效预防疾病进展。如果 ZiPP 研究产生阳性结果，那么与预防性双膦酸盐治疗相结合的基因检测可能代表未来几年这些高效骨吸收抑制剂的新适应证。
