Miller Paul D
Department of Medicine, University of Colorado Health Sciences Center & Colorado Center for Bone Research, Denver, CO 80227, USA.
Expert Opin Pharmacother. 2003 Dec;4(12):2253-8. doi: 10.1517/14656566.4.12.2253.
Bisphosphonates have been in clinical use since the first approval of etidronate for myositis ossficans progressiva. They have now been used since the early 1990s for osteoporosis. As patients are continued on bisphosphonates and with consideration for bisphosphonate application in younger postmenopausal women, questions of 'how long to treat' are emerging in the clinical community. What is the evidence for continual efficacy and safety? The longest efficacy data where a placebo group was maintained is the 5-year risedronate vertebral fracture data, which demonstrated additional fracture reduction benefit with this bisphosphonate during years 4-5 of use. As bone mineral density (BMD) or biochemical markers of bone resorption (BCM) change very little for at least 1-2 years (and possibly longer) after discontinuing long-term (3-5 years) bisphosphonate use, it seems reasonable to suggest discontinuation for some indefinite period of time after 5 years of use in younger lower-risk postmenopausal women. Monitoring of both BMD and BCM may indicate when to consider reinitiation of bisphosphonate therapy. In higher-risk elderly postmenopausal women who are doing well on long-term bisphosphonate therapy as defined by a stable BMD, height and no incident fractures, the same discussion of a 'honeymoon' period of no treatment could be entertained. However, because there are no data on fracture events post-treatment even without changing BMD or BCM, this author is reluctant to stop bisphosphonates in elderly high-risk patients. My opinion on the continuation of the use in high-risk patients is also predicated on the observations that there does not appear to be any clinically important safety issues with long-term (10-year) use. Concerns about 'oversuppression' of bone turnover and accumulation of microdamage are theoretical and, so far, have no clinical basis for discontinuation in high-risk patients. It will be important, however, for the continual surveillance of bone safety issues by capturing postmarketing fracture data in patients on long-term therapy as well as long-term bone histomorphometry and measurements of bone quality to reassure clinicans about long-term bisphosphonate continuation.
自依替膦酸首次获批用于进行性骨化性肌炎以来，双膦酸盐类药物一直在临床中使用。自20世纪90年代初以来，它们就被用于治疗骨质疏松症。随着患者持续使用双膦酸盐类药物，并且考虑到在年轻的绝经后女性中应用双膦酸盐类药物，临床界出现了“治疗多长时间”的问题。持续有效性和安全性的证据是什么？有安慰剂组的最长有效性数据是利塞膦酸盐治疗5年的椎体骨折数据，该数据表明在使用该双膦酸盐类药物的第4至5年期间，骨折减少有额外益处。在停止长期（3至5年）使用双膦酸盐类药物后，骨矿物质密度（BMD）或骨吸收生化标志物（BCM）至少1至2年（可能更长时间）变化很小，因此对于年轻的低风险绝经后女性，在使用5年后建议在一段不确定的时间内停药似乎是合理的。对BMD和BCM的监测可能会表明何时考虑重新开始双膦酸盐治疗。对于长期双膦酸盐治疗效果良好的高风险老年绝经后女性，如BMD稳定、身高未变且无新发骨折，也可以考虑关于不治疗的“蜜月期”的相同讨论。然而，由于即使不改变BMD或BCM也没有治疗后骨折事件的数据，本文作者不愿意在老年高风险患者中停用双膦酸盐类药物。我对高风险患者继续使用双膦酸盐类药物的看法还基于以下观察结果：长期（10年）使用似乎没有任何临床上重要的安全问题。对骨转换的“过度抑制”和微损伤积累的担忧是理论上的，到目前为止，在高风险患者中没有停药的临床依据。然而，通过收集长期治疗患者的上市后骨折数据以及长期骨组织形态计量学和骨质量测量来持续监测骨安全问题，对于让临床医生放心长期使用双膦酸盐类药物将很重要。
