停用双膦酸盐后每年监测不能预测骨折

《美国医学会杂志·内科》5月5日在线发表的一项研究显示，对于停止双膦酸盐类药物治疗的女性，可以在停药时通过检测骨密度加以评估，但后续定期监测的预测价值似乎很有限（doi:10.1001/jamainternmed.2014.1232）。

加州大学旧金山分校的Douglas Bauer博士及其同事分析了大约1000名年龄61~86岁、接受了4~5年阿仑膦酸钠治疗的绝经后女性的数据。这些女性参加了一项试验，随机分组后额外接受5年阿仑膦酸钠治疗或使用安慰剂。

在437名接受安慰剂治疗的女性中，22%（n=94）在随访期间发生了1次或多次骨折。研究者在基线、1年和3年时通过双能X线吸收测定仪（DXA）检测了受试者的髋部和颈部骨密度，并且对骨转换标志物（BTMs）进行了分析。

结果显示，1年时髋部DXA改变和1或3年时BTM水平变化均与骨折风险无关。仅有停止治疗时的年龄和髋部骨密度较低可显著预测骨折。基线时髋部骨密度处于最低三分位数者的相对风险比为1.87（95%可信区间平[CI]：1.20~2.92），基线时年龄每增加5岁的相对风险比为1.54（95%CI：1.26~1.85）。

研究者指出，很多专家推荐在停用双膦酸盐类药物之后每年监测，然而该研究结果提示此类监测并不能预测骨折。“这些个体测量指标的短期变化与停药后骨折风险无关，这多少有些令人惊讶。”

研究者提醒，正在考虑治疗5年后暂时停药的临床医生和患者应意识到，“与停药时年龄和骨密度检测值相比，旨在找出风险较高、可能应恢复双膦酸盐治疗或启动其他治疗者的短期监测，或许并无额外的风险预测价值”。

Bauer博士承认，这项研究的局限性包括，观察到的骨折例数相对较少因而降低了其统计学效力，以及仅使用一种双膦酸盐类药物。

研究者没有接受外部资助，不过其研究结果来源于对FLEX试验安慰剂组的分析。这项由药企资助的试验在一个接受了5年阿仑膦酸治疗的女性队列中，对延长阿仑膦酸钠治疗和安慰剂进行了对比（JAMA 2006;296:2927-38）。Bauer博士报告称没有与该研究相关的利益冲突；其他研究者披露称与安进、葛兰素史克、默克、诺华、奈科明和礼来等公司存在利益关系。

相关评论：这项研究令人信服

在我们更了解如何开始而非如何停止阿仑膦酸钠治疗的这个时代，Bauer博士及其同事的研究结果提示，能最好地识别停止治疗后骨折风险高的患者的，是停止治疗时的骨密度检测值而非停止治疗后短期频繁监测到的骨密度值或骨转换标志物水平。

这项研究令人信服，因为它依赖于临床骨折结局而不是诸如骨密度下降或骨转换标志物水平变化等替代指标。未来研究的持续时间应更长，以积累更多有关停用双膦酸盐后远期骨折发生率预测因素的证据，并为序贯治疗试验确定基于结局的双膦酸盐洗脱期。

评论作者：Margaret L. Gourlay博士供职于北卡罗来那大学家庭医学部，Kristine E. Ensrud博士供职于明尼苏达大学公共卫生学院。Ensrud博士披露称与默沙东存在顾问关系。他们的评论摘自一篇随刊述评（JAMA Intern. Med. 2014 May 5 [doi:10.1001/jamainternmed.2014.162]）。

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By: JENNIE SMITH, Ob.Gyn. News Digital Network

Fracture risk in women who discontinue therapy with bisphosphonates can be assessed by measuring bone mineral density at the time of discontinuation, but subsequent frequent monitoring appears to have little predictive value, according to researchers.

The findings were published online May 5 in JAMA Internal Medicine (doi:10.1001/jamainternmed.2014.1232).

Dr. Douglas Bauer of the University of California, San Francisco, and his colleagues looked at data from a trial of about 1,000 postmenopausal women aged 61-86 who had been treated for 4-5 years with alendronate and were randomized to an additional 5 years of alendronate treatment or placebo.

Among the 437 women assigned to placebo, 22% (n = 94) experienced one or more fractures during follow-up. Hip and neck BMD were assessed via dual-energy x-ray absorptiometry (DXA) at baseline and at 1 and 3 years, and bone turnover markers (BTMs) were also analyzed.

Neither 1-year changes in hip DXA nor 1- or 3-year changes in BTM levels were associated with fracture risk. Only age and lower hip BMD at the time of treatment discontinuation were significantly predictive of fracture, according to Dr. Bauer and his associates.

The relative hazard ratio was 1.87 (95% confidence interval, 1.20-2.92) for fracture risk in lowest tertile of baseline hip BMD, and 1.54 (95% CI, 1.26-1.85) per 5-year increase in age.

Yearly monitoring – recommended by many experts after discontinuation of bisphosphonates – should not be considered predictive of fractures, the researchers noted. It was "somewhat surprising that short-term changes in these individual measurements are not associated with fracture risk after discontinuation," they wrote.

The researchers cautioned clinicians and patients contemplating a drug holiday after 5 years of treatment to "be aware that short-term monitoring to detect individuals at higher risk who might resume bisphosphonate therapy, or initiate another therapy, may not add to risk prediction over and above age and BMD measured at the time of discontinuation."

The study’s limitations include its relatively small number of fractures observed, reducing its statistical power, and the use of a single bisphosphonate medication, Dr. Bauer acknowledged.

The researchers received no outside funding, though their findings were derived from an analysis of the placebo group of the FLEX trial, a manufacturer-sponsored study comparing extended alendronate sodium treatment with placebo in a large cohort of women treated 5 years on alendronate (JAMA 2006;296:2927-38).

Dr. Bauer reported no conflicts of interest related to the study; other study authors disclosed financial relationships with Amgen, GlaxoSmithKline, Merck, Novartis, Nycomed, and Eli Lilly.

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The study is convincing

In an era when we know much more about how to start than how to stop alendronate therapy, the results of Bauer and colleagues suggest that identification of patients at high risk of fracture after treatment discontinuation is best accomplished by BMD measurement at the time of discontinuation rather than frequent short-term monitoring with BMD or bone turnover marker measurements after treatment discontinuation.

The study is convincing because of its reliance on a clinical fracture outcome rather than surrogate measures such as rates of BMD loss or changes in bone turnover marker levels. Future studies should be longer in duration to accumulate more evidence regarding predictors of long-term fracture incidence after bisphosphonate withdrawal and to identify an outcomes-based bisphosphonate washout period for trials of sequential therapy.

Dr. Margaret L. Gourlay is in the department of family medicine at the University of North Carolina, Chapel Hill, and Dr. Kristine E. Ensrud is in the school of public health at the University of Minnesota, Minneapolis. Dr. Ensrud disclosed a consulting relationship with Merck Sharp &Dohme. Their comments were taken from an editorial (JAMA Intern. Med. 2014 May 5 [doi:10.1001/jamainternmed.2014.162]).