ORLANDO (EGMN)–Bisphosphonate therapy was associated with a reduced prevalence of cardiovascular calcification in older women but a paradoxical increased prevalence in women under age 65 years, compared with bisphosphonate nonusers in the Multi-Ethnic Study of Atherosclerosis.

Since MESA is an observational study, this novel finding has to be considered hypothesis generating rather than definitive. It remains unclear whether the unexpectedly higher prevalence of cardiovascular calcification in younger bisphosphonate users in MESA is the result of their likely shorter duration of treatment, differential drug effects, age-related differences in the pathogenesis of calcification, indication bias related to osteoporosis, or even chance, Dr. Sammy Elmariah observed at the annual scientific sessions of the American Heart Association.

Given the profound tolls that cardiovascular disease and osteoporosis take in women, replication of these new MESA findings should be sought in other large data sets, added Dr. Elmariah of Mount Sinai School of Medicine, New York.

MESA is an ongoing U.S. National Heart, Lung, and Blood Institute–funded longitudinal study of an ethnically diverse group of 6,814 men and women aged 45-84 years in six U.S. communities. All were free of cardiovascular symptoms at baseline.

Dr. Elmariah and his coworkers analyzed baseline data on bisphosphonate use and cardiovascular calcification in 3,636 participating women, 2,181 of whom were under age 65. MESA included 214 women on baseline bisphosphonate therapy. Cardiovascular calcification was assessed via multidetector row helical CT or electron-beam CT.

Among women aged 65 or older, bisphosphonate use was associated with a significantly lower prevalence of cardiovascular calcification at nearly all anatomic sites assessed.

For example, aortic valve calcification was 33% less common in the older bisphosphonate users than in nonusers in multivariate analyses adjusted for age, body mass index, ethnicity, socioeconomic variables, cardiovascular risk factors, statins, and hormone replacement therapy. Aortic valve ring calcification was 35% less common. Calcification of the mitral annulus was 46% less common in older bisphosphonate users, and thoracic aorta calcification was 32% less prevalent.

The only anatomic site where calcification wasn’t significantly less common in older bisphosphonate users than nonusers was in the coronary arteries, where the adjusted 10% reduction in favor of the bisphosphonate users fell short of statistical significance, Dr. Elmariah continued.

The story was very different in women under 65 years of age. Younger bisphosphonate users were an adjusted fourfold more likely to have aortic valve calcification than were bisphosphonate nonusers, 1.9-fold more likely to have aortic valve ring calcification, and 2.4-fold more likely to have calcification of the mitral annulus. They also had 2.2-fold and 1.2-fold increased rates of calcification of the thoracic aorta and coronary arteries, respectively. All of these differences achieved statistical significance.

When the women were grouped in 10-year age subsets, a gradual reduction in the adjusted prevalence of cardiovascular calcification accompanied increasing age among bisphosphonate users.

The increased prevalence of cardiovascular calcification in younger bisphosphonate users came as a surprise in light of the known pharmacologic actions of the nitrogen-containing bisphosphonates, according to Dr. Elmariah. He noted that the bisphosphonates have several statin-like effects stemming from their inhibition of farnesyl pyrophosphate synthase, an enzyme downstream from HMG-CoA reductase in the mevalonate pathway.

Dr. Elmariah’s work was funded by the New York Academy of Medicine, the GlaxoSmithKline Research & Education Foundation for Cardiovascular Disease, and the U.S. National Heart, Lung, and Blood Institute.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

奥兰多(EGMN) ­­——动脉粥样硬化多种族研究(MESA)表明，与没有使用双磷酸盐类药物的对照者相比，使用双磷酸盐类药物治疗的老年女性患者心血管钙化的患病率下降，但对于年龄在65岁以下的年轻女性，用药后心血管钙化的患病率反而上升。

 

在美国心脏协会2009年科学年会上，Sammy Elmariah博士指出，鉴于MESA是一项观察性研究，因此这一新发现只能视为一种假设，而非确切结论。尚不清楚MESA中接受双磷酸盐类药物治疗的年轻女性心血管钙化的患病率意外增加是否是因该年龄组的疗程可能偏短、药物效应存在差异、年龄不同导致钙化发病机理也不同或骨质疏松症相关指征偏倚所致，甚至也可能是偶然事件。

 

美国纽约西奈山医学院的Elmariah博士补充道，鉴于心血管疾病和骨质疏松症都会对女性患者的健康产生严重影响，因此应在其他大规模数据集中对这一MESA新发现进行进一步的论证。

 

MESA是一项由美国国家心肺血液研究所资助的纵向研究，目前仍在进行中。该研究纳入了来自美国6个社区的6,814例年龄在45~84岁的男性或女性，受试者来自不同的种族。基线时所有受试者均无心血管症状。

 

Elmariah博士及其同事分析了3,636例女性受试者的关于双磷酸盐类药物使用情况及心血管钙化情况的基线数据，其中，2,181例年龄小于65岁。在MESA所纳入的受试者中，基线时共有214例女性接受了双磷酸盐类药物治疗。通过多排螺旋CT或电子束CT评估受试者的心血管钙化情况。

 

在年龄≥65岁的女性受试者中，对于几乎所有被评估的解剖部位，使用双磷酸盐类药物均使心血管钙化的患病率显著下降。

 

例如，对年龄、体重指数、种族、社会经济变量、心血管危险因素、他汀类药物以及激素替代治疗等因素进行校正后，多变量分析显示，在老年女性中，使用了双磷酸盐类药物的受试者主动脉瓣钙化的患病率比没有用药者低33%，主动脉瓣环钙化的患病率低35%，二尖瓣环钙化的患病率低46%，胸主动脉钙化的患病率低32%。

 

Elmariah博士指出，在使用了双磷酸盐类药物的老年女性中，唯一一处钙化患病率并未显著低于没有用药者的解剖部位是冠状动脉，校正后用药者的患病率比没有用药者低10%，但没有达到统计学意义。

 

然而，对年龄在65岁以下的女性受试者进行的分析结果却大相径庭。校正后，使用了双磷酸盐类药物的年轻女性主动脉瓣钙化的患病率比没有用药者高4倍，主动脉瓣环钙化的患病率高1.9倍，二尖瓣环钙化的患病率高2.4倍，胸主动脉和冠状动脉钙化的患病率也分别要高2.2倍和1.2倍。上述所有差异均有统计学意义。

 

在使用了双磷酸盐类药物的女性受试者中，如果以每10岁为一个年龄段来划分亚组，校正后的心血管钙化患病率随着年龄的增加而逐渐下降。

 

Elmariah博士表示，从含氮的双磷酸盐类药物已知的药理作用来看，使用了双磷酸盐类药物的年轻女性心血管钙化的患病率反而增加的确令人意外。Elmariah博士指出，双磷酸盐类药物的多种药理效应都与他汀类药物相似，因为这两类药物均可抑制法呢基焦磷酸合酶，这种酶是甲羟戊酸途径中HMG-CoA还原酶的下游产物。

 

Elmariah博士的研究工作得到美国纽约医学会、葛兰素史克心血管疾病研究与教育基金以及美国国家心肺血液研究所的资助。

 

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