Giant osteoclast formation and long-term oral bisphosphonate therapy.
Giant osteoclast formation and long-term oral bisphosphonate therapy.
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DOI：
10.1056/nejmoa0802633
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Manolagas SC
中科院分区：
文献类型：
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作者：
Weinstein RS;Roberson PK;Manolagas SC
双膦酸盐可减少骨吸收，通常用于治疗或预防骨质疏松症。然而，双磷酸盐对其靶细胞的影响仍然是个谜，因为在受益于治疗的患者中，破骨细胞（负责骨吸收的细胞）的数量几乎没有观察到变化（如果有的话）。我们检查了 51 份骨活检标本，这些标本是在一项为期 3 年的双盲、随机、安慰剂对照、剂量范围试验后获得的，口服阿仑膦酸钠可预防 40 至 59 岁健康绝经后妇女的骨吸收。这些患者被分配到五组中的一组：接受安慰剂 3 年的组；接受安慰剂治疗 3 年的组；阿仑膦酸钠的剂量为每天 1、5 或 10 mg，持续 3 年；或阿仑膦酸钠每天 20 毫克，持续 2 年，然后使用安慰剂 1 年。通过骨组织形态计量学方法评估福尔马林固定、未脱钙的平面切片。与安慰剂组相比，每天接受 10 mg 阿仑膦酸钠治疗 3 年的患者破骨细胞数量增加了 2.6 倍（P<0.01）。此外，破骨细胞的数量随着药物累积剂量的增加而增加（r = 0.50，P<0.001）。这些破骨细胞中有百分之二十七是具有紧邻浅表吸收腔的核固缩的巨细胞。此外，在阿仑膦酸钠治疗停止1年后，发现了具有20至40个细胞核的巨大、多核、分离的破骨细胞。根据其形态特征和原位末端标记的阳性结果，在这些大细胞中，20% 至 37% 发生凋亡。长期阿仑膦酸钠治疗与破骨细胞数量增加有关，其中包括正在经历长期细胞凋亡的独特巨大、高核、分离的破骨细胞。
Bisphosphonates decrease bone resorption and are commonly used to treat or prevent osteoporosis. However, the effect of bisphosphonates on their target cells remains enigmatic, since in patients benefiting from therapy, little change, if any, has been observed in the number of osteoclasts, which are the cells responsible for bone resorption. We examined 51 bone-biopsy specimens obtained after a 3-year, double-blind, randomized, placebo-controlled, dose-ranging trial of oral alendronate to prevent bone resorption among healthy postmenopausal women 40 through 59 years of age. The patients were assigned to one of five groups: those receiving placebo for 3 years; alendronate at a dose of 1, 5, or 10 mg per day for 3 years; or alendronate at a dose of 20 mg per day for 2 years, followed by placebo for 1 year. Formalin-fixed, undecalcified planar sections were assessed by bone histomorphometric methods. The number of osteoclasts was increased by a factor of 2.6 in patients receiving 10 mg of alendronate per day for 3 years as compared with the placebo group (P<0.01). Moreover, the number of osteoclasts increased as the cumulative dose of the drug increased (r = 0.50, P<0.001). Twenty-seven percent of these osteoclasts were giant cells with pyknotic nuclei that were adjacent to superficial resorption cavities. Furthermore, giant, hypernucleated, detached osteoclasts with 20 to 40 nuclei were found after alendronate treatment had been discontinued for 1 year. Of these large cells, 20 to 37% were apoptotic, according to both their morphologic features and positive findings from in situ end labeling. Long-term alendronate treatment is associated with an increase in the number of osteoclasts, which include distinctive giant, hypernucleated, detached osteoclasts that are undergoing protracted apoptosis.