Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor-mediated arthritis
Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor-mediated arthritis
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DOI：
10.1002/art.20384
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发表时间：
2004-07-01
影响因子：
--
通讯作者：
Schett, G
中科院分区：
文献类型：
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作者：
Herrak, P;Görtz, B;Schett, G
Objective.破骨细胞活性增加是类风湿性关节炎（RA）骨丢失的关键因素。这表明破骨细胞靶向治疗可以有效预防RA患者的骨骼损伤。唑来膦酸（ZA）是阻断破骨细胞功能最有效的药物之一。因此，我们研究了ZA是否可以抑制与慢性炎症条件相关的骨丢失。人肿瘤坏死因子（TNF）转基因（hTNFtg）小鼠在关节炎发作时，给予磷酸盐缓冲盐水、单次或多次剂量的ZA、降钙素或抗TNF治疗，这些小鼠会发展为严重的破坏性关节炎以及骨质疏松症。滑膜炎症不受ZA的影响。相比之下，骨侵蚀被单剂量的ZA延缓（~ 60%），并且被重复施用ZA几乎完全阻断（~ 95%）。ZA治疗可部分抑制软骨损伤，并显著降低滑膜破骨细胞计数。给予ZA后，hTNFtg小鼠全身骨量显著增加，这归因于骨小梁数量和连接性的增加。此外，ZA给药后骨吸收参数显著降低。降钙素对滑膜炎症、骨侵蚀、软骨损伤或全身骨量无影响。抗TNF完全阻断滑膜炎症、骨侵蚀、滑膜破骨细胞形成和软骨损伤，但对全身骨量仅有轻微影响。ZA似乎是保护骨免受关节炎损伤的有效工具。除了它们在抗肿瘤药物治疗中的作用外，现代双膦酸盐是维持关节完整性和逆转关节炎患者全身骨丢失的有希望的候选药物。
Objective. Increased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast-targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function. We therefore investigated whether ZA can inhibit the bone loss associated with chronic inflammatory conditions.Methods. Human tumor necrosis factor (TNF)-transgenic (hTNFtg) mice, which develop severe destructive arthritis as well as osteoporosis, were treated with phosphate buffered saline, single or repeated doses of ZA, calcitonin, or anti-TNF, at the onset of arthritis.Results. Synovial inflammation was not affected by ZA. In contrast, bone erosion was retarded by a single dose of ZA (-60%) and was almost completely blocked by repeated administration of ZA (-95%). Cartilage damage was partly inhibited, and synovial osteoclast counts were significantly reduced with ZA treatment. Systemic bone mass dramatically increased in hTNFtg mice after administration of ZA, which was attributable to an increase in trabecular number and connectivity. In addition, bone resorption parameters were significantly lowered after administration of ZA. Calcitonin had no effect on synovial inflammation, bone erosion, cartilage damage, or systemic bone mass. Anti-TNF entirely blocked synovial inflammation, bone erosion, synovial osteoclast formation, and cartilage damage but had only minor effects on systemic bone mass.Conclusion. ZA appears to be an effective tool for protecting bone from arthritic damage. In addition to their role in antiinflammatory drug therapy, modern bisphosphonates are promising candidates for maintaining joint integrity and reversing systemic bone loss in patients with arthritis.