Bisphosphonates Inhibit Pain, Bone Loss, and Inflammation in a Rat Tibia Fracture Model of Complex Regional Pain Syndrome.
Bisphosphonates Inhibit Pain, Bone Loss, and Inflammation in a Rat Tibia Fracture Model of Complex Regional Pain Syndrome.
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DOI：
10.1213/ane.0000000000001518
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发表时间：
2016-10
影响因子：
5.7
通讯作者：
Kingery WS
中科院分区：
文献类型：
--
作者：
Wang L;Guo TZ;Hou S;Wei T;Li WW;Shi X;Clark JD;Kingery WS
二膦酸盐用于预防骨质疏松症、骨转移、多发性骨髓瘤和畸形成骨细胞相关的骨丢失和骨折。远端肢体骨折导致局部骨丢失，并伴有受伤肢体的皮肤炎症和疼痛，可发展为复杂性局部疼痛综合征（CRPS）。临床试验已经报道，抗吸收双膦酸盐可以预防骨质疏松引起的骨丢失，抑制血清炎性细胞因子水平，并减轻CRPS疼痛。以前，我们观察到抑制炎性细胞因子或适应性免疫反应减弱了CRPS大鼠骨折模型中疼痛行为的发展，我们假设双膦酸盐可以预防疼痛行为，骨小梁丢失，骨折后皮肤细胞因子上调，以及CRPS模型中的适应性免疫反应。大鼠经历胫骨骨折和石膏固定4周，并长期皮下灌注阿仑膦酸钠或口服唑来膦酸钠。行为测量包括后爪von Frey异常性疼痛、减重、发热和水肿。通过uCT测量骨微结构，通过静态和动态组织形态计量学评价骨细胞活性。脊髓Fos免疫组化染色，EIA法测定皮肤细胞因子（TNF、IL-1、IL-6）和神经生长因子（NGF）的含量。EIA法测定皮肤和坐骨神经免疫球蛋白水平。胫骨骨折大鼠发生后爪异常性疼痛、失重、发热和水肿，脊髓Fos表达增加，腰椎和双侧股骨远端骨小梁丢失（通过uCT测量），骨小梁吸收和破骨细胞表面增加，骨形成率降低，皮肤炎性细胞因子和NGF表达增加，皮肤和神经中免疫复合物沉积增加。阿仑膦酸钠（60 μg/kg/天s.c.）或唑来膦酸盐（3 mg/kg/天p.o.）治疗28天，在骨折时开始，完全抑制后爪异常性疼痛的发展，并分别使后爪失重减少44 ± 13%和58 ± 5%。在骨折后4周开始，口服唑来膦酸盐（3 mg/kg/天，持续21天）治疗也完全逆转了已建立的异常性疼痛和体重减轻。组织形态学和uCT分析表明，3和60 μg/kg/天阿仑膦酸钠治疗逆转了骨小梁丢失（同侧股骨远端BV/TV分别增加88 ± 25%和188 ± 39%），并阻止了在骨折大鼠双侧股骨远端和L5椎骨中观察到的破骨细胞数量和侵蚀表面的增加。阿仑膦酸钠治疗抑制了骨折诱导的后爪炎症介质的增加，使骨折后TNF水平降低43 ± 9%，IL-1降低60 ± 9%，IL-6降低56 ± 14%，NGF降低37 ± 14%，但对脊髓Fos表达增加或皮肤和坐骨神经免疫复合物沉积没有影响。总的来说，这些结果表明，双膦酸盐治疗抑制疼痛，破骨细胞活化，小梁骨丢失，和皮肤炎症大鼠骨折模型的CRPS，数据支持的假设，双膦酸盐治疗可以提供有效的多模式治疗CRPS。
Bisphosphonates are used to prevent the bone loss and fractures associated with osteoporosis, bone metastases, multiple myeloma, and osteogenis deformans. Distal limb fractures cause regional bone loss with cutaneous inflammation and pain in the injured limb that can develop into complex regional pain syndrome (CRPS). Clinical trials have reported that anti-resorptive bisphosphonates can prevent fracture-induced bone loss, inhibit serum inflammatory cytokine levels, and alleviate CRPS pain. Previously we observed that the inhibition of inflammatory cytokines or adaptive immune responses attenuated the development of pain behavior in a rat fracture model of CRPS and we hypothesized that bisphosphonates could prevent pain behavior, trabecular bone loss, post-fracture cutaneous cytokine up-regulation, and adaptive immune responses in this CRPS model. Rats underwent tibia fracture and cast immobilization for 4 weeks and were chronically administered either subcutaneously perfused alendronate or oral zoledronate. Behavioral measurements included hindpaw von Frey allodynia, unweighting, warmth, and edema. Bone microarchitecture was measured by uCT and bone cellular activity was evaluated by static and dynamic histomorphometry. Spinal cord Fos immunostaining was performed and skin cytokine (TNF, IL-1, IL-6) and nerve growth factor (NGF) levels were determined by EIA. Skin and sciatic nerve immunoglobulin levels were determined by EIA. Tibia fracture rats developed hindpaw allodynia, unweighting, warmth, and edema, increased spinal Fos expression, trabecular bone loss in the lumbar vertebra and bilateral distal femurs as measured by uCT, increased trabecular bone resorption and osteoclast surface with decreased bone formation rates, increased cutaneous inflammatory cytokine and NGF expression and elevated immunocomplex deposition in skin and nerve. Alendronate (60 μg/kg/day s.c.) or zoledronate (3 mg/kg/day p.o.) treatment for 28 days, started at the time of fracture, completely inhibited the development of hindpaw allodynia and reduced hindpaw unweighting by 44 ± 13% and 58 ± 5%, respectively. Orally administered zoledronate (3 mg/kg/day for 21 days) treatment also completely reversed established allodynia and unweighting when started at 4-weeks post-fracture. Histomorphometric and uCT analysis demonstrated that both the 3 and 60 μg/kg/day alendronate treatments reversed trabecular bone loss (a 88 ± 25% and 188 ± 39% increase in the ipsilateral distal femur BV/TV, respectively) and blocked the increase in osteoclast numbers and erosion surface observed in bilateral distal femurs and in L5 vertebra of the fracture rats. Alendronate treatment inhibited fracture-induced increases in hindpaw inflammatory mediators, reducing post-fracture levels of TNF by 43 ± 9%, IL-1 by 60 ± 9%, IL-6 by 56 ± 14%, and NGF by 37 ± 14%, but had no effect on increased spinal cord Fos expression, or skin and sciatic nerve immunocomplex deposition. Collectively, these results indicate that bisphosphonate therapy inhibits pain, osteoclast activation, trabecular bone loss, and cutaneous inflammation in the rat fracture model of CRPS, data supporting the hypothesis that bisphosphonate therapy can provide effective multimodal treatment for CRPS.