【作者】 金小岚；

【导师】 孟迅吾； 周学瀛； 刘鸿瑞；

【作者基本信息】 中国协和医科大学 ， 内分泌学， 1995， 博士

【摘要】 氟主要通过刺激成骨前体细胞的增殖达到刺激骨形成，增加骨量的效应。活性维生素D₃是一种分化诱导因子，能诱导成骨前体细胞分化成熟。骨计骨学研究表明：氟治疗骨质疏松常伴有矿化缺陷和继发性甲状旁腺功能亢进（甲旁亢）的表现，提示在氟的强烈的刺激成骨作用下，有钙缺乏状态存在。因此，联合应用氟和活性维生素D₃，不仅有可能通过刺激成骨前体细胞的增殖和分化成熟两个环节，产生更大的成骨效应，还能促进肠钙的吸收，纠正氟治疗引起的钙缺乏状态，消除矿化缺陷和继发性甲旁亢，达到增加骨的力学性质和抗骨折能力的目的。 双磷酸盐是无机焦磷酸盐的类似物，它主要通过抑制破骨细胞的募集和破骨前体细胞的分化成熟，从而抑制骨吸收，降低骨转换，在骨计量学上表现为降低小梁骨的“吸收深度”和“刺激频率”，因而能减少“穿孔”吸收的发生，保护骨的的显微结构。氟虽能刺激骨的形成，但并不影响骨的转换，在高的骨转换状态下，氟治疗有可能加重骨的矿化异常，导致骨力学稳定性的破坏，因此，联合应用刺激骨形成的氟和抑制骨吸收的双磷酸盐，可能达到增加骨量，减少“穿孔”吸收，抑制骨转换，改善骨的力学性质，增加抗骨折效应的目的。 本研究，选用4 1／2月龄的健康雌性Wistar大鼠48只，随机分为六组：假手术组（Sham），去卵巢不处理组（OVX），去卵巢单用氟钙制剂处理组(0.45mgF^-+13.56mg ca⁺⁺／kg／d)（O+F），和氟钙制剂与1、25（OH）₂D₃联合处理组(0.45mgF^-+13.56mg ca⁺⁺／kg／d+135pmol 1，25（OH）₂D₃／d)（O+F+D），去卵巢单用羟乙磷酸钠处理组（1mg／kg／d）（O+EP）和氟钙制剂与羟乙磷酸钠联合用药组(0.45mgF^-+13.56mg ca⁺⁺+1mg EHDP／kg／d)。采用预防性给药方式，共给药7周。我们研究了这四种不同干预措施对胫骨干骺端次级小梁骨的骨计量学指标和股骨中段生物力学性质影响，结果发现： ①去卵巢组与假手术组比较，去卵巢组大鼠的刺激频率增加74％（P＜0.001），破骨细胞侵蚀表面增加100％（P＜0.05）。小梁骨数量减少49％（P＜0.05），小梁骨分离度增加80％（P＜0.001），而小梁骨面积减少39.4％（P＜0.05），表明去卵巢早期（7周），破骨细胞活性增加，骨转换加速，小梁骨骨量的丢失主要是由于“穿孔”吸收导致显微结构的破坏所致。 ②与OVX组比较O+F组，O+F+D组，O+EP组和O+EP+F组小更多还原

【Abstract】 Fluoride stimulates the bone formation and increases bone mass by means of stimulating mainly proliferation of osteoblast precursors. 1,25-dihydroxyvitamin D., a differentiation agent, can induces differentiation of osteoblast. A recent histomorphometric study demonstrated that fluoride treatment of osteoporosis may result in defect of mineralization and secondary hyperparathyroidism. These findings suggested that the strong stimulus for bone formation brought about by fluoride therapy led to relative calcium deficiency. Thus, use of a combination of fluoride and 1,25-dihydroxyvitamin D₃ can produced greater effect on bone formation by ttimulating both the differentiation and proliferation of osteoblast precursors. 1,25-dihydroxyvitamin D₃can promote intestinal absorption of calcium, correct calcium deficiency, eliminate the defects of mineralization and secondary hyperparathyroidism resulted from fluoride therapy. We supposed a combination of fluoride and 1,25（OH）₂D₃ treatment may increase bone mechanical strength, then enhance antifracture efficacy.Bisphosphonates are analogues of pyrophosphate. They can inhibit osteoclast-mediated resorption of bone, decrease bone turnover by inhibiting the recruitment of osteoclast and differentiation of osteoclast precursors. These effects manifest as decrease of resorption depth and activation frequency in histomorphometric analysis. By which bisphosphonate can decrease "perforation" resorption of trabeculae to protect bone microarchitecture. Althought fluoride can stimulate bone formation, but no effect on bone turnover. In high bone turnover, fluoride may aggravate defect of mineralization, lead to a destroy in mechanical stability of the skeleton,therefore, use of fluoride stimulating bone formation and bisphosphonates inhibiting bone resorption at the same time may augment bone mass, decrease "perforation" resorption, inhibit bone turnover, improve mechanical properties of bone, enhance antifracture efficacy. At present study, 48 four and a half month old virgin female Wistar rats were randomly divided into six groups: ovariectomized group （OVX）, sham-operated group, OVX treated with fluoride-Ca (0. 45ngF + 13. 56mg Ca⁺⁺/kg/d) （O+F）, OVX treated with combination of fluoride-Ca and 1, 25-dihydroxyvitamin D₃ (0. 45mgF^- + 13.56mg Ca⁺⁺/kg/d + 135pmol 1, 25（OH）₂D₃,/d), （O+F + D）, OVX treated with disodium ethane-l-hydroxy-l,1-bisphosphonate （EHDP 1mg/kg/d） （O + EP）, OVX treated with combination of EHDP and fluoride-Ca （O+EP+F）. Administration in a preventive mode lasted for seven weaks after OVX. We observed the更多还原