维生素K2及其联合维生素D3对去卵巢大鼠骨及骨外的影响
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摘要
研究背景随着人口老龄化进展,骨质疏松症患者日趋增多。由于女性峰骨量较低,绝经后雌激素水平显著下降,骨丢失加速,因此绝经后女性是骨质疏松症和骨质疏松性骨折的高危人群。尽管雌激素治疗是预防绝经后骨质疏松的最佳选择之一,但长期应用存在一定风险,中国的绝经妇女亦未普遍接受。维生素D(vitamin D,VD)作为防治骨质疏松症的基础用药已普遍为患者接受,但单一用药作用有限。研究发现维生素K(vitamin K,VK)除凝血功能之外,尚能促进骨形成、抑制骨吸收,能够防治骨质疏松症。在理论上,VK与VD联合使用具有协同或增强效应。此外,VK2可以预防血管钙化,降低心血管病的发生率。目前的研究结果未发现用于骨质疏松防治剂量的VK2对凝血系统的不利影响,安全性较好。
目的观察VK2及其与维生素D3联合应用对去卵巢大鼠骨质疏松模型的预防效果,同时观察其对血管钙化、血脂和凝血系统的影响,为VK2预防绝经后骨质疏松症提供实验证据。
方法模拟人绝经后骨质疏松的动物模型:选择37只SPF级10月龄雌性SD大鼠,按体重随机分为5组:假手术组(Sham)(8只)、去卵巢组(OVX)(8只)、OVX+VK2组(7只)、OVX+VD3组(VD3)(7只)及OVX+VK2+VD3组(7只)。双侧卵巢切除术后2周进行药物灌胃,VK2剂量为30mg/kg/d、VD3剂量为0.1ug/kg/d,Sham组及OVX组喂以净化水2.5ml/kg/d。14周后进行骨密度、骨转换指标、骨组织计量学和骨生物力学测定,并检测血脂、凝血指标,组织学观察胸主动脉的钙化情况。
结果对骨的影响:(1)骨转换指标:OVX组BALP和uDPYD显著升高。与OVX组比较,VK2组uDPYD和uCa/uCr明显增加。VD3组BALP明显降低,VK2+VD3组各项指标和OVX组比较无明显变化。与sham组相比,VK2组uDPYD显著升高。VK2和VD3对uDPYD的作用存在交互效应。(2)骨密度(BMD):OVX组腰椎BMD显著低于sham组和各用药组;用药组腰椎BMD与sham之间没有明显差异。与OVX组相比,VD3组左侧股骨、VD3+VK2组和Sham组双侧股骨BMD显著升高。与sham组比较,VK2组双侧股骨BMD明显降低,而VD3组和联合用药组较之无明显差异。VK2+VD3组与VK2组相比,其右侧股骨BMD较之明显升高。(3)骨组织形态计量学:OVX组的骨形成参数和骨吸收参数均高于sham组,其中%L.Pm与sham组有统计学差异。OVX组较sham组的骨小梁数量减少,厚度变薄,分离度增加,但无统计学意义。各用药组与OVX组比较,VK2+VD3组和VD3组的骨小梁形成参数增高,其中BFR/BS和MAR的差异有统计学意义;VK2组骨形成参数和OVX组相似。各用药组的骨吸收参数及骨量和骨结构参数与OVX组比较亦无明显差异。VK2+VD3组与VK2组相比,MAR和BFR/BS显著升高;而%E.Pm显著下降。骨量和骨结构参数值在各用药组之间无明显差异。各用药组与sham组相比,骨形成参数值均升高,尤其以VD3组和VK2+VD3组更为显著,此两组的%L.PM、MAR和BFR/BS均与Sham组有统计学差异。VK2组与之相比,%L.PM呈升高趋势,BV/TV明显低于Sham组,而Tb.Sp显著高于sham组;其它组的骨量和骨结构参数与sham组相比未见明显差异。(4)生物力学指标:OVX组和sham组比较各项指标没有统计学差异。用药组和OVX组、Sham比较,各项生物力学指标亦无显著差异。(5)血钙:与OVX组和Sham比较,VD3组和VK2+VD3组血钙升高;VK2组无明显变化。VK2+VD3组血钙水平高于VK2组,两者间差异有统计学意义。
骨外影响:(1)凝血酶原时间:各组无统计学差异。(2)血脂:与OVX组比较,VK2组除LDL升高外其它指标无显著性改变;VD3组TC和LDL较OVX组有显著升高;VD3+VK3组TC、HDL和LDL均显著升高;VD3组和VK2+VD3组各项指标与Sham组比较无差异。VK2和VD3在LDL上有交互作用。(3)主动脉:胸主动脉钙化在sham组1例、OVX组3例,VD3组及VD3+VK2组各2例,VK2组未发现血管钙化。
结论(1)30mg/kgBW的VK2可以维持去卵巢大鼠BMD,同时可能预防血管钙化,且不增加大鼠高凝风险,对血脂无不利影响;(2)0.1ug/kgBW的VD3可以维持去卵巢大鼠BMD,并且对血管钙化和血脂无不利影响;(3)VK2与VD3联合用药的促进骨形成和抑制骨吸收作用优于VK2单药,有效地维持了去卵巢大鼠骨密度。二者合用对血脂、凝血、血管钙化无明显影响。
【Background】
Osteoporosis is becoming prevalent with the aging of the world population. Postmenopausal women are at increased risk of osteoporosis and osteoporostic fracture for low peak bone mass and fast bone loss resulting from estrogen deficiency.Estrogen therapy is one of the best treatment protocols for postmenopausal osteoporosis,but it has not been accepted by most menopausal women in China.Although vitamin D(VD) regarded as basal drug is widely used for preventing and curing osteoporosis in the world,it has limited efficacy on protection against osteoporosis.Nowadays,vitamin K' s(VK) effects has extended beyond blood clotting to include a role in bone metabolism and potential protection against osteoporosis.In theory,the efficacy of combined treatment with VK and VD may be greater than alone.Furthermore,it is pointed out that VK_2 may prevent from vessel calcification and decrease the incidence of cardiovascular disease.In addition,few side effects have been observed concerning its coagulatory properties under the dosage for osteoporosis.So it is a fairly safe drug.
【Objective】
This study is designed to investigate the effects of VK_2(menatetrenone) and combined therapy with VD_3(1,25-dihydroxyvitaminD_3,calcitriol) on ovariectomized rats concerning prevention of osteoporosis as well as vessel calcification,blood lipid metabolism and coagulation.The results will serve as evidences guiding clinical application of VK_2 in postmenopausal osteoporosis.
【Methods】
Establishment of rats model for postmenopausal osteoporosis:37 SD and SPF female rats of 10 months old were randomized into 5 groups according to weight:sham(8), OVX(8),OVX+VK_2(7),OVX+VD_3(7) and OVX+VK_2+VD_3(7).Gastric infusion of corresponding drugs was performed 2 weeks after operation.VK_2:30mg/kg/d;VD_3: 0.1ug/kg/d;Sham and OVX:purified water 2.5ml/kg/d.Variables were evaluated 14 weeks later including bone density,bone turnover parameters,bone histomorphometry, bone biomechanies,blood lipids,coagulatory parameters and aorta calcification.
【Results】
Effects on bone:(1) turnover parameters:BALP and uDPYD are much increased in OVX group than those in Sham group,revealing an increased bone turnover rate.VK_2 group presents much higher uDPYD and uCa/uCr compared with OVX group,but the BALP is not statistically different between the two groups.The BALP in VD_3 group is lower than that in OVX group.The three parameters are not significantly changed in VK_2+VD_3 group compared with OVX group.VK2 group presents an apparent increase in uDPYD compared with the Sham group.The interaction between VK2 and VD3 on uDPYD is found.(2)BMD:The lumbar BMD in OVX group is lower than Sham group and other groups with drug treatment,while no difference is observed in drug treatment groups compared with sham group.The significant BMD decrease of both femurs in OVX group is observed compared with sham group.Meanwhile,the significant increase of BMD is found in both femurs of VK2+VD3 group and in left femur of VD3 group compared with OVX group.The BMD of both femurs in group VK2 is similar to that in OVX group and is lower than that in sham group.However,no difference is found in VD3 group and combined treatment group compared with sham group regarding BMD of the femurs.In addition,the BMD of right femurs in VK2 group is markedly lower than that in combined treatment group.But no interaction between VK2 and VD3 is showed on both lumbar BMD and femoral BMD.(3) bone morphometry:All the bone formation parameters and absorption parameters in OVX group are higher than Sham group,among which%L.Pm is statistically different.OVX group presents a decreased trabecular thickness,a larger trabecular separation and a lower trabecular count than sham group but the difference is not significant.Compared with OVX group,all bone formation parameters increase in VD3 group and VK2+VD3 group,among which BFR/BS and MAR are much higher than those in OVX group;%E.Pm,one of bone absorption parameters,decreases in the two groups,but it does not attach statistical significance.All parameters indicating bone mass and bone structure in administered groups are not significantly different from those in OVX group.With MAR and BFR/BS significantly increasing and%E.Pm significantly decreasing in VK2+VD3 group,the combined therapy group shows better efficacy for promoting bone formation and suppressing bone absorption than that in VK2 group.Regarding all parameters mentioned above,no difference is observed between VK2 group and VK2+VD3 group. Concerning BV/TV,Tb.N,Tb.Th and Tb.Sp,no difference is found between OVX group and administered groups.Compared with the sham group,the administered groups present same changes in parameters of bone content and structure including downgrading of BV/TV and Tb.N and upgrading of Tb.Sp.Both BV/TV and Tb.Sp in VK2 group are significantly different from sham group,which suggests lower bone mass in VK2.The formation parameters increase in administered groups,and%L.PM、MAR and BFR/BS significantly upgrade in VD3 group and in VK2+VD3 group compared with sham group.(4) biomechanics:No difference for all parameters is observed between OVX group and Sham group.As for maximum load,maximum strain and Young's modulus, all the administered groups present no difference from the Sham and OVX group. However,for maximum load,VK2 group is significantly lower than VD3 group. (5)serum calcium ion:The level of serum calcium in VD3 group and VK2+VD3 group is higher than that in OVX group and in sham group,while that in VK2 group is not different from that in the two groups.The level of serum calcium shows a marked increase in VK2 group compared with combined treatment group.
Effects on other systems:(1) prothrombin time:no difference between the groups. (2)serum lipids:Compared with OVX group,VK2 group presents an significant increase of LDL,VD3 group shows a increase of LDL and TC,and VK2+VD3 group reveals a upgrade of LDL,HDL and TC.The LDL is higher in VK2 group than that in sham group.However,no difference is revealed in VD3 group and VK2+VD3 group compared with sham group.The two drugs' interaction is found on LDL.(3)aorta:Thoracic aorta calcification is observed in one case in sham group,in three cases in OVX group and two cases in VD3 group as well as VK2+VD3 group,respectively.No calcification is found in VK2 group.
【Conclusion】
(1) Administration of VK2 alone can sustain the lumbar BMD of ovariectomized rats with unidentifying mechanism.A dosage of 30mg/kgBW adds no risk to coagulation function in rats and is beneficial for preventing vessel calcification.VK2 has no advantages on serum lipids.(2) Administration of VD3 alone can sustain the BMD of ovariectomized rats both in lumbar and in femur by promoting bone formation.In addition,it does not show disadvantages to aorta and serum lipid.(3) The combined therapy with VK2 and VD3 presents better efficacy for sustaining BMD ovariectomized rats than that administered group with VK2 alone because of increasing bone formation and suppressing bone absorption.Meanwhile,no apparent side effect is observed on coagulation,serum lipid and aorta.
目的观察VK2及其与维生素D3联合应用对去卵巢大鼠骨质疏松模型的预防效果,同时观察其对血管钙化、血脂和凝血系统的影响,为VK2预防绝经后骨质疏松症提供实验证据。
方法模拟人绝经后骨质疏松的动物模型:选择37只SPF级10月龄雌性SD大鼠,按体重随机分为5组:假手术组(Sham)(8只)、去卵巢组(OVX)(8只)、OVX+VK2组(7只)、OVX+VD3组(VD3)(7只)及OVX+VK2+VD3组(7只)。双侧卵巢切除术后2周进行药物灌胃,VK2剂量为30mg/kg/d、VD3剂量为0.1ug/kg/d,Sham组及OVX组喂以净化水2.5ml/kg/d。14周后进行骨密度、骨转换指标、骨组织计量学和骨生物力学测定,并检测血脂、凝血指标,组织学观察胸主动脉的钙化情况。
结果对骨的影响:(1)骨转换指标:OVX组BALP和uDPYD显著升高。与OVX组比较,VK2组uDPYD和uCa/uCr明显增加。VD3组BALP明显降低,VK2+VD3组各项指标和OVX组比较无明显变化。与sham组相比,VK2组uDPYD显著升高。VK2和VD3对uDPYD的作用存在交互效应。(2)骨密度(BMD):OVX组腰椎BMD显著低于sham组和各用药组;用药组腰椎BMD与sham之间没有明显差异。与OVX组相比,VD3组左侧股骨、VD3+VK2组和Sham组双侧股骨BMD显著升高。与sham组比较,VK2组双侧股骨BMD明显降低,而VD3组和联合用药组较之无明显差异。VK2+VD3组与VK2组相比,其右侧股骨BMD较之明显升高。(3)骨组织形态计量学:OVX组的骨形成参数和骨吸收参数均高于sham组,其中%L.Pm与sham组有统计学差异。OVX组较sham组的骨小梁数量减少,厚度变薄,分离度增加,但无统计学意义。各用药组与OVX组比较,VK2+VD3组和VD3组的骨小梁形成参数增高,其中BFR/BS和MAR的差异有统计学意义;VK2组骨形成参数和OVX组相似。各用药组的骨吸收参数及骨量和骨结构参数与OVX组比较亦无明显差异。VK2+VD3组与VK2组相比,MAR和BFR/BS显著升高;而%E.Pm显著下降。骨量和骨结构参数值在各用药组之间无明显差异。各用药组与sham组相比,骨形成参数值均升高,尤其以VD3组和VK2+VD3组更为显著,此两组的%L.PM、MAR和BFR/BS均与Sham组有统计学差异。VK2组与之相比,%L.PM呈升高趋势,BV/TV明显低于Sham组,而Tb.Sp显著高于sham组;其它组的骨量和骨结构参数与sham组相比未见明显差异。(4)生物力学指标:OVX组和sham组比较各项指标没有统计学差异。用药组和OVX组、Sham比较,各项生物力学指标亦无显著差异。(5)血钙:与OVX组和Sham比较,VD3组和VK2+VD3组血钙升高;VK2组无明显变化。VK2+VD3组血钙水平高于VK2组,两者间差异有统计学意义。
骨外影响:(1)凝血酶原时间:各组无统计学差异。(2)血脂:与OVX组比较,VK2组除LDL升高外其它指标无显著性改变;VD3组TC和LDL较OVX组有显著升高;VD3+VK3组TC、HDL和LDL均显著升高;VD3组和VK2+VD3组各项指标与Sham组比较无差异。VK2和VD3在LDL上有交互作用。(3)主动脉:胸主动脉钙化在sham组1例、OVX组3例,VD3组及VD3+VK2组各2例,VK2组未发现血管钙化。
结论(1)30mg/kgBW的VK2可以维持去卵巢大鼠BMD,同时可能预防血管钙化,且不增加大鼠高凝风险,对血脂无不利影响;(2)0.1ug/kgBW的VD3可以维持去卵巢大鼠BMD,并且对血管钙化和血脂无不利影响;(3)VK2与VD3联合用药的促进骨形成和抑制骨吸收作用优于VK2单药,有效地维持了去卵巢大鼠骨密度。二者合用对血脂、凝血、血管钙化无明显影响。
【Background】
Osteoporosis is becoming prevalent with the aging of the world population. Postmenopausal women are at increased risk of osteoporosis and osteoporostic fracture for low peak bone mass and fast bone loss resulting from estrogen deficiency.Estrogen therapy is one of the best treatment protocols for postmenopausal osteoporosis,but it has not been accepted by most menopausal women in China.Although vitamin D(VD) regarded as basal drug is widely used for preventing and curing osteoporosis in the world,it has limited efficacy on protection against osteoporosis.Nowadays,vitamin K' s(VK) effects has extended beyond blood clotting to include a role in bone metabolism and potential protection against osteoporosis.In theory,the efficacy of combined treatment with VK and VD may be greater than alone.Furthermore,it is pointed out that VK_2 may prevent from vessel calcification and decrease the incidence of cardiovascular disease.In addition,few side effects have been observed concerning its coagulatory properties under the dosage for osteoporosis.So it is a fairly safe drug.
【Objective】
This study is designed to investigate the effects of VK_2(menatetrenone) and combined therapy with VD_3(1,25-dihydroxyvitaminD_3,calcitriol) on ovariectomized rats concerning prevention of osteoporosis as well as vessel calcification,blood lipid metabolism and coagulation.The results will serve as evidences guiding clinical application of VK_2 in postmenopausal osteoporosis.
【Methods】
Establishment of rats model for postmenopausal osteoporosis:37 SD and SPF female rats of 10 months old were randomized into 5 groups according to weight:sham(8), OVX(8),OVX+VK_2(7),OVX+VD_3(7) and OVX+VK_2+VD_3(7).Gastric infusion of corresponding drugs was performed 2 weeks after operation.VK_2:30mg/kg/d;VD_3: 0.1ug/kg/d;Sham and OVX:purified water 2.5ml/kg/d.Variables were evaluated 14 weeks later including bone density,bone turnover parameters,bone histomorphometry, bone biomechanies,blood lipids,coagulatory parameters and aorta calcification.
【Results】
Effects on bone:(1) turnover parameters:BALP and uDPYD are much increased in OVX group than those in Sham group,revealing an increased bone turnover rate.VK_2 group presents much higher uDPYD and uCa/uCr compared with OVX group,but the BALP is not statistically different between the two groups.The BALP in VD_3 group is lower than that in OVX group.The three parameters are not significantly changed in VK_2+VD_3 group compared with OVX group.VK2 group presents an apparent increase in uDPYD compared with the Sham group.The interaction between VK2 and VD3 on uDPYD is found.(2)BMD:The lumbar BMD in OVX group is lower than Sham group and other groups with drug treatment,while no difference is observed in drug treatment groups compared with sham group.The significant BMD decrease of both femurs in OVX group is observed compared with sham group.Meanwhile,the significant increase of BMD is found in both femurs of VK2+VD3 group and in left femur of VD3 group compared with OVX group.The BMD of both femurs in group VK2 is similar to that in OVX group and is lower than that in sham group.However,no difference is found in VD3 group and combined treatment group compared with sham group regarding BMD of the femurs.In addition,the BMD of right femurs in VK2 group is markedly lower than that in combined treatment group.But no interaction between VK2 and VD3 is showed on both lumbar BMD and femoral BMD.(3) bone morphometry:All the bone formation parameters and absorption parameters in OVX group are higher than Sham group,among which%L.Pm is statistically different.OVX group presents a decreased trabecular thickness,a larger trabecular separation and a lower trabecular count than sham group but the difference is not significant.Compared with OVX group,all bone formation parameters increase in VD3 group and VK2+VD3 group,among which BFR/BS and MAR are much higher than those in OVX group;%E.Pm,one of bone absorption parameters,decreases in the two groups,but it does not attach statistical significance.All parameters indicating bone mass and bone structure in administered groups are not significantly different from those in OVX group.With MAR and BFR/BS significantly increasing and%E.Pm significantly decreasing in VK2+VD3 group,the combined therapy group shows better efficacy for promoting bone formation and suppressing bone absorption than that in VK2 group.Regarding all parameters mentioned above,no difference is observed between VK2 group and VK2+VD3 group. Concerning BV/TV,Tb.N,Tb.Th and Tb.Sp,no difference is found between OVX group and administered groups.Compared with the sham group,the administered groups present same changes in parameters of bone content and structure including downgrading of BV/TV and Tb.N and upgrading of Tb.Sp.Both BV/TV and Tb.Sp in VK2 group are significantly different from sham group,which suggests lower bone mass in VK2.The formation parameters increase in administered groups,and%L.PM、MAR and BFR/BS significantly upgrade in VD3 group and in VK2+VD3 group compared with sham group.(4) biomechanics:No difference for all parameters is observed between OVX group and Sham group.As for maximum load,maximum strain and Young's modulus, all the administered groups present no difference from the Sham and OVX group. However,for maximum load,VK2 group is significantly lower than VD3 group. (5)serum calcium ion:The level of serum calcium in VD3 group and VK2+VD3 group is higher than that in OVX group and in sham group,while that in VK2 group is not different from that in the two groups.The level of serum calcium shows a marked increase in VK2 group compared with combined treatment group.
Effects on other systems:(1) prothrombin time:no difference between the groups. (2)serum lipids:Compared with OVX group,VK2 group presents an significant increase of LDL,VD3 group shows a increase of LDL and TC,and VK2+VD3 group reveals a upgrade of LDL,HDL and TC.The LDL is higher in VK2 group than that in sham group.However,no difference is revealed in VD3 group and VK2+VD3 group compared with sham group.The two drugs' interaction is found on LDL.(3)aorta:Thoracic aorta calcification is observed in one case in sham group,in three cases in OVX group and two cases in VD3 group as well as VK2+VD3 group,respectively.No calcification is found in VK2 group.
【Conclusion】
(1) Administration of VK2 alone can sustain the lumbar BMD of ovariectomized rats with unidentifying mechanism.A dosage of 30mg/kgBW adds no risk to coagulation function in rats and is beneficial for preventing vessel calcification.VK2 has no advantages on serum lipids.(2) Administration of VD3 alone can sustain the BMD of ovariectomized rats both in lumbar and in femur by promoting bone formation.In addition,it does not show disadvantages to aorta and serum lipid.(3) The combined therapy with VK2 and VD3 presents better efficacy for sustaining BMD ovariectomized rats than that administered group with VK2 alone because of increasing bone formation and suppressing bone absorption.Meanwhile,no apparent side effect is observed on coagulation,serum lipid and aorta.
引文
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