辛伐他汀对糖尿病大鼠骨密度及1型胶原氨基端肽的影响
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摘要
目的近年研究发现他汀类药物除调脂作用外,对骨代谢亦有影响。以往一些研究以观察他汀类药物促进骨形成为主,该药是否抑制骨吸收报道极少。本实验设计了糖尿病大鼠应用辛伐他汀的实验性研究以观察该药是否可以通过抑制骨吸收而阻止糖尿病大鼠骨质疏松的发生及发展,并探讨其可能的机制,进而为糖尿病合并骨质疏松的防治提供实验依据。
方法健康雄性Wistar大鼠24只(安徽医学研究所实验动物中心提供),2月龄,体重200±20克,实验前测鼠尾血糖均正常,随机分为三组:A组,正常对照组;B组,糖尿病对照组;C组,辛伐他汀治疗组,每组各8只。糖尿病模型建立成功后,C组每日以辛伐他汀20mg/kg.d(默沙东中国有限公司),溶于蒸馏水中灌胃给药,A,B组喂以等量生理盐水。检测各组第2,4,8周血糖,于第2周、第8周以代谢笼收集12小时尿液,准确计量,混匀后留取5ml,用酶联免疫法测尿I型胶原氨基端肽,第8周末处死大鼠经股动脉取血,用酶联免疫法测血I型胶原氨基端肽,骨密度仪测全身骨密度。后仔细剔除大鼠双下肢股骨周围肌肉组织,测定双侧股骨骨密度,并留取三组大鼠的股骨骨标本光镜观察镜下改变。
结果(1)各组间血糖比较:2,8周时B,C组均显著高于A组(P<0.01),B,C组组间无统计学差异(P>0.05)。
(2)各组间尿NTX比较:第2周末B组、C组显著高于A组(P<0.01);第8周末与第2周末组内比较B组尿NTX有上升,而C组经辛伐他汀治疗后NTX较治疗前有明显下降,差异有统计学意义(P<0.05),但仍然高于A组。
(3)各组间血NTX比较: B组、C组显著高于A组(P<0.01),C组经辛伐他汀治疗后较B组有明显下降。
(4)各组间骨密度比较: B,C组较正常对照组明显低减, C组经辛伐他汀治疗后骨密度较B组高,差异有统计学意义P<0.05,但与A组相比,仍有较大差距,差异有统计学意义(P<0.01)。
(5)各组光镜下骨组织病理变化与A组比较,B组光镜下所见(1:400)骨小梁明显变细、稀疏、断裂,其间较多脂肪组织。C组投食辛伐他汀后骨质疏松病理改变有所改善,但与A组相比,仍有明显骨质疏松表现。
结论:辛伐他汀对糖尿病大鼠骨组织有明确的保护作用,其作用机制可能与抑制骨吸收有一定关系,确切的机制值得进一步深入研究。
Objective: Some recent researches have show that statins have some influence on bone metabolism besides its fat adjustment. Most researches paid close attention mainly about its promotion to bone formation, and few reports showed that statins can restrains bone absorption. This experiment was designed to observe if simvastatin can hold back the development and progression of osteoporosis through restraining bone absorption, then we can provide experimental base for the prevention and treatment of osteoporosis related to diabetes mellitus
Method :24 healthy male Wistar rats (provided by Experimental Animal Centre of Anhui Medical Graduate School, two months old, 200±20g weight, with blood glucose up to snuff before experiment) were randomly assigned t three groups. normal control group (groupA,n=8), diabetic rats group( groupB,n=8) and simvastatin(20mg/kg/d) treatment group (group C, n =8). After diabetic models were estabished, group C were given simvastatin (MERCK China C.Ld) 20mg/kg each day ( with simvastatin dissolved in distilled water). Group A and Group B were given equal distilled water. The peripheral blood glucose at the 2nd , 4th , 8th week, and N-terminal telopeptide of type I Collagen (NTX) at 2nd and 8th week(24 hours urine) were measured with enzyme-linked immunosorbent assay( ELISA). By the 8th week, rats were killed to collect blood and bone specimen, the blood NTX was measured by ELISA, the bone mineral density(BMD) of lower limbs was measured by Dual Energy X-ray Absorptiometry(DXA), Bone specimen of lower limbs from rats of each group were kept to observe their morphology under light microscope.
Results:(1)The peripheral blood glucoses of group B and group C at the 2nd and 8th week of were markedly higher than that of Group A(P<0.01), there was no statistical difference between Group B and group C(P>0.05). (2)The 12 urine NTX in group B and group C by the end of 2nd week was markedly higher than that of group A(P<0.01), the urine NTX of the 8th week of group B was higher than that of the 2nd week. The urinary NTX of group C declined markedly after statins treatment, and the difference has statistical meanings(P<0.05), but still higher than that of the group A. (3)The blood NTX of group B and group C was markedly higher than that group A(P<0.01), but the level in group C declined greatly when compared with that of group B after treatment with statins. (4)The BMD of group B and group C declined markedly compared with group A; The BMD of group C was higher than that of group B after the treatment with statins, and the difference had statistical signficant(P<0.05), but still lower much than that of group A, and the difference had statistical significance, too(P<0.01). (5)Compared with group A, the bone trabecula of group B markedly turned thin, sparseness and rupturable under light microscope(1:400) with much adipose tissue. the bone trabecula in group C had became better in osteoporosis after treatment with simvastatin for 8weeks, but still had distinct osteoporosis characteristic under light microscope.
Conclusion: Simvastatin has some protective effect against osteoporosis in STZ-induced diabetes rats , which may be partly related to its effect in inhibting bone absorption, exact mechanisms need to be evaluated futher.
方法健康雄性Wistar大鼠24只(安徽医学研究所实验动物中心提供),2月龄,体重200±20克,实验前测鼠尾血糖均正常,随机分为三组:A组,正常对照组;B组,糖尿病对照组;C组,辛伐他汀治疗组,每组各8只。糖尿病模型建立成功后,C组每日以辛伐他汀20mg/kg.d(默沙东中国有限公司),溶于蒸馏水中灌胃给药,A,B组喂以等量生理盐水。检测各组第2,4,8周血糖,于第2周、第8周以代谢笼收集12小时尿液,准确计量,混匀后留取5ml,用酶联免疫法测尿I型胶原氨基端肽,第8周末处死大鼠经股动脉取血,用酶联免疫法测血I型胶原氨基端肽,骨密度仪测全身骨密度。后仔细剔除大鼠双下肢股骨周围肌肉组织,测定双侧股骨骨密度,并留取三组大鼠的股骨骨标本光镜观察镜下改变。
结果(1)各组间血糖比较:2,8周时B,C组均显著高于A组(P<0.01),B,C组组间无统计学差异(P>0.05)。
(2)各组间尿NTX比较:第2周末B组、C组显著高于A组(P<0.01);第8周末与第2周末组内比较B组尿NTX有上升,而C组经辛伐他汀治疗后NTX较治疗前有明显下降,差异有统计学意义(P<0.05),但仍然高于A组。
(3)各组间血NTX比较: B组、C组显著高于A组(P<0.01),C组经辛伐他汀治疗后较B组有明显下降。
(4)各组间骨密度比较: B,C组较正常对照组明显低减, C组经辛伐他汀治疗后骨密度较B组高,差异有统计学意义P<0.05,但与A组相比,仍有较大差距,差异有统计学意义(P<0.01)。
(5)各组光镜下骨组织病理变化与A组比较,B组光镜下所见(1:400)骨小梁明显变细、稀疏、断裂,其间较多脂肪组织。C组投食辛伐他汀后骨质疏松病理改变有所改善,但与A组相比,仍有明显骨质疏松表现。
结论:辛伐他汀对糖尿病大鼠骨组织有明确的保护作用,其作用机制可能与抑制骨吸收有一定关系,确切的机制值得进一步深入研究。
Objective: Some recent researches have show that statins have some influence on bone metabolism besides its fat adjustment. Most researches paid close attention mainly about its promotion to bone formation, and few reports showed that statins can restrains bone absorption. This experiment was designed to observe if simvastatin can hold back the development and progression of osteoporosis through restraining bone absorption, then we can provide experimental base for the prevention and treatment of osteoporosis related to diabetes mellitus
Method :24 healthy male Wistar rats (provided by Experimental Animal Centre of Anhui Medical Graduate School, two months old, 200±20g weight, with blood glucose up to snuff before experiment) were randomly assigned t three groups. normal control group (groupA,n=8), diabetic rats group( groupB,n=8) and simvastatin(20mg/kg/d) treatment group (group C, n =8). After diabetic models were estabished, group C were given simvastatin (MERCK China C.Ld) 20mg/kg each day ( with simvastatin dissolved in distilled water). Group A and Group B were given equal distilled water. The peripheral blood glucose at the 2nd , 4th , 8th week, and N-terminal telopeptide of type I Collagen (NTX) at 2nd and 8th week(24 hours urine) were measured with enzyme-linked immunosorbent assay( ELISA). By the 8th week, rats were killed to collect blood and bone specimen, the blood NTX was measured by ELISA, the bone mineral density(BMD) of lower limbs was measured by Dual Energy X-ray Absorptiometry(DXA), Bone specimen of lower limbs from rats of each group were kept to observe their morphology under light microscope.
Results:(1)The peripheral blood glucoses of group B and group C at the 2nd and 8th week of were markedly higher than that of Group A(P<0.01), there was no statistical difference between Group B and group C(P>0.05). (2)The 12 urine NTX in group B and group C by the end of 2nd week was markedly higher than that of group A(P<0.01), the urine NTX of the 8th week of group B was higher than that of the 2nd week. The urinary NTX of group C declined markedly after statins treatment, and the difference has statistical meanings(P<0.05), but still higher than that of the group A. (3)The blood NTX of group B and group C was markedly higher than that group A(P<0.01), but the level in group C declined greatly when compared with that of group B after treatment with statins. (4)The BMD of group B and group C declined markedly compared with group A; The BMD of group C was higher than that of group B after the treatment with statins, and the difference had statistical signficant(P<0.05), but still lower much than that of group A, and the difference had statistical significance, too(P<0.01). (5)Compared with group A, the bone trabecula of group B markedly turned thin, sparseness and rupturable under light microscope(1:400) with much adipose tissue. the bone trabecula in group C had became better in osteoporosis after treatment with simvastatin for 8weeks, but still had distinct osteoporosis characteristic under light microscope.
Conclusion: Simvastatin has some protective effect against osteoporosis in STZ-induced diabetes rats , which may be partly related to its effect in inhibting bone absorption, exact mechanisms need to be evaluated futher.
引文
1 Consensus Development Conference.Diagnosis,prophylaxis and treatment ofosteoporosis .Am J Med,1993,94:664-650
2 Staal A, Frith JC, French MH, Swartz J, Gungor T, Harrity TW, Tamasi J, Rogers MJ, Feyen JH (2003) The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity. J Bone Miner Res 18: 88–96.
3 Torikai E, Kageyama Y, Takahashi M et al. The effect of methotrexate on bone metabolism markers in patients with rheumatoid arthritis. Mod Rheumatol. 2006,16(6):350-4.
4 Oxlund H,Dalstra M,Andeassen TT,et al.Statin given perorally to adult rats increases cancellous bone mass and compressive strength[J]. Cleif tissue lnt,2001,69(5):299-304.
5 Liu EY, Wactawski-Wende J,Donahue RP,et al.Does low mineral density start in post-teenage years in women with type 1 diabetes? .[J ] , Diabetes Care,2003,26(8):2365-2369
6周连华,周湘兰,施晓红.糖尿病患者合并骨质疏松症的多因素分析[J].中国临床康复,2004, 8(24): 5074-5075
7 Hein G,Weiss C,Lehmann G,et al.Advanced glycation end product modification of bone proteins and bone remodeling:hypothesis and preliminary immunohistochemical findings[J].Ann Rheum Dis,2006,65(1):101-104
8 Dominguez LJ, Muratore M,Quarta E,et al.Osteoporosis and diabetes [J].Reumatismo,2004,56(4):235-241
9 Clausen P,Feldt-rasmussen B,Jacobsen P,et al.Microalbuminuria as an early indicator of osteopenia in male insulin 2 dependent diabetic patients[J].Diabet Med,1997,14(12):1038-1043
10 Mundy G,Garrett R, Harris S,et al.Stimulation of bone formation in vitro and in rodents by statins[J].Science,1999,286(5446):1946-1949.
11 Yee AJ, Bae HW, Friess D, et al. The use of simvastatin in rabbit posterolateral lumbar intertransverse process spine fusion. [J] Spine, 2006,6(4):391-6.
12 Lupattelli G,Scarponi AM,Vaudo G,et al. Simvastatin increases bone mineral density in hypercholesterolemic postmenopausal women. [J]. Metabolism,2004,53 (6):744-748.
13 Cauley JA,Jackson R, Pettinger M,et al. Statin use and bone mineral density in older wowen : the Women's Health Initiative Observational Study . Journal of Bone and Mineral Research,2000,
14 Sirola J,Honkanen R,Kroger H,et al. Relation of statin use and bone loss:a prospective population–based cohord study in early postmenopausal women[J]. Osteopros Int,2002,13(7):537-541.
15于纪珠,刘晓民,林春艳,等.辛伐他汀体外促进骨形成作用的初步研究[J].中国骨质疏松杂志,2004,10(2):230-231.
16 Beicher J,Benhuzzi H,Franklin L ,et al.Comparison between mevinolin and PTH action on MG63 osteoblast-like cells. Biomed Sci Instrum,2006;42:267-72
17 Takanaka M,Hirade K,Tanabe K et al.Simvastatin stimulates VEGF release via p44/p42 MAP kinase in vascular smooth muscle cells。[J].Biochem Biophys Res Commun , 2003;301(1):198-203
18 Sugiyama M,Kodama T,Konishi K,et al. Compactin and simvastatins but not pravastatin induce bone morphogenetic protein-2 in humam osteosarcoma cells[J].Biochem Biophys Res Commun,2000,271(3):688-692.
19 Ohnaka K, Shimoda S, Nawata H, et al.Pitavastatin enhanced BMP-2 and osteocaclin expression by inhibition of Rho-associated kinase in human osteoblasts. Biochem Biophys Res Commun,2001,287(2):337-342
20 Baldini V, Mastropasqua M, Francucci CM, et al. Cardiovascular disease and osteoporosis.[J ]Endocrinol Invest. 2005;28(10 Suppl):69-72
21宋纯理,贾弘埘,马庆军,等.骨髓基质细胞成脂分化及辛伐他汀对其分化及辛伐他汀对其影响的实验研究.[J].中华老年医学杂志,2004;23(4):263-266
22 Kuzuya M,Suzuki Y, Asai T ,et al. Atorvastatin,3-Hydroxy-3-MethylglutarylCoenzyme A Reductase Inhibitor,Reduces Bone Resorption in the Elderly[J]. J Am Geriatr Soc,2003,51 (11):1677–1678. PMID :14687410Mendoza S,Noa M,Mas R , et al.Comparison of the effects of D-003 , a mixture of high-molecular-weight aliphatic acids from sugarcane wax,and pravastatin on bones and osteoclast apoptosis of ovariectomized rats[J]. Drugs Exp Clin Res,2005,31(5-6):181-191.
23 Majima T, Shimatsu A, Komatsu Y, et al. Short-term effects of pitavastatin on biochemical markers of bone turnover in patients with hypercholesterolemia Intern Med. 2007;46(24):1967-73.
24 Woo JT,Kasai S,Stern PH,et al.Compactin suppresses bone resorption by inhibiting the fusion of prefusion osteoclasts and disrupting the actin ring in osteoclasts[J].J Bone Miner,2000,15(4):650-651.
25 Mendoza S,Noa M,Mas R,et al.Comparison of the effects of D-003,a mixture of high-molecular-weight aliphatic acids from sugarcane wax,and pravastatin on bones and osteoclast apoptosis of ovariectomized rats[J]. Drugs Exp Clin Res,2005,31(5-6):181-19Beicher J,Benhuzzi H,Franklin L,et al.Comparison between mevinolin and PTH action on MG63 osteoblast-like cells[J]. Biomed Sci Instrum,2006,42(2):267-272.
26 Grasser WA, Baumann AP, Petras SF Regulation of osteoclast differentiation by statinsJ Musculoskelet Neuronal Interact. 2003,3(1):53-62.
27 Van Beek E,Lowik C,Van der Pluijm G et al.The role of geranylgeranylation in bone resorption and its susppression by bisphosphonates in fetal bone explants in vitro :a clue to the mechanism of action of nitrogen-containing bisphosphonates.[J].J bone Miner Res,1999;14(5):722-729
1 Consensus Development ConferencE.Diagnosis,prophylaxis and treatment of osteoporosis.Am J Med,1993,94:664-650
2 Mundy G, Garrett R, Harris S et al.Stimulation of bone formation in vitro and in rodents by statins. [J].Science, 1999;286(5446):1946-1949
3 Sugiyama M,Kodama T,Konishi K,et al. Compactin and simvastatins but not pravastatin induce bone morphogenetic protein-2 in humam osteosarcoma cells. [J].Biochem Biophys Res Commun,2000;271(3):688-692
4 Ohnaka K, Shimoda S, Nawata H, et al.Pitavastatin enhanced BMP-2 and osteocaclin expression by inhibition of Rho-associated kinase in human osteoblasts. Biochem Biophys Res Commun,2001;287(2):337-342
5 Baldini V, Mastropasqua M, Francucci CM, et al. Cardiovascular disease and osteoporosis.[J ]Endocrinol Invest. 2005;28(10 Suppl):69-72
6 Masafumi K, Yusuke S, Toshinobu As, et al. Atorvastatin, 3-Hydroxy -3- Methylglutaryl Coenzyme A Reductase Inhibitor, Reduces Bone Resorption in the Elderly. Journal of the American Geriatrics Society,2003; 51 (11), 1677–1678.
7 Beicher J,Benhuzzi H,Franklin L ,et al.Comparison between mevinolin and PTH action on MG63 osteoblast-like cells. Biomed Sci Instrum,2006;42:267-72
8 Woo JT ,Kasai S, Stern PH , et al.Compactin suppresses bone resorption by inhibiting the fusion of prefusion osteoclasts and disrupting the actin ring in osteoclasts.[J].J Bone Miner ,2000;,15(4):650-651
9 Mendoza S, Noa M, Mas R, et al.Comparison of the effects of D-003, a mixture of high-molecular-weight aliphatic acids from sugarcane wax, and pravastatin on bones and osteoclast apoptosis of ovariectomized rats. Drugs Exp Clin Res. 2005;31(5-6):181-91.
10 Lupattelli G, Scarponi AM, Vaudo G,et al. Simvastatin increases bone mineral density in hypercholesterolemic postmenopausal women. Metabolism. 2004 Jun;53(6):744-8.
11 Oxlund H,Dalstra M,Andeassen TT , et al.Statin given perorally to adult rats increases cancellous bone mass and compressive strength. Cleif tissue lnt,2001;69(5):299-304
12 Yee AJ, Bae HW, Friess D, et al. The use of simvastatin in rabbit posterolateral lumbar intertransverse process spine fusion.. Spine J. 2006 Jul-Aug;6(4):391-6.
13 Sirola J,Honkanen R,Kroger H , et al. Relation of statin use and bone loss:a prospective population–based cohord study in early postmenopausal women. Osteopros Int,2002;13(7):537-541
14 Rejnmark L, Olsen ML, Johnsen SP, et al.Hip fracture risk in statin users--a population-based Danish case-control study. Osteoporos Int. 2004 Jun;15(6):452-8.
15 Ray WA, Daugherty JR , Griffin MR . Lipid-lowering agents and the risk of hip fracture in a Medicaid population. Inj Preve,2002;8(4):276-279
16 Yao W, Farmer R, Cooper R, et al. Simvastatin did not prevent nor restore ovariectomy-induced bone loss in adult rats. J Musculoskelet Neuronal Interact. 2006 Jul-Sep;6(3):277-83.
17 Hatzigeorgiou C, Jackson JL. Hydroxymethylglutaryl-coenzyme A reductase inhibitors and osteoporosis: a meta-analysis. Osteoporos Int. 2005 Aug;16(8):990-8.
18于纪珠,刘晓民,林春艳.辛伐他汀体外促进骨形成作用的初步研究.中国骨质疏松杂志,2004; 10(2):230-231
19杨允,张左伦,张立平.他汀类药物对小鼠颅骨的局部作用.山东大学学报(医学版),2004;42(2):196-199
20 Takenaka M,Hirade K,Tanabe K , et al.Simvastatin stimulates VEGF release via p44/p42 MAP kinase in vascular smooth muscle cells. [J].Biochem Biophys Res Commun , 2003;301(1):198-203
21张春玉,王波,赵明.阿托伐他汀钙对糖尿病大鼠骨代谢的影响.[J]中国临床康复,2003;7(15):2138-2139
2 Staal A, Frith JC, French MH, Swartz J, Gungor T, Harrity TW, Tamasi J, Rogers MJ, Feyen JH (2003) The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity. J Bone Miner Res 18: 88–96.
3 Torikai E, Kageyama Y, Takahashi M et al. The effect of methotrexate on bone metabolism markers in patients with rheumatoid arthritis. Mod Rheumatol. 2006,16(6):350-4.
4 Oxlund H,Dalstra M,Andeassen TT,et al.Statin given perorally to adult rats increases cancellous bone mass and compressive strength[J]. Cleif tissue lnt,2001,69(5):299-304.
5 Liu EY, Wactawski-Wende J,Donahue RP,et al.Does low mineral density start in post-teenage years in women with type 1 diabetes? .[J ] , Diabetes Care,2003,26(8):2365-2369
6周连华,周湘兰,施晓红.糖尿病患者合并骨质疏松症的多因素分析[J].中国临床康复,2004, 8(24): 5074-5075
7 Hein G,Weiss C,Lehmann G,et al.Advanced glycation end product modification of bone proteins and bone remodeling:hypothesis and preliminary immunohistochemical findings[J].Ann Rheum Dis,2006,65(1):101-104
8 Dominguez LJ, Muratore M,Quarta E,et al.Osteoporosis and diabetes [J].Reumatismo,2004,56(4):235-241
9 Clausen P,Feldt-rasmussen B,Jacobsen P,et al.Microalbuminuria as an early indicator of osteopenia in male insulin 2 dependent diabetic patients[J].Diabet Med,1997,14(12):1038-1043
10 Mundy G,Garrett R, Harris S,et al.Stimulation of bone formation in vitro and in rodents by statins[J].Science,1999,286(5446):1946-1949.
11 Yee AJ, Bae HW, Friess D, et al. The use of simvastatin in rabbit posterolateral lumbar intertransverse process spine fusion. [J] Spine, 2006,6(4):391-6.
12 Lupattelli G,Scarponi AM,Vaudo G,et al. Simvastatin increases bone mineral density in hypercholesterolemic postmenopausal women. [J]. Metabolism,2004,53 (6):744-748.
13 Cauley JA,Jackson R, Pettinger M,et al. Statin use and bone mineral density in older wowen : the Women's Health Initiative Observational Study . Journal of Bone and Mineral Research,2000,
14 Sirola J,Honkanen R,Kroger H,et al. Relation of statin use and bone loss:a prospective population–based cohord study in early postmenopausal women[J]. Osteopros Int,2002,13(7):537-541.
15于纪珠,刘晓民,林春艳,等.辛伐他汀体外促进骨形成作用的初步研究[J].中国骨质疏松杂志,2004,10(2):230-231.
16 Beicher J,Benhuzzi H,Franklin L ,et al.Comparison between mevinolin and PTH action on MG63 osteoblast-like cells. Biomed Sci Instrum,2006;42:267-72
17 Takanaka M,Hirade K,Tanabe K et al.Simvastatin stimulates VEGF release via p44/p42 MAP kinase in vascular smooth muscle cells。[J].Biochem Biophys Res Commun , 2003;301(1):198-203
18 Sugiyama M,Kodama T,Konishi K,et al. Compactin and simvastatins but not pravastatin induce bone morphogenetic protein-2 in humam osteosarcoma cells[J].Biochem Biophys Res Commun,2000,271(3):688-692.
19 Ohnaka K, Shimoda S, Nawata H, et al.Pitavastatin enhanced BMP-2 and osteocaclin expression by inhibition of Rho-associated kinase in human osteoblasts. Biochem Biophys Res Commun,2001,287(2):337-342
20 Baldini V, Mastropasqua M, Francucci CM, et al. Cardiovascular disease and osteoporosis.[J ]Endocrinol Invest. 2005;28(10 Suppl):69-72
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