摘要
背景:骨硬化蛋白的研究为骨质疏松的治疗提供了一个新的方向,通过促进骨生成,抑制骨吸收改善骨质疏松。目的:系统梳理骨硬化蛋白与骨质疏松相关文献,为进一步研究和促进骨硬化蛋白应用于骨质疏松的临床治疗和预防提供理论支持,提高骨质疏松的诊断和治疗效果。方法:以"Osteoporosis,Sclerostin,Sclerosteosis,Wnt/β-catenin,LRP5/6,Sclerostin antibody,Sclerostin and life style,Romosozumab、Blosozumab"为英文检索词,检索Pub Med数据库相关文献,经过筛选对其中的58篇文献进行分析探讨。结果与结论:(1)骨硬化蛋白的缺失或合成减少能促进骨的生成,骨硬化蛋白抗体在动物实验和临床试验中表现良好,能很好的促进骨生成,抑制骨吸收;(2)临床Ⅲ期试验结果支持前期试验所表现出的骨硬化蛋白单克隆抗体在骨代谢中的双重作用,表现出较好的治疗骨质疏松的应用前景;(3)研究发现血清骨硬化蛋白水平与生活方式关系密切,具体的对应关系还需进一步的验证;(4)大量的实验结果支持骨硬化蛋白应用于临床,骨硬化蛋白的研究为骨质疏松的预防和治疗提供一个新的方向。
BACKGROUND: Sclerostin has been shown to promote bone formation and decrease bone resorption, which provides a new idea for the treatment of osteoporosis. OBJECTIVE: To review the literatures related to sclerostin and osteoporosis, thereby providing theoretical basis for sclerostin applied in the treatment and prevention of osteoporosis, so as to improve the diagnosis and curative efficacy of osteoporosis. METHODS: Pub Med database was searched using the keywords of "osteoporosis, sclerostin, sclerosteosis, Wnt/β-catenin, LRP5/6, sclerostin antibody, sclerostin and expertise, romosozumab, blosozumab". Finally, 58 pertinent articles were enrolled for analysis. RESULTS AND CONCLUSION: Sclerostin inhibits bone formation, so anti-sclerostin antibody is utilized, andanimal experiments and clinical trials have shown that it can promote bone formation and inhibit bone reaorption. Phase III trial results potentially signify a significant step in achieving market approval, which support the preclinical and clinical emergence of sclerostin antibody therapies for both osteoporosis and alternative applications. The serum level of sclerostin is found to be closely related to lifestyle, but still need to be studied in depth. Increasing trial results show that sclerostin is the promising therapeutic candidate, which provides a new direction in the prevention and treatment of osteoporosis.
引文
[1]Lim HS,Kim SK,Lee HH,et al.Comparison in Adherence to Osteoporosis Guidelines according to Bone Health Status in Korean Adult.J Bone Metab.2016;23(3):143-148.
[2]Lin X,Xiong D,Peng YQ,et al.Epidemiology and management of osteoporosis in the People's Republic of China:current perspectives.Clin Interv Aging.2015;25(10):1017-1033.
[3]Hernlund E,Svedbom A,et al.Osteoporosis in the European Union:medical management,epidemiology and economic burden:A report prepared in collaboration with the International Osteoporosis Foundation(IOF)and the European Federation of Pharmaceutical Industry Associations(EFPIA).Arch Osteoporosis.2013;8(1-2):136.
[4]Baccaro LF,Conde DM,Costapaiva L,et al.The epidemiology and management of postmenopausal osteoporosis:a viewpoint from Brazil.Clin Interv Aging.2015;10:583-591.
[5]L?tters FJ,Jp VDB,De VF,et al.Current and Future Incidence and Costs of Osteoporosis-Related Fractures in The Netherlands:Combining Claims Data with BMD Measurements.Calcif Tissue Int.2016;98(3):235-243.
[6]Takahara K,Kamimura M,Moriya H,et al.Risk factors of adjacent vertebral collapse after percutaneous vertebroplasty for osteoporotic vertebral fracture in postmenopausal women.Bmc Musculoskelet Disord.2016;17(1):1-7.
[7]Chen YC,Lin WC.Can anti-osteoporotic therapy reduce adjacent fracture in magnetic resonance imaging-proven acute osteoporotic vertebral fractures?.Bmc Musculoskelet Disord.2016;17(1):1-5.
[8]Hadji P,Jacob L,Kostev K.Gender-and age-related treatment compliance in patients with osteoporosis in Germany.Patient prefer adherence.2016;10.2379-2385.
[9]Chen Z,Arendell L,Aickin M,et al.Hip bone density predicts breast cancer risk independently of Gail score:Results From the Women's Health Initiative.Cancer.2008;113(5):907-15.
[10]Mcgraw RL,Riggs JE.Osteoporosis,sedentary lifestyle,and increasing hip fractures:Pathogenic relationship or differential survival bias.Calcif Tissue Int.1994;55(2):87-89.
[11]Shah AD,Shoback D,Lewiecki EM.Sclerostin inhibition:a novel therapeutic approach in the treatment of osteoporosis.Int J Womens Health.2015;7:565-580.
[12]Appelman-Dijkstra NM,Papapoulos SE.Sclerostin Inhibition in the Management of Osteoporosis.Calcif Tissue Int.2016;98(4):370-380.
[13]Yao Q,Ni J,Hou Y,et al.Expression of sclerostin sc Fv and the effect of sclerostin sc Fv on healing of osteoporotic femur fracture in rats.Cell Biochem Biophys.2014;69(2):1-7.
[14]Yang X,Deng Z,Wen T,et al.Network Meta-Analysis of Pharmacological Agents for Osteoporosis Treatment and Fracture Prevention.Cell Physiol Biochem.2016;40(3-4):781-795.
[15]Genant HK,Engelke K,Bolognese MA,et al.Effects of Romosozumab Compared with Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women with Low Bone Mass.J Bone Miner Res.2017;32(1):181-187.
[16]Lindsay R,Krege JH,Marin F,et al.Teriparatide for osteoporosis:importance of the full course.Osteoporosis Int.2016;27(8):2395-2410.
[17]Hay E,Bouaziz W,Funckbrentano T,et al.Sclerostin and Bone Aging:A Mini-Review.Gerontology.2016;62(6):618-623.
[18]Balemans W,Ebeling M,Patel N,et al.Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein(SOST).Hum Mol Genet.2001;10(5):537-543.
[19]Balemans W,Van Hul W.Human genetics of SOST.J Musculoskeletal Neuronal Interact.2006;6(6):355-356.
[20]Van HW,Balemans W,Van HE,et al.Van Buchem disease(hyperostosis corticalis generalisata)maps to chromosome17q12-q21.Am J Hum Genet.1998;62(2):391-399.
[21]Balemans W,Ende JV,Paesalves AF,et al.Localization of the gene for sclerosteosis to the van Buchem disease-gene region on chromosome 17q12-q21.Am J Human Genet.1999;64(6):1661-1669.
[22]Brunkow M.Bone dysplasia sclerosteosis results from loss of the SOST gene product,a novel cystine knot-containing protein.Am J Human Genet.2001;64(3):577-589.
[23]Piters E,Culha C,Moester M,et al.First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function.Hum Mutat.2010;31(7):E1526–E1543.
[24]Balemans W,Patel N,Ebeling M,et al.Identification of a 52kb deletion downstream of the SOST gene in patients with van Buchem disease.J Med Genet.2002;39(2):91-97.
[25]van Bezooijen RL,Roelen BA,Visser A,et al.Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation,But Not a Classical BMP Antagonist.J Exp Med 2004;199(6):805-814.
[26]Sem?nov M,Tamai K,He X.SOST is a ligand for LRP5/LRP6and a Wnt signaling inhibitor.J Biol Chem.2005;280(29):26770-26775.
[27]Semenov M V,He X.LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST.J Biol Chem.2006;281(50):38276-38284.
[28]Li X,Zhang Y,Kang H,et al.Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling.J Biol Chem.2005;280(20):19883-19887.
[29]Chang MK,Kramer I,Keller H,et al.Reversing LRP5-dependent osteoporosis and SOST deficiency-induced sclerosing bone disorders by altering WNT signaling activity.J Bone Miner Res.2014;29(1):29-42.
[30]Yorgan TA,Peters S,Jeschke A,et al.The Anti-Osteoanabolic Function of Sclerostin Is Blunted in Mice Carrying a High Bone Mass Mutation of Lrp5.J Bone Miner Res.2015;30(7):1175-1183.
[31]Wang Y,Li YP,Paulson C,et al.Wnt and the Wnt signaling pathway in bone development and disease.Front Biosci(Landmark Ed).2014;19:379-407.
[32]Rudnicki MA,Williams BO.Wnt signaling in bone and muscle.Bone.2015;80:60-66.
[33]Li X,Ominsky MS,Warmington KS,et al.Sclerostin antibody treatment increases bone formation,bone mass,and bone strength in a rat model of postmenopausal osteoporosis.J Bone Miner Res.2009;24(4):578-588.
[34]Ominsky MS,Vlasseros F,Jolette J,et al.Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation,bone mineral density,and bone strength.J Bone Miner Res.2010;25(5):948-959.
[35]Virk MS,Alaee F,Tang H,et al.Systemic Administration of Sclerostin Antibody Enhances Bone Repair in a Critical-Sized Femoral Defect in a Rat Model.J Bone Joint Surg Am.2013;95(8):694-701.
[36]Padhi D,Jang G,Stouch B,et al.Single-dose,placebo-controlled,randomized study of AMG 785,a sclerostin monoclonal antibody.J Bone Miner Res.2011;26(1):19-26.
[37]Mc Clung MR,Grauer A,Boonen S,et al.Romosozumab in Postmenopausal Women with Low Bone Mineral Density.N Enl J Med.2014;370:412-420.
[38]Cosman F,Crittenden DB,Adachi JD,et al.Romosozumab Treatment in Postmenopausal Women with Osteoporosis.New Engl J Med.2016;375(16):1532-1543.
[39]Mccolm J,Hu L,Womack T,et al.Single-and multiple-dose randomized studies of blosozumab,a monoclonal antibody against sclerostin,in healthy postmenopausal women.J Bone Miner Res.2014;29(4):935–943.
[40]Recker R,Benson C,Matsumoto T,et al.A randomized,double-blind phase 2 clinical trial of blosozumab,a sclerostin antibody,in postmenopausal women with low bone mineral density.J Bone Miner Res.2015;30(2):216-224.
[41]Recknor CP,Recker RR,Benson CT,et al.The Effect of Discontinuing Treatment With Blosozumab:Follow-up Results of a Phase 2 Randomized Clinical Trial in Postmenopausal Women With Low Bone Mineral Density.J Bone Miner Res.2015;30(9):1717-1725.
[42]Claire MN,Patton D,Hayes JS.Sclerostin Antibody Therapy for the Treatment of Osteoporosis:Clinical Prospects and Challenges.J Osteoporosis.2016;2016(6217286).
[43]Sugiyama T,Torio T,Miyajima T,et al.Romosozumab and Blosozumab:Alternative Drugs of Mechanical Strain-Related Stimulus Toward a Cure for Osteoporosis.Front Endocrinol(Lausanne).2015;6:54.
[44]Florio M,Gunasekaran K,Stolina M,et al.A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair.Nat Commun.2016;7:11505.
[45]Boschert V,Frisch C,Back JW,et al.The sclerostinneutralizing antibody Ab D09097 recognizes an epitope adjacent to sclerostin's binding site for the Wnt co-receptor LRP6.Open Biol.2016;6(8).pii:160120.
[46]Basha G,Ordobadi M,Scott W R,et al.Lipid Nanoparticle Delivery of si RNA to Osteocytes Leads to Effective Silencing of SOST and Inhibition of Sclerostin In Vivo.Molecular Therapy-Nucleic Acids.2016;5(9):e363.
[47]Armamento-Villareal R,Sadler C,Napoli N,et al.Weight loss in obese older adults increases serum sclerostin and impairs hip geometry but both are prevented by exercise training.J Bone Miner Res.2012;27(5):1215-1221.
[48]Gombos GC,Bajsz V,Pék E,et al.Direct effects of physical training on markers of bone metabolism and serum sclerostin concentrations in older adults with low bone mass.Bmc Musculoskelet Disord.2016;17(1):1-8.
[49]Ardawi MS,Rouzi AA,Qari MH.Physical Activity in Relation to Serum Sclerostin,Insulin-Like Growth Factor-1,and Bone Turnover Markers in Healthy Premenopausal Women:A Cross-Sectional and a Longitudinal Study.J Clin Endocrinol Metab.2012;97(10):3691-3699.
[50]Compton JT,Lee FY.A review of osteocyte function and the emerging importance of sclerostin.J Bone Joint Surg Am.2014;96(19):1659-1668.
[51]Spatz JM,Fields EE,Yu EW,et al.Serum sclerostin increases in healthy adult men during bed rest.J Clin Endocrinol Metabo.2012;97(9):1736-1740.
[52]Zagrodna A,Jó?ków P,M?dra?M,et al.Sclerostin as a novel marker of bone turnover in athletes.Biol Sport.2016;33(1):83-87.
[53]Christen P,Ito K,Ellouz R,et al.Bone remodelling in humans is load-driven but not lazy.Nat Commun.2014;5(5):4855-4855.
[54]Galea GL,Lanyon LE,Price JS.Sclerostin's role in bone's adaptive response to mechanical loading.Bone.2017;96:38-44.
[55]Robling AG,Niziolek PJ,Baldridge LA,et al.Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin.J Biol Chem.2008;283(9):5866-5875.
[56]Silverman SL.Sclerostin.J Osteoporos.2010;2010:941419
[57]Gupta A,March L.Treating osteoporosis.Australian Prescriber.2016;39(2):40-46.
[58]Thouverey C,Caverzasio J.Sclerostin inhibits osteoblast differentiation without affecting BMP2/SMAD1/5 or Wnt3a/β-catenin signaling but through activation of platelet-derived growth factor receptor signaling in vitro.Bonekey Rep.2015;4:757.
