CN1233325C - 治疗骨坏死和处理有发展为骨坏死危险的患者用的药物 - Google Patents
治疗骨坏死和处理有发展为骨坏死危险的患者用的药物 Download PDFInfo
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Abstract
一种用于治疗骨坏死和/或剥脱性骨坏死的双膦酸盐。所述药物进一步可用来预防骨坏死和/或剥脱性骨坏死以及与两种疾病关联的任何并发症的发作。
Description
发明领域
本发明涉及某类药物的新适应证。更特定地，本发明涉及双膦酸盐在治疗骨坏死以及相关的疾病例如剥脱性骨软骨炎(osteochondrifis dissecans)中的用途。在更深层次的公开中，本发明涉及双膦酸盐在处理有发展为骨坏死危险的患者中的用途。
发明背景
骨坏死是一种临床和病理上清楚的疾病，具有许多不同的病因和相异的发病机理。尽管已经有许多关于该疾病的报道，但所有的病因学和发病机理因素目前还不为人所知道。骨坏死会自发地侵袭成人和儿童(Perthes疾病)，或由下述疾病过程产生，如酒精中毒，暴露于糖皮质激素和或细胞毒性药物，暴露于高压环境(caisson疾病)i，骨折，感染，血液学疾病等。目前没有经证实的药理试剂可用来治疗骨坏死。
骨坏死这类疾病后果很严重，通常影响关节的功能，最常见髋关节的功能。如果髋关节受到侵袭，股骨头容易导致塌陷(collapse)，导致疼痛，强直和长期不能活动。受累关节进一步容易导致畸形和骨关节炎。不明病因的骨坏死影响很大比例的人群(包括儿童)。具体地，Perthes病(Legg-Calve-Perthes病)较为常见，发病率为每年8.5～21每100,000儿童ii，iii，iv，v。Perthes病的病因还不清楚，但大多数理论的共同终通路认为血管侵袭导致一段时期的相对缺血和骨坏死，导致坏死骺的再吸收和塌陷vi，vii，viii。
Perthes病公知会导致骨关节炎。在一项研究中的56岁的患者中，40％受累患者进行了整个髋置换手术。由于股骨头变得更虚弱和更骨质疏松，发生软骨下的塌陷。目前没有公知有效的医学手段治疗Perthes病。机械治疗例如支撑法很大程度上已经摒弃，因为其已经证明不能改变疾病的自然进程ix，x。目前的观点认为如果儿童的髋达到一定程度的畸形，需要进行手术以将股骨头放置关节中较好的位置，以尽量产生更球形的髋，这样可以得到较好的长期效果。几乎没有手术选择是为了预防塌陷以及用来一旦髋的塌陷和畸形相继发生后的治疗措施。目前的手术治疗的效果有限或很固定。xi，xii，xiii。
也有股骨头骨坏死发生在儿童中的情形。患有恶性疾病的儿童特别易发展为骨坏死。Mattano等报道患有急性淋巴细胞白血病(ALL)的1,409儿童在3年生存期中的发展为骨坏死的发生率为9.3％xiv。在该项研究中，疼痛和/或活动受限症状在84％的患者中延续很长时间，24％进行了外科整形，另外的15％考虑将来进行外科手术。在24个患急性淋巴细胞白血病儿童的前瞻性MRI的研究中，Ojala等记载骨坏死的发生率为38％xv。
骨坏死也发生在接受骨髓，肾，肺和肝移植恢复期的患者中xvi，xvii，xviii，xix。发生股骨颈骨折的儿童也会继续发生股骨头坏死，正如上部股骨骺滑动的儿童一样。如果他们发展为无血管性坏疽，患者的后果通常很差xx。在最近儿童的股骨颈骨折的研究中，无血管性坏疽的发生率为40％xxi。
在成年患者中，相继发生进行性骨和软骨关节的塌陷，通常伴随软骨下骨折。在股骨头坏死的前瞻性的研究中，Ito等发现在平均6年的随访中64％患者是有症状的xxii。在老年患者中，股骨头进行性塌陷和畸形进展迅速，66％的患者在短期内发展为塌陷，并且22％表现为股骨头的快速再吸收和破坏xxiii。对这些老年患者，用以解决随后的髋疼痛和活动受限的整个髋关节造形术具有相当的风险性。
骨坏死的手术方案包括中心解压以减少骨内的压力以及增加新鲜血液供应；骨移植物，无论是通过中心解压或通过关节(活盖方法)；血管化骨和/或组织移植；和将受累部位远离负重的再定位(redirectional)骨切开术。Perthes病中的牵引治疗，非手术或手术性的，以使塌陷的股骨头再成形，已经进行了充分的描述。利用外部固定器或支撑物以使关节不负重并预防受累部分的塌陷也进行了充分的描述。相关疾病剥脱性骨软骨炎的外科治疗通常涉及用固定的装置来固定软骨下骨片段，后者已经偏离了相邻骨，用或不用骨移植物和骨钻孔技术。有时需要切除片段。
最近的技术涉及用高压氧治疗骨坏死，但是，一些作者认为沉箱(caisson)病可能是由于高压氧而不是氮气引起Xxiv。确实，在最近的患有骨坏死的20名儿童在进行细胞毒性化疗的一项研究中，在随后的MRI中，没有发现用高压氧治疗组与对照患者组之间的差异性xxv。
尽管有上述这些治疗方法，疾病例如骨坏死和剥脱性骨软骨炎的预后很差。一旦疾病存在，患骨塌陷将持续数月至数年，导致相应关节的畸形和骨关节炎。
两种病理情况都会导致患者不能活动，其对个人和社会的代价都很高，特别是骨坏死和剥脱性骨软骨炎通常发生在年轻，健康的患者中。
整个关节置换手术，通常在年轻的患者中伴随并发症和短时疗效，需要缓解疼痛以及减轻个人的痛苦。因此药物治疗将为这些患者提供极大的益处。
本说明书中已经包括的任何讨论的文献，条例，材料，装置，文章等只作为为本发明提供参考的目的。并不能视为这些材料的任何部分或整体构成了本申请任何权利要求的优先目前的在澳大利亚存在的现有技术的部分基础或在本发明相关领域中是公知的。
发明概述
第一方面，本发明当用于治疗骨坏死时，由选自至少一种双膦酸盐的药物组成。
第二方面，本发明当用于治疗剥脱性骨软骨炎时，由选自至少一种双膦酸盐的药物组成。
第三方面，本发明是关于一种治疗骨坏死和/或剥脱性骨软骨炎患者的方法，所述方法包括给患者施用选自至少一种双膦酸盐的药物的步骤。
第四方面，本发明是关于预防骨坏死和/或剥脱性骨软骨炎和有患两种疾病之一的危险患者中的与所述疾病关联的任何并发症一种的方法，所述方法包括给患者施用选自至少一种双膦酸盐的药物的步骤。
第五方面，本发明是关于选自至少一种双膦酸盐的药物在制备用于治疗骨坏死的药剂中的用途。
第六方面，本发明是关于选自至少一种双膦酸盐的药物在制备用于治疗剥脱性骨软骨炎的药剂中的用途。
第七方面，本发明是关于选自至少一种双膦酸盐的药物在制备药剂中的用途，所述药剂适合于预防有发展为骨坏死和/或剥脱性骨软骨炎的危险的患者用药。
第八方面，本发明是关于选自至少一种双膦酸盐的药物，用于预防与骨坏死和/或剥脱性骨软骨炎相关的软骨破坏或软骨溶解。
第九方面，本发明是关于一种预防与骨坏死和/或剥脱性骨软骨炎相关的软骨破坏或软骨溶解的方法，所述方法包括向患者施用选自至少一种双膦酸盐的药物的步骤。
所选择的双膦酸盐优选地至少减轻或预防骨和软骨的畸形和/或塌陷的严重性并使患者的新骨形成。
其中所述药物对有骨坏死或剥脱性骨软骨炎的危险的患者进行预防性地给药，所述预防性给药优选地具有在患者体内形成治疗有效的双膦酸盐储备的效果，从而使骨塌陷和畸形的发生可能性降低到最低，并刺激新骨形成，并且保持骨结构，避免发生骨坏死。
在优选的实施方案中，所述药物为静脉给药。或者，所述药物可给药口服。此外，所述药物也可皮下，肌肉内，经皮，局部或用任何其他可以产生治疗效果的途径给药。所述药物也可对靶点进行局部地给药。例如，所述药物可在骨坏死的手术过程中局部地给药。
在所述药物为局部给药的实施方案中，作为方法的一部分，所述药物可直接对骨表面给药，或作为局部传送体系的部分。局部传送体系可为骨移植物替代物或补充剂(extender)的形式，或自体的或异体的骨移植物。骨移植物替代物或补充剂可包含硫酸钙，碳酸钙，磷酸三钙，羟基磷灰石，或其他含钙化合物，单独或以任何联合形式。骨移植物替代物，补充剂，自体移植物或异体移植物，除与有效量的双膦酸盐混合的物质外，也可包含载体媒介例如胶原质，白明胶，甘油，丙二醇，树脂，聚乙醇酸(PGA)，聚-1乳酸(PLLA)，聚d-1乳酸(PLLA)，多孔硅，或任何其他再吸收生物可容性媒介，以可注射的液体，凝胶，油灰或乳膏形式或以可塑的液体，乳膏，油灰，凝胶软片，筛孔或海绵体形式或其他方便应用的方法。也包括任何上述媒介和任何黏合剂的混合物。双膦酸盐和载体单独也可用于局部给药。初始局部或全身剂量之后，进一步的全身剂量也许有利或不利。
载体可包含参与骨形成细胞或其他细胞需要的营养成分并且优选地可以再吸收。载体可进一步包括公知的参与骨愈合的基因产品。合适的基因产品实例包括，但不限于，骨形态形成蛋白7(OP-1)，BMP-2和-4，其他的骨形态形成蛋白，β-转化生长因子，成纤维细胞生长因子(碱性或酸性)，胰岛素样生长因子-1或-2，骨钙蛋白，或其它已知的生物活性蛋白，多肽，或基因产物。所述方法比单用双膦酸盐可能具有有益的协同效果：双膦酸盐稳定骨骼结构并且生长因子潜在地刺激增加脉管化和新骨形成。同样地联合使用可能比单独使用生长因子基因产品更有效，因为使用双膦酸盐将使响应生长因子而形成的新骨得到更好的维持。
载体媒介也可包含含生长因子或细胞，“暗黄色膜(buffy coat)”(例如AGF)，骨髓吸出液或培养的成骨细胞或前体，或多能的干细胞的血液制品。载体也可包含转染了骨形成基因的细胞，例如通过腺病毒载体，以使参与骨愈合的基因过量表达，导致增加的骨形成。此外所述联合治疗比单用双膦酸盐可能有协同作用：双膦酸盐稳定骨骼结构并且细胞刺激增加的新骨形成。
许多细胞，基因产物生长因子，营养成分，载体媒介和骨移植物替代物的联合应用当与至少一种双膦酸盐混合时，可证明有效。
在另一个实施方案中，所述药物为佐来双膦酸(zoledronic acid)(佐来膦酸盐(zoledronate)){1-羟基-2-[(1H-咪唑-1-基)亚乙基]双膦酸}。或者，所述药物可为氨羟二磷酸二钠(pamidronate){3-氨基-1-羟基亚丙基双膦酸}，阿仑特罗(alendronate){4-氨基-1-羟基亚丁基双膦酸}，依替膦酸钠(etidronate){1-羟基亚乙基双膦酸}，氯屈膦酸二钠(clodronate){二氯亚甲基双膦酸}，利塞膦酸钠(risedronate){2-(3-吡啶基)-1-羟基亚乙基双膦酸}，替鲁膦酸钠(tiludronate){氯-4-苯基硫代亚甲基双膦酸}，伊本膦酸钠(ibandronate){1-羟基3(甲基戊基氨基)-亚丙基双膦酸}，因卡膦酸钠(incadronate){环庚基-氨基-亚甲基双膦酸}，米诺膦酸钠(minodronate){[1-羟基-2-(咪唑[1，2-a]吡啶-3-基)亚乙基]双膦酸}，奥巴膦酸钠(olpadronate){(3-二甲基氨基-1-羟基亚丙基)双膦酸}，乃立膦酸钠(neridronate)(6-氨基-1-羟基亚己基-1，1-双膦酸)，EB-10531-羟基-3-(1-吡咯烷基)-亚丙基-1，1-双膦酸，或任何其他的治疗有效的双膦酸盐或其可药用盐或酯。
在一种实施方案中，骨坏死或剥脱性骨软骨炎侵袭股骨头，远端股骨，近端胫骨，距骨(talus)，舟状骨(navicular)或其他的跗骨，骨头，肱骨头或近端肱骨，小头或远端肱骨，桡骨头，舟骨(scaphoid)，月骨或其他腕骨。然而，应该注意到所述疾病会影响患者体内的任何其他骨或关节。
在另一个实施方案中，骨坏死存在于诊断患有Perthes病(Legg-Calve-Perthes病)的儿童患者中。
在另一个实施方案中，骨坏死或骨软骨炎可为不明原因的。
在其他的实施方案中，骨坏死或剥脱性骨软骨炎可继发于某种疾病过程。实例为，骨坏死或剥脱性骨软骨炎可继发于疾病例如Gaucher氏病，镰状细胞疾病或其他血液疾病，肾衰，肝衰，内分泌疾病，HIV及相关的综合征，白血病或其他恶性病，原发骨发育异常，结缔组织疾病，自身免疫疾病，或免疫抑制疾病。
骨坏死或剥脱性骨软骨炎可在暴露于已知的引起骨坏死的高危险物质后发生，所述物质包括但不限于皮质类固醇(糖皮质激素)，环孢菌素或其他免疫抑制药物，用于恶性疾病或风湿性关节炎形式的细胞毒性药物，滥用违法药物，酗酒，和/或吸烟。
骨坏死或剥脱性骨软骨炎可在骨髓移植或器官移植后发生。
在另一个实施方案中，骨坏死或剥脱性骨软骨炎可关联于外伤例如骨折。骨折可为股骨头，股骨颈或股骨粗隆间的骨折，桡骨头或颈部，肱骨小头的骨折，距骨或其他跗骨的骨折，肱骨头，颈部或肩胛下窝的骨折，舟骨，月骨或其他腕骨的骨折。或者一些其他骨的骨折。
骨坏死或剥脱性骨软骨炎可以不是与骨折的损伤相关，例如，脱臼或半脱位。
可以给骨坏死或剥脱性骨软骨炎手术前后的患者用药。手术涉及中心解压，骨移植物，血管化骨或组织移植物或转移，“活盖(trapdeor)”骨移植方法，骨成形术或软骨成形术，骨切开术，或内部或外部固定。
在选自至少一种双膦酸盐的药物为预防性给药的情况下，所述药物可对以前在某个部位已患骨坏死的患者给药，所述患者因此在其他部位有发生骨坏死的高危险性。在这种情况下，已知的骨坏死可以涉及股骨头，远端股骨，近端胫骨，距骨或其他跗骨，骨头，肱骨头或近端肱骨，小头或远端肱骨，桡骨头，舟骨，月骨或其他腕骨。
在其他的实施方案中，所述药物可以对曾经骨折的患者预防性地给药，其中存在骨折导致骨坏死的高风险。骨折可为股骨头，股骨颈或股粗隆间骨折，滑动的股骨头骺或其他骨骺，桡骨头或颈部骨折，肱骨小头，距骨或其他跗骨的骨折，肱骨头骨折，颈部或肩胛下窝，舟骨，月骨或其他腕骨骨折。或者，预防性治疗可以在患者患有非骨折损伤之后进行，例如，脱臼或半脱位，其中损伤具有导致骨坏死危险性，例如，外伤性髋脱位和外伤性肩脱位。
在另一个实施方案中，可以对将要、正在或已经接受与骨坏死关联的手术的患者给药。在该实施方案中，所述手术涉及用于治疗骨坏死的减轻先天性或进展性髋脱位，任何近关节的骨切开术，骨成形术，中心解压或骨移植物，血管化骨或软组织迁移，“活盖”骨移植方法。
用于预防性治疗的另一适应证是继发于疾病过程的骨坏死或剥脱性骨软骨炎，疾病例如Gaucher氏病，镰状细胞疾病或其他血液疾病，肾衰，肝衰，内分泌疾病，HIV及相关的综合征，白血病或其他恶性病，原发骨发育异常，结缔组织疾病，自身免疫疾病，或免疫抑制疾病。
可以进行预防性治疗的患者是曾经暴露于具有引起骨坏死高危物质的主体，所述物质包括但不限于皮质类固醇(糖皮质激素)，环孢菌素或其他免疫抑制药物，用于恶性疾病或风湿性关节炎形式的细胞毒性药物，滥用违法药物，酗酒，和/或吸烟。
在另一个实施方案中，患者为骨髓移植或器官移植后处于发展骨坏死或剥脱性骨软骨炎高危中的主体。
在其他的实施方案中，本发明所述药物可以与放射治疗药物一起使用。
双膦酸盐可为佐来双膦酸(或zoledronate)，或其任何可药用盐或酯。优选地，佐来双膦酸以肠胃外给药并优选地大约每3个月以约0.25mg至约12mg的剂量对成人给药或以约0.005mg/kg至约0.5mg/kg对儿童给药。但是，应该注意到，佐来双膦酸可以4周，6周或每2个月给药。此外，佐来双膦酸可以作为单剂量给药以及如果需要可以进一步给药。
在另一个实施方案中，佐来双膦酸可以按下列方式进行肠胃外给药：大约每3个月对成年患者以剂量约2mg，约4mg，约6mg或约8mg进行给药，或对儿童患者以约0.025mg/kg，约0.05mg/kg，约0.075mg/kg或约0.1mg/kg给药。佐来双膦酸可以按下列方式进行肠胃外给药：大约每6个月对成年患者以剂量约2mg，约4mg，约6mg或约8mg进行给药或约0.025mg/kg，约0.05mg/kg，约0.075mg/kg或约0.1mg/kg对儿童患者给药。在另一个实施方案中，佐来双膦酸可以按下列方式进行肠胃外给药：大约每12个月对成年患者以剂量约2mg，约4mg，约6mg或约8mg进行给药或约0.025mg/kg，约0.05mg/kg，约0.075mg/kg或约0.1mg/kg对儿童患者给药。在其他的实施方案中，佐来双膦酸可以按下列方式进行肠胃外给药：一单剂量对成年患者以剂量约2mg，约4mg，约6mg或约8mg进行给药或约0.025mg/kg，约0.05mg/kg，约0.075mg/kg或约0.1mg/kg对儿童患者给药。或者，佐来双膦酸可口服给药。
在另一个实施方案中，双膦酸盐为氨羟二磷酸二钠或其任何可药用盐或酯。优选地，氨羟二磷酸二钠以肠胃外给药并且优选地对成年患者大约每1～3个月以剂量从约15至约90mg给药或对儿童患者每1～3个月以剂量0.25mg/kg～3.0mg/kg给药。在另一个实施方案中，氨羟二磷酸二钠可以经肠胃外给药，每1到3个月对成年患者以剂量约15mg，约30mg，约60mg或约90mg或每1～3个月对儿童患者以0.25mg/kg，约0.5mg/kg，约1.0mg/kg，约2.0mg/kg或约3.0mg/kg给药。在另一个实施方案中，氨羟二磷酸二钠可以经肠胃外给药，大约每6个月对成年患者以剂量约15mg，约30mg，约60mg或约90mg或大约每6个月对儿童患者以0.25mg/kg，约0.5mg/kg，约1.0mg/kg，约2.0mg/kg或约3.0mg/kg给药。在另一个实施方案中，氨羟二磷酸二钠可以经肠胃外给药，大约每12个月对成年患者以剂量约15mg，约30mg，约60mg或约90mg或大约每12个月对儿童患者以0.25mg/kg，约0.5mg/kg，约1.0mg/kg，约2.0mg/kg或约3.0mg/kg给药。在另一个实施方案中，氨羟二磷酸二钠可以经肠胃外给药，以单剂量对成年患者以剂量约15mg，约30mg，约60mg或约90mg或对儿童患者以0.25mg/kg，约0.5mg/kg，约1.0mg/kg，约2.0mg/kg或约3.0mg/kg给药。
在另一个实施方案中，双膦酸盐为阿仑特罗或其任何可药用盐或酯。优选地，阿仑特罗口服给药并且优选地对成年患者每天以剂量从约2.5mg至约50mg或每周约10mg至约300mg给药。对儿童患者优选口服剂量为每天从约0.05mg/kg～1.0mg/kg或每周约0.2mg/kg～6.0mg/kg。对成年患者，阿仑特罗可以每天约5mg，约10mg，约20mg或每周约40mg或约35mg，约70mg约140mg或约280mg的剂量口服给药。对儿童，阿仑特罗可以每天约0.1mg/kg，约0.2mg/kg，约0.4mg/kg，或每周约0.8mg/kg每天，或约0.8mg/kg，约1.5mg/kg，约3.0mg/kg或约5.0mg/kg的剂量口服给药。或者，阿仑特罗优选地以大约每1～3个月从约0.25mg至约30mg的剂量，或以单剂量肠胃外给药。
在其他的实施方案中，双膦酸盐为利塞膦酸钠或其任何可药用盐或酯。优选地，利塞膦酸钠以给药口服并且优选地对成年患者每周以从约2.5mg至约60mg每天或约10mg至约300mg的剂量给药或约0.05mg/kg至约1.0mg/kg每天，或对儿童患者每周以从约0.25mg/kg至约7.0mg/kg给药。利塞膦酸钠可每天约2.5mg，约5mg，约10mg或约30mg，或每周约15mg，约30mg，约60mg，或约210mg的剂量对成年患者口服给药或，对儿童，以每天约0.05mg/kg，约0.1mg/kg，约0.2mg/kg，约0.5mg/kg，或每周约0.25mg/kg，或约0.5mg/kg，约1.0mg/kg，或约2.5mg/kg给药。或者，利塞膦酸钠可以静脉给药。
在其他的实施方案中，双膦酸盐为伊本膦酸钠或其任何可药用盐或酯。优选地，伊本膦酸钠用肠胃外给药并且优选地大约每1～3个月以剂量从约0.25mg至约30mg，并且更优选地以剂量约2mg～10mg，或以单剂量给药。
在另一个实施方案中，伊本膦酸钠以每天约2.5mg，约5mg，约10mg或约30mg，或每周约15mg，约30mg，约60mg，或约210mg的剂量对成年患者口服给药或，对儿童，以每天约0.05mg/kg，约0.1mg/kg，约0.2mg/kg，约0.5mg/kg，或每周约0.25mg/kg，或约0.5mg/kg，约1.0mg/kg，或约2.5mg/kg的剂量给药。
在另一个实施方案中，双膦酸盐为因卡膦酸钠或其任何可药用盐或酯。优选地，因卡膦酸钠用肠胃外给药并且优选大约每1～3个月以剂量从约0.25mg至约30mg，更优选地约10mg对成年患者给药或，对儿童，从约0.005mg/kg～0.6mg/kg，更优选地约0.025mg/kg～0.25mg/kg给药，或以单剂量给药。
在另一个实施方案中，因卡膦酸钠以口服方式以每天约2.5mg，约5mg，约10mg或约30mg，或每周约15mg，约30mg，约60mg，或约210mg的剂量对成年患者给药或，对儿童，以每天约0.05mg/kg，约0.1mg/kg，约0.2mg/kg，约0.5mg/kg，或每周约0.25mg/kg，或约0.5mg/kg，约1.0mg/kg，或约2.5mg/kg给药。
在另外一个实施方案中，双膦酸盐为米诺膦酸钠或其任何可药用盐或酯。优选地，米诺膦酸钠以大约每1～3个月给药0.25mg至约30mg，或以单剂量给药。更优选地，米诺膦酸钠用肠胃外给药并且优选地大约每3个月以剂量从约0.25mg至约12mg对成年患者或约0.005mg/kg至约0.5mg/kg对儿童患者的剂量进行给药。在另一个实施方案中，米诺膦酸钠可以肠胃外给药，大约每3个月以约2mg，约4mg，约6mg或约8mg的剂量对成年患者给药或约0.025mg/kg，约0.05mg/kg，约0.075mg/kg或约0.1mg/kg对儿童患者给药。米诺膦酸钠可用肠胃外给药，大约每6个月以剂量约2mg，约4mg，约6mg或约8mg对成年患者给药或约0.025mg/kg，约0.05mg/kg，约0.075mg/kg或约0.1mg/kg对儿童患者给药。
在另一个实施方案中，米诺膦酸钠可以肠胃外给药，大约每12个月以剂量约2mg，约4mg，约6mg或约8mg对成年患者给药或约0.025mg/kg，约0.05mg/kg，约0.075mg/kg或约0.1mg/kg对儿童患者给药。在其他的实施方案中，米诺膦酸钠可以肠胃外给药，以单剂量约2mg，约4mg，约6mg或约8mg对成年患者或约0.025mg/kg，约0.05mg/kg，约0.075mg/kg或约0.1mg/kg对儿童患者给药。或者，米诺膦酸钠可给药口服。
在另一个实施方案中，双膦酸盐为氯屈膦酸二钠或其任何可药用盐或酯。氯屈膦酸二钠口服给药剂量范围为对成年患者每天约400mg～2400mg或，对儿童，50mg/kg～250mg/kg或静脉给药剂量范围为150mg～300mg或，对儿童，以1mg/kg～5mg/kg的剂量每天重复给药，持续2～5天，需要的时候重复给药，可能每1～6个月。
在另一个实施方案中，双膦酸盐为依替膦酸钠或其任何可药用盐或酯。依替膦酸钠口服给药剂量范围为约100～400mg(每天5～20mg/kg)或，对儿童，每天5～20mg/kg。
在另一个实施方案中，双膦酸盐为替鲁膦酸钠或其任何可药用盐或酯。替鲁膦酸钠口服给药剂量范围对成年患者为每天约400mg或，对儿童，为每天5～20mg/kg。
在另一个实施方案中，双膦酸盐为奥巴膦酸钠或其任何可药用盐或酯。奥巴膦酸钠口服给药剂量范围为对成年患者约50-400mg每天或，对儿童，1mg/kg～10mg/kg或给药静脉剂量范围为每1～3个月1mg～20mg或，对儿童，0.1mg/kg～0.5mg/kg。
在另一个实施方案中，双膦酸盐为乃立膦酸钠或其任何可药用盐或酯。在另一个实施方案中，乃立膦酸钠以肠胃外方式给药，剂量范围对成年患者为10mg～100mg，或对儿童，每1～3个月静脉给药0.1～2mg/kg。
在另一个实施方案中，所述药物为EB-1053。
附图简介
只作为实例，本发明的优选实施方案参考附图进行描述。
图1为一类双膦酸盐的通式。
图2A和2B诊断患有Perthes病的患者的X光照片。
图3为实施例1中大鼠的近端股骨的一组代表性X光照片。
图4为实施例1中每只大鼠的近端股骨的一组X光照片。
图5为一组TC99骨扫描图，表明实施例1中每只大鼠的近端股骨的血管的再形成。
图6为一组Von Kossa未除石灰质(undecalcified)组织学切片，显示实施例1中大鼠的近端股骨的骨结构保持。
图7为一组甲苯胺蓝组织学切片，显示实施例1中大鼠的关节软骨保持。
图8为一组荧光组织学切片，显示实施例1中大鼠组近端股骨中的骨形成活性。
本发明优选实施方案
本发明涉及图1中通式表示的双膦酸盐的应用，其中改变R1和R2得到不同活性和其他性质的双膦酸盐。
本发明涉及针对骨坏死，包括骨坏死受累的关节相邻的骨和软骨的新型药物治疗。施用治疗有效的剂量的至少一种双膦酸盐，例如佐来双膦酸，由于降低了破骨细胞的活性，坏死骨的塌陷可以延缓，同时新骨矿化以增加及提高机械完整性的新骨可能会加速修缮过程，进而减少受累骨和软骨的任何塌陷范围。这种治疗关节或骨的畸形危险性降至最低，并且，进一步降低疼痛和骨关节炎发展的风险。
双膦酸盐在很长的时间内保持治疗有效的特点已经为人所知。因此，当血液返回坏死区域时，正如受累骨的骨扫描图象证实，坏死骨开始摄取任何循环中双膦酸盐。开始发挥双膦酸盐的保护和修缮作用，因此延缓坏死骨的塌陷同时高度矿化的新骨响应于双膦酸盐治疗而沉淀下来。高度矿化的新骨改善了受累关节的机械性能。
其它研究认为佐来双膦酸在本研究的剂量范围内抑制血管生成xxvi，因此作为佐剂将无助于骨坏死的治疗。我们以前的结果表明施用佐来双膦酸导致兔的胼胝形成增加，矿化以及撑开牵引血管生成的强度增加，与这些观察不一致。这基于血管生成是骨形成中的关键因素的理解。用来设计本实验的假设是基于双膦酸盐治疗会导致抑制再吸收和前成骨细胞效果的知识。双膦酸盐对成骨细胞的积极作用目前广为人知，其并不是只作用于破骨细胞。由于双膦酸盐治疗为易导致骨坏死的骨折提供了解决方案，如股骨颈，距骨颈或舟骨，可以增加新骨形成和预防骨坏死导致的塌陷。
实例见图2。X射线照片(A)显示拍摄X-线前诊断患有Perthes疾病6个月7岁男孩的髋关节。射线照片(B)显示拍摄X-线前诊断前患Perthes疾病12个月另一个男孩的髋关节。可以看出在Perthes疾病发展过程中具有下列典型的特征。骺(正成长的股骨头)10已经明显坏死。坏死骺中的高度矿化的骨在各种内源性调节因子的作用下正在被吸收，这样其机械完整性被破坏，并且正在塌陷。伴随坏死骨的再吸收，也有骨11(骨体内的骨并且特别是邻接骺或生长板的区域)的再吸收，可能也是有相同调节因子作用的结果。这种作用移去了生长板12的结构支持，其不久就会塌陷并变得无组织，限制了股骨头10的生长和恢复可能性。在股骨头10侧面形成的新骨质量很差，只具有很少的力学完整性。其随时间缓慢从关节突出，使股骨头10成为鞍形。
应用治疗有效量的的双膦酸盐将减缓坏死骨的再吸收和塌陷，限制 骨的再吸收并且促进骺侧部形成的新骨中的矿物含量增加。通过预防坏死骨的塌陷以及增加新骨的力学完整性，将维持更加球形的股骨头。由于Perthes病的预后与股骨头球形直接相关，治疗有效的剂量双膦酸盐的这种应用可能为患Perthes病的患者提供显著改善的结果。
实施例1
下列实施例概述了可以观察到双膦酸盐对坏死骨的效果的过程。
外伤骨坏死模型在24只雌性14-周龄Wistar大鼠上应用。对动物进行中断向股骨头供血的手术后，观察6周。选6周时间点作为股骨头塌陷已经在这种模型中出现的时间点。已经得到动物伦理方面的批准。按照下列方案，大鼠随机分成3组。对照组通过皮下途径只接受盐水(S)注射。术后给药动物组在手术前只接受盐水，但手术后在第1和4周以0.1mg/kg的剂量皮下注射佐来双膦酸(ZA)(Novartis)，药品来源于商业途径。术前术后给药动物组在所有的3个时间点接受0.1mg/kg的佐来双膦酸。
在时间0点在每一只大鼠上进行同样的操作。所有的动物在麻醉前准确称量。在手术和恢复期中，将动物置于温暖环境中。用克他命75mg/kg和甲苯噻嗪10mg/kg的混合物诱导麻醉。在给药之前，在同样的注射器中混合药物，以0.2mL每100g BW IM给药。在5-10分钟内发生诱导。
消毒处理并剃光右后腿，对髋关节进行切开手术。打开被膜，右股骨头从关节窝脱位。分开圆助状的韧带，破坏从该途径的任何血液供应。用vicryl缝合进行抛光处理，使整个股骨颈从软组织剥离。这种方法破坏了侧面骺动脉以及任何其他的通过股骨颈向头部供应的脉管。
动物可以随意取食压缩饲料和水并且分成4组关在笼中。
在第4周和第5周进行双荧光标记：在第4周腹膜内给药去甲金霉素(demeclocycline)30mg/kg，并且在第5周腹膜内给药钙黄绿素20mg/kg。进行挑出杀死(culling)前1小时，皮下给药70MBq Tc99 MDP，可以对收集的标本上进行骨闪烁扫描法。
挑出杀死后，收集右和左近端大腿骨并在4％多聚甲醛中固定。用Faxitron Shielded Cabinet X-Ray System(Hewlett Packard，McMinnville，OR)在高质量膜上成对进行X光拍片。X-ray图象用连有数字化书写板(GTCOCalComp，Inc.，Columbia，MD)的Bioquant图象分析系统(R & M BiometricsInc.，Nashville，TN)数字化并且分析。记录骨面积，股骨头高度和宽度并与对侧边的进行比较。用4mm小孔进行闪烁扫描。用pDEXA Sabre scanner(Norland，Ft Atkinson WI)测量BMD和BMC。
标本进行树脂包埋并进行未脱钙切片。冠状切片(6微米)切过股骨头。切片用von Kossa染色以评估小梁骨容积和结构。用荧光显微镜来观察未染色的切片以获得荧光标记图象并评价骨形成。
实验中一只对照鼠死亡，未替换，余下23对近端大腿骨进行分析。
结果
代表性的X射线照片见图3。每个近端股骨的整套X射线照片见图4。在该图中，最上排为盐水组，第二排为术后给药组，第三排为术前术后给药组。右髋进行了手术而左髋没有。
形态学上讲，在术后给药组中的骨结构保持较好，除了一些股骨颈状再吸收。在术前术后给药组中，股骨头几乎完全保持。
盐水组中的股骨头较小，以未手术侧的百分比表示，如用Bioquant图象分析系统测量的那样(表I)。手术盐水组的股骨头减少到对侧的63％(未手术髋)。当两种治疗组与盐水处理的未手术对照组(p＜0.01，ANOVA)比较时这种效果显著降低。股骨头的最大程度的保持在术前术后给药组(85％)中，但是术后给药组(79％)的保持仍然显著好于对照组(p＜0.01，t检验)。
表I-结果
| 未手术对照 | 手术对照 | 术后给药 | 术前术后给药 | |
| XR头面积(％对照) | - | 63 | 79 | 85 |
| BMD(g/cm2) | 0.11 | 0.07 | 0.11 | 0.12 |
| BMC(g) | 0.017 | 0.006 | 0.012 | 0.015 |
DEXA扫描显示：处理组与对照组相比，在股骨头BMD和BMC中显著的增加(P＜0.01，ANOVA)，其保持值为或接近未手术对照组(表II)。在以前的研究中，我们发现强度与BMC很好地关联，其在盐水组中减少到接近1/3。骨闪烁扫描显示完全的血管再形成，手术侧产生吸收在所有的情况下高于未手术侧，如图5所表示。在该图中，上排为盐水组，第二排为术后给药组，第三排为术前术后给药组。右髋进行了手术而左侧没有。
组织学显示在两种治疗组中都保持了骨结构，而手术的对照组再吸收了大多数的骺，使其变得宽而平(图6)。
在所有的治疗组中，有较好的关节软骨的保持(图7)。用甲苯胺蓝染色的术前和后大鼠表现出厚的关节软骨，与进一步的软骨生长但继发于无血管侵袭的延迟骨化一致。在术后给药和未手术处理的标本中的关节软骨看起来相当，但在对照组中最糟，其中软骨薄，许多区域染色较差。
四环素标记显示在所有的实验组中骨形成在第4周又重新开始(Fig8)。在手术组中，骨形成很明显，(右上)但直到第6周依然没有修复大量的再吸收。术后给药组中股骨头的骨形成与未手术对照组(左下)类似。术前术后给药组中的动物在第4周和5周之间(右下)具有明确但较少量的骨形成，由于其浓密地充满伴有很少成骨表面。在手术的标本中在长骨体生长部(physis)没有骨形成的证据。
讨论
施用佐来双膦酸降低了骺破坏(抗再吸收效果)，也使新骨形成和矿化，生成存活的保持骺。关节软骨保持在治疗组中也很明显。
术后给药组中的股骨颈发生部分再吸收。估计这发生在施用佐来双膦酸的前一周，由于这种现象没有以相同的程度出现在术前术后给药组中。
本领域普通技术人员可以理解，对于特定实施方案中所述的发明可以在不偏离本发明的构思或范围的条件下作出多种变化和/或修饰由此而对其进行较宽范围的描述。因此，本发明的这些实施方案从各个方面都应被认为是说明性的而不是限制性的。
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Claims (23)
1.一种选自至少一种双膦酸盐的药物的用途，其用于制备治疗骨坏死的药物。
2.一种选自至少一种双膦酸盐的药物的用途，其用于制备治疗剥脱性骨软骨炎的药物。
3.权利要求1或2所述的药物的用途，其中双膦酸盐为佐来双膦酸或其任何可药用盐、水合物或酯。
4.权利要求1或2所述的药物的用途，其中双膦酸盐选自氨羟二磷酸二钠，阿仑特罗，依替膦酸钠，氯屈膦酸二钠，利塞膦酸钠，替鲁膦酸钠，伊本膦酸钠，因卡膦酸钠，米诺膦酸钠，奥巴膦酸钠，乃立膦酸钠，1-羟基-3-(1-吡咯烷基)-亚丙基-1，1-双膦酸或其任何可药用盐、水合物或酯。
5.权利要求1-4任何一项所述的药物的用途，其用于制备治疗骨坏死或剥脱性骨软骨炎侵袭的股骨头，远端股骨，近端胫骨，距骨或其他跗骨，庶骨头，肱骨头或近端肱骨，小头或远端肱骨，桡骨头，舟骨，月骨或其他腕骨的药物。
6.权利要求1-4任何一项所述的药物的用途，其中所述药物包含至少一种双膦酸盐和合适的载体。
7.权利要求6所述的药物的用途，其中载体包括骨移植物替代物或补充剂，或自体或异体骨移植物。
8.权利要求6所述的药物的用途，其中所述药物进一步包括骨形态形成蛋白和/或生长因子。
9.权利要求8所述的药物的用途，其中骨形态形成蛋白选自骨形态形成蛋白7，骨形态形成蛋白2和骨形态形成蛋白4。
10.权利要求9所述药物的用途，其中所述药物进一步包括β-转化生长因子，和/或胰岛素样生长因子-1或-2，和/或成纤维细胞生长因子1或成纤维细胞生长因子2。
11.权利要求3所述的药物的用途，其中双膦酸盐为佐来双膦酸或其任何可药用盐、水合物或酯，单剂量范围为0.25mg～12mg。
12.权利要求所4述的药物的用途，其中双膦酸盐为氨羟二磷酸二钠或其任何可药用盐、水合物或酯，单剂量范围为15～90mg。
13.权利要求4所述的药物的用途，其中双膦酸盐为阿仑特罗或任何可药用盐、水合物或酯，单剂量范围为2.5mg～50mg。
14.权利要求4所述的药物的用途，其中双膦酸盐为利塞膦酸钠或其任何可药用盐、水合物或酯，单剂量范围为2.5mg～60mg。
15.权利要求4所述的药物的用途，其中双膦酸盐为伊本膦酸钠或其任何可药用盐、水合物或酯，单剂量范围为0.25mg～30mg。
16.权利要求4所述的药物的用途，其中双膦酸盐为因卡膦酸钠或其任何可药用盐、水合物或酯，单剂量范围为0.25mg～30mg。
17.权利要求4所述的药物的用途，其中双膦酸盐为米诺膦酸钠或其任何可药用盐、水合物或酯，单剂量范围为0.25mg～30mg。
18.权利要求4所述的药物的用途，其中双膦酸盐为氯屈膦酸二钠或其任何可药用盐、水合物或酯，单剂量范围为200mg～2400mg。
19.权利要求4所述的药物的用途，其中双膦酸盐为依替膦酸钠或其任何可药用盐、水合物或酯，单剂量范围为100mg～800mg。
20.权利要求4所述的药物的用途，其中双膦酸盐为替鲁膦酸钠或其任何可药用盐、水合物或酯，单剂量范围为200mg～800mg。
21.权利要求4所述的药物的用途，其中双膦酸盐为奥巴膦酸钠或其任何可药用盐、水合物或酯，单剂量范围为50mg～400mg。
22.权利要求4所述的药物的用途，其中双膦酸盐为乃立膦酸钠或其任何可药用盐、水合物或酯，单剂量范围为10mg～100mg。
23.选自至少一种双膦酸盐的药物的用途，其用于制备预防与骨坏死和/或剥脱性骨软骨炎关联的软骨破坏或软骨溶解的药物。
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| NZ528659A (en) * | 2001-04-03 | 2005-02-25 | Royal Alexandra Hosp Children | A drug for use in bone grafting |
| JP2005514400A (ja) * | 2001-12-21 | 2005-05-19 | ザ プロクター アンド ギャンブル カンパニー | 骨疾患の治療方法 |
| ATE376444T1 (de) * | 2002-05-10 | 2007-11-15 | Hoffmann La Roche | Ibandronsäure zur behandlung und vorbeugung von osteoporose |
| BR0309691A (pt) * | 2002-12-20 | 2005-08-02 | Hoffmann La Roche | Formulação de ibandronato em alta dose |
| PL1534305T3 (pl) | 2003-05-07 | 2007-03-30 | Osteologix As | Leczenie zaburzeń chrząstek i kości solami strontu rozpuszczalnymi w wodzie |
| JPWO2005072747A1 (ja) * | 2004-02-02 | 2007-09-13 | 小野薬品工業株式会社 | 骨吸収抑制剤 |
| ITMI20040218A1 (it) * | 2004-02-10 | 2004-05-10 | Abiogen Pharma Spa | Uso di neridronato sodico per promuovere la neoformazione ossea |
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| US7425549B2 (en) | 2008-09-16 |
| AU2002221339B2 (en) | 2006-04-27 |
| US7612050B2 (en) | 2009-11-03 |
| BR0116862A (pt) | 2004-01-13 |
| NO20033446D0 (no) | 2003-08-04 |
| NZ527351A (en) | 2005-01-28 |
| WO2002062351A1 (en) | 2002-08-15 |
| SI1365769T1 (sl) | 2011-06-30 |
| HUP0303013A3 (en) | 2007-06-28 |
| NO20033446L (no) | 2003-10-01 |
| IL157201A (en) | 2010-04-29 |
| HUP0303013A2 (hu) | 2003-12-29 |
| EP1365769B1 (en) | 2011-01-26 |
| CY1111402T1 (el) | 2015-08-05 |
| CA2435552C (en) | 2010-04-27 |
| JP2004527479A (ja) | 2004-09-09 |
| HK1061797A1 (en) | 2004-10-08 |
| ATE496624T1 (de) | 2011-02-15 |
| CN1529604A (zh) | 2004-09-15 |
| MXPA03007029A (es) | 2004-10-15 |
| US20090005347A1 (en) | 2009-01-01 |
| KR20030072399A (ko) | 2003-09-13 |
| DE60143964D1 (de) | 2011-03-10 |
| ZA200305890B (en) | 2005-01-26 |
| CZ301361B6 (cs) | 2010-01-27 |
| SK9862003A3 (en) | 2004-02-03 |
| DK1365769T3 (da) | 2011-05-16 |
| CZ20032408A3 (cs) | 2004-06-16 |
| CA2435552A1 (en) | 2002-08-15 |
| PL361909A1 (en) | 2004-10-04 |
| US20040097469A1 (en) | 2004-05-20 |
| EP1365769A4 (en) | 2005-08-10 |
| EP1365769A1 (en) | 2003-12-03 |
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