CN100479823C - 双膦酸盐在制造药物套盒中的用途以及用于增加骨质的套盒 - Google Patents
双膦酸盐在制造药物套盒中的用途以及用于增加骨质的套盒 Download PDFInfo
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- CN100479823C CN100479823C CNB028256271A CN02825627A CN100479823C CN 100479823 C CN100479823 C CN 100479823C CN B028256271 A CNB028256271 A CN B028256271A CN 02825627 A CN02825627 A CN 02825627A CN 100479823 C CN100479823 C CN 100479823C
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/66—Phosphorus compounds
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- A—HUMAN NECESSITIES
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- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- Organic Chemistry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了用于治疗哺乳动物骨疾的方法。所述方法包括一个使用双膦酸盐的起始期和一个紧跟起始期的维持期。每天的起始剂量比相应的维持剂量大两倍至二十倍。本发明还公开了用于实施本文中公开的方法的组合物和套盒。
Description
发明领域
本发明涉及增加骨质和减少骨折的方法，该方法用于治疗骨质疏松和其它代谢性骨疾。具体地讲，本发明涉及这样的治疗方法，其按照骨活性膦酸盐的起始剂量和随后按照维持剂量的方式给药。
发明背景
最常见的代谢性骨疾是骨质疏松。骨质疏松可通常被定义为由于在骨头重整单位中骨头的正常再吸收与形成循环的不平衡而导致的骨质的减少，或骨骼组织的萎缩。一般来讲，有两种类型的骨质疏松：原发性和续发性。续发性骨质疏松是由可确认的疾病过程或病体导致的。例如，糖皮质素甾体化合物诱导骨质疏松已为人们所知。参见，例如“美国风湿病学会糖皮质素诱导的骨质疏松特设委员会”(American College of Rheumatology Ad HocCommittee on Glucocorticoid-Induced Osteoporosis)，“防止和治疗糖皮质素诱导的骨质疏松的建议”(Recommendations for the Preventionand Treatment of Gluococorticoid-Induced Osteoporosis)，Arthritis& Rheumatism，第44卷，第7期，2001年7月，第1496页至1503页
2001；B.P.Lukert，M.D.，F.A.C.P.“皮质素诱导的骨质疏松”(Glucocorticoid-Induced Osteoporosis)，Primer in the Metabolic BoneDiseases and Disorders of Mineral Metabolism，第四版，第55章，第292页至296页，American Society for Bone and Mineral Research出版，Murray J.Favus，M.D.编著，Dept of Medicine，University ofChicago Medical Center，Chicago，Illinois。在所有骨质疏松中，约85％是原发性骨质疏松。参见例如，Marjorie M.Luckey，M.D.，“绝经后骨质疏松评估”(Evaluation of Postmenopausal Osteoporosis)，Primer inthe Metabolic Bone Diseases and Disorders of Mineral Metabolism，第四版，第273页至277页，Murray J.Favus，M.D.Editor，Dept ofMedicine，University of Chicago Medical Center，Chicago，Illinois；和“骨质疏松的预防、诊断和治疗”(Osteoporosis Prevention，Diagnosis，and Therapy)，JAMA，2001年2月14日-第285卷，第6期，第785页至795页。这些原发性骨质疏松包括绝经后骨质疏松、与年龄相关的骨质疏松(影响年龄在70至80岁的大多数个体)和先天的骨质疏松。
对一些骨质疏松的个人，骨组织的流失十分大，以致引起骨结构的机械受损。骨折常出现在，例如，患绝经后骨质疏松症妇女的髋部和脊骨。也可能导致驼背(反常增大的胸脊骨曲率)。尽管还没有完全了解其病因，但有很多危险因素被认为与骨质疏松有关。这些因素包括低的体重、低的钙摄入量、身体缺少运动、以及雌性激素的缺乏。
对于骨质疏松的“治疗”描述了许多组合物和方法。其中许多包括使用双膦酸盐或其它骨活性膦酸盐。参见，例如，J.Y.Reginster等人，“利塞膦酸盐在慢性绝经后骨质疏松的女性脊椎骨折方面效果的随机实验”(Randomized Trial of the Effects of Risedronate on VertebralFractures in Women with Established Postmenopausal Osteoporosis)，Osteoporosis International，(2000)11：第83页至91页；Steven T.Harris，MD等人，“利塞膦酸盐在绝经后骨质疏松的女性脊椎和非脊椎骨折方面治疗效果，随机对照实验”(Effects of Risedronate Treatment ofVertebral and Nonvertebral Fractures in Women With PostmenopausalOsteoporosis，A Randomized controlled Trial)，Journal of theAmerican Medical Association，1999年10月13日，第282卷，第14期，第1344页至1352页。
双膦酸盐单独或与其它药物如甲状旁腺激素、钙和维生素D一起的持续和周期的给药被建议用于治疗骨质疏松。参见，例如“美国风湿病学会糖皮质素诱导的骨质疏松特设委员会”(American College of Rheumatology AdHoc Committee on Glucocorticoid-Induced Osteoporosis)，“防止和治疗糖皮质素诱导的骨质疏松的建议”(Recommendations for the Preventionand Treatment of Gluococorticoid-Induced Osteoporosis)，Arthritis &Rheumatism，第44卷，第7期，2001年7月，第1496页至1503页
2001；J.Y.Reginster等人，“利塞膦酸盐在慢性绝经后骨质疏松的女性脊椎骨折方面效果的随机实验”(Randomized Trial of the Effects ofRisedronate on Vertebral Fractures in Women with EstablishedPostmenopausal Osteoporosis)，Osteoporosis International，(2000)11：第83页至91页；Steven T.Harris，MD等人，“利塞膦酸盐在绝经后骨质疏松的女性脊椎和非脊椎骨折方面治疗效果，随机对照实验”(Effectsof Risedronate Treatment of Vertebral and Nonvertebral Fractures inWomen With Postmenopausal Osteoporosis，A Randomized controlledTrial)，Journal of the American Medical Association，1999年10月13日，第282卷，第14期，第1344页至1352页。
申请者已令人惊讶地发现，以高剂量和随后以较低的维持剂量给药骨活性膦酸盐，以较快的速度减少了骨转换并增加了骨质，致使能够更快地减少骨折。这点对经历高度骨转换的患者例如癌症和移植患者尤其有用。
发明概述
本发明提供了增加患有骨流失疾病的患者的骨质和/或减少骨折的方法。该方法包括以下步骤：(a)以双膦酸盐的起始剂量给药一段时间，约7至约180天，更优选地约14至约60天，随后(b)以连续维持剂量给药双膦酸盐。起始剂量包括双膦酸盐的含量比相应的维持剂量大约2至约20倍，优选地约3倍至约10倍，更优选地约3倍至约6倍。起始剂量给药超过约7至约180天的一段时间。对于口服给药，起始剂量每天或每两天给药，但是维持剂量可每天一次、每周两次、每周一次、每两周一次或每月一次给药。
发明描述
本发明的方法包括骨活性膦酸盐以起始剂量和骨活性膦酸盐以维持剂量给药。将要用于这些方法中的具体化合物和组合物因此必须是可药用的。
定义：
本文所用的“给药”是指依据可靠的医学经验将本发明中使用的活性物质递送给受治疗个体的任何方法，受治疗个体被治疗的方式对于骨的建造是有效的。活性物质可以以多种已知的给药方法中的任何一种给药，例如，口服，皮肤粘膜(如皮肤、舌下、鼻内和直肠)，注射(如，皮下注射、肌肉内注射、关节内注射、静脉内注射)，局部用(透皮)和吸入。因此，给药的具体方式包括，但不限于，口服、透皮、粘膜、舌下、肌肉、静脉内、腹腔内、皮下给药、和其它局部应用。
本文所用的“起始剂量”是指最初给患者施用的剂量。该剂量是达到预期结果的有效的量。
本文所用的“起始期”是指最初剂量施用给受治疗个体的一段时期。
本文所用的“维持剂量”是指在起始期之后施用给受治疗个体的剂量。该剂量是达到预期结果的有效的量。
本文所用的“维持期”是指在起始期之后的一段时期，在维持期中，对受治疗个体以双膦酸盐的剂量低于起始剂量的剂量含量连续给药。
本文所用的“安全有效量”是指该量足够大以致能在受治疗个体待被治疗的症状和/或情形上有效地诱导出积极的改变，但该量又足够小以致于能避免严重不利的副作用，即具有合理的效/险比。安全有效量随下列因素而变化，例如特定的治疗条件、年龄和患者的身体状况、治疗的持续时间、协同治疗的性质、待使用的具体剂型、和所用的剂量疗法。
方法：
本发明的方法包括以下步骤：
(a)以双膦酸盐的起始剂量给药约7天至约180天的双膦酸盐；和
(b)在步骤(a)后以双膦酸盐的持续的维持剂量给药。
其中所述起始剂量比所述维持剂量大约两(2)倍至约二十(20)倍。
因此，起始剂量期包括双膦酸盐单独的给药方案。为了获得被治疗个体的生理效果，双膦酸盐必须在起始剂量期中以足够的频率服用。例如，双膦酸盐的口服剂量单位在起始期中优选地为每天给药。可能需要在某些治疗日内给药一种类型的双膦酸盐，而在另一个治疗日内给药另一种类型。
此外，在起始期后必须至少每三个月一次服用双膦酸盐。然而，也可以每天一次、每两天一次、每周两次、每周一次、每两周一次、每月一次或每两月一次服用双膦酸盐。可能需要在某些治疗日内施用一种类型的双膦酸盐，而在另一个治疗日内施用另一种类型。
足以达到受治疗个体净骨骼质量增加的具体的给药期和频率可能取决于各种因素。这类因素包括，例如，使用的具体的活性物质，施用的活性物质的量，给药方式(即，口服或非肠道)，受治疗个体的年龄和性别，待治疗的具体疾病，使用的伴随治疗，受治疗个体的综合身体健康状况，个人骨流失的程度，以及个人的营养习惯。
利用本发明方法的治疗方案优选地延续至少约二十四个月。当然，治疗方案可依照可靠的医学经验无限期地延续。
治疗骨疾的优选的方法包括最初的诊断步骤，以确定该疾病的存在。因此，本发明优选的方法包括对受治疗个体进行诊断以发现高度骨转换的步骤。高度骨转换可被定义为当净骨转换被提高和骨的再吸收大于骨的形成时。在从所述诊断中获得肯定结果后，依照本发明的方法施用活性物质。生物化学标记量度可用来确定骨转换的速率。骨的重建可通过组织形态学来证实。
用于检测确定的骨质疏松的合适诊断学也是本领域所熟知的。这样的方法包括骨骼X光照片放射密度的测量，定量的计算机处理的X线断层摄影术，单能光子吸光测定法，和双能光子吸光测定法。本文中那些有用的诊断技术描述于W.A.Peck等人的《关于骨质疏松的医师方法手册》(Physician’s Resource Manual on osteoporosis)(1987)，NationalOsteoporosis Foundation出版(引入本文以供参考)。
用于本文的骨活性膦酸盐(双膦酸盐，二膦酸盐)包括酸、盐以及它们的衍生物。可用于本文的双膦酸盐的非限制性实施例包括下列各项：1-羟基-2-(3-吡啶基)-亚乙基-1，1-双磷酸(利塞膦酸盐)，描述于1996年12月10日授予Benedict等人的美国专利5,583,122，其全文引入本文以供参考。4-氨基-1-羟基亚丁基-1，1-双磷酸(阿仑膦酸)，描述于1986年11月4日授予Rosini等人的美国专利4,621,077，1990年5月1日授予Kieczykowski等人的美国专利4,922,007，和1991年5月28日授予Kieczykowski的美国专利5,019,651，所有这些专利均全文引入本文以供参考。3-氨基-1-羟基亚丙基-1，1-双磷酸(帕米膦酸盐)，(4-氯苯基)硫代甲基-1，1-双磷酸(替鲁膦酸盐)，描述于1989年10月24日授予Breliere等人的美国专利4,876,248，该专利全文引入本文以供参考。1.1-二氯亚甲基-1-1-二磷酸(氯膦酸盐)，描述于比利时专利672,205(1966)，该专利全文引入本发明以供参考。环庚胺亚甲基-1，1-双磷酸(斯孟膦酸盐)，描述于1990年11月13日授予Isomura等人的美国专利4,970,335，该专利全文引入本文以供参考。1-羟基-3-(N-甲基-N-戊胺基)亚丙基-1，1-双磷酸(伊本膦酸盐)，描述于1990年5月22日的美国专利4,927,814，该专利全文引入本文以供参考。1-羟基-2-(1H-1-咪唑基)亚乙基-1，1-双磷酸(唑来膦酸盐)。
优选的双膦酸盐选自利塞膦酸盐、伊本膦酸盐、帕米膦酸盐、阿仑膦酸盐、斯孟膦酸盐、替鲁膦酸盐、唑来膦酸盐、氯膦酸盐、吡膦酸盐(piridronate)，它们可药用的盐和它们的混合物。
待给药的双膦酸盐的量取决于其药力。特定的双膦酸盐的药力可用其“LED”或“最小有效剂量”表示，LED是用毫克磷/千克(mg P/kg)表示的双膦酸盐的最小剂量(化合物中毫克磷/每千克受治疗个体重量)，其自身显著地抑制了骨再吸收。具体的双膦酸盐的LED将根据它们的化学组成和它们的给药方法(即，口服或非肠道)而不同。LED越低，双膦酸盐越有效，且一般来讲，高效的双膦酸盐希望以较低的剂量和较少的天数给药。同样地，LED越高，双膦酸盐的功效就越低，且一般来讲，低效的双膦酸盐希望以较高的剂量和较多的天数给药。用于口服给药的LED将较高，其取决于膦酸盐的全身吸收。典型地，口服给药吸收为约1％至约10％。因此，口服LED比注射LED典型地高约10至约100倍。
有许多方式可用来确定骨活性膦酸盐的LED。这些进一步描述于1988年8月2日授予Flora等人的美国专利4,761,406中，该专利全文引入本文以供参考。
剂型：
骨活性膦酸盐可使用多种可药用的组合物中的任何一种给药。这样的组合物可包括活性物质和可药用载体。可药用载体包括固体或液体填充剂稀释剂或胶囊物质，和它们的混合物，其适于对人类或低等动物给药。本文所用术语“相容的”是指制药组合物的组分能与活性物质混合，且彼此以一个没有交互作用的方式混合，该交互作用在普通的使用情形下将会实质性地降低制药组合物的药物功效。当然，可药用载体必须具有充分高的纯度和充分低的毒性，使它们适于施用给被治疗的个体。
可用作药物载体的物质的一些实施例为：糖，例如乳糖、葡萄糖和蔗糖；淀粉，例如玉米淀粉和马铃薯淀粉；纤维素和其衍生物，例如羧甲基纤维素钠、乙基纤维素、纤维素乙酸盐；粉末状黄蓍胶；麦芽；明胶；滑石；硬脂酸；硬脂酸镁；植物油，例如花生油、棉籽油、芝麻油、橄榄油、玉米油和可可属的油；多羟基化合物例如丙二醇、甘油、山梨醇、甘露糖醇和聚乙二醇；琼脂；藻酸；不含热原的水；等渗盐水；磷酸盐缓冲溶液；润湿剂和润滑剂例如月桂基硫酸钠；着色剂；调味剂；和防腐剂。其它相容的药物添加剂和活性物质可包括在用于本发明组合物的可药用的载体中。
与活性物质一起使用的可药用载体的选择由活性物质的给药方式决定。如果活性物质被注射，优选的药物载体是消过毒的水、生理盐水、或它们的混合物。这类注射用药物组合物的pH优选地被调节至约7.4。用于局部应用的合适的可药用载体包括本领域已知的以霜膏、凝胶、贴膏(tapes)、贴剂和类似的局部用递送方式使用的那些。
与活性物质一起使用的可药用载体应以足以给剂量关系提供实用的大小的浓度使用。可药用的载体，总体上，可占本发明的药物组合物重量的约0.1％至约99.9％，优选地约5％至约80％，且最优选地约10％至约50％。
双膦酸盐给药的优选方法是以单位剂型(即，依照可靠的医学经验，包含适于单剂给药的活性物质的量的剂型)口服。双膦酸盐的优选单位剂型包括片、胶囊、悬浮液和溶液，其包括安全有效量的活性物质。适于制备口服给药单位剂型的可药用载体剂型是本领域所熟知的。它们的选择依赖于对本发明目的而言非关键的次要考虑因素，如味道、成本、架藏稳定性，且该选择可被本领域的技术人员毫无困难地做出。优选地，用于起始剂量的利塞膦酸盐的口服单位剂型包括每天约15毫克至约50毫克，更优选每天约20毫克至约40毫克，且最优选每天约25毫克至约35毫克。用于维持剂量的骨活性膦酸盐的口服单位剂型优选包含每天约2.5至约15毫克，更优选每天约5至10毫克。对于阿仑膦酸盐，起始剂量包括每天约15毫克至约70毫克。更优选地每天约20毫克至约50毫克，且最优选地每天约25毫克至约40毫克。相同剂量可两天一次、每周两次、每周一次、每两周一次或每月一次服用。
双膦酸盐给药的另一个优选的方法是以单位剂型皮下注射。可注射的骨活性双膦酸盐的优选的单位剂型包括消过毒的水溶液、生理盐水或它们的混合物。所述溶液的pH应当被调节至约7.4。优选地，用于起始剂量的利塞膦酸盐的单位剂型包括每月约0.75毫克至约15.0毫克，且更优选地每月约1.5毫克至约10毫克。用于维持剂量的骨活性膦酸盐单位剂型优选地包括每月约0.75毫克至约6毫克，且更优选地每月约1.5毫克至约3毫克。相同剂量可每两周、每月、每两月、或每三个月服用。
套盒：
本发明也提供了便利有效地实施本发明方法的套盒。这种套盒包括用于起始期一个或多个单位剂量的骨活性膦酸盐、用于维持期的一个或多个单位剂量的骨活性膦酸盐，和促进对于本发明方法顺应性的手段。这种套盒提供了便利有效的方法确保受治疗个体以正确的方式和正确的剂量服用适当的活性物质。这种套盒的顺应性手段包括依照本发明的方法促进活性物质给药的任何手段。这种顺应性手段包括使用说明、包装、分配方法、以及它们的组合。包装与分配方法的实施例是本领域所熟知的，包括在1988年8月2日公布的Flora等人的美国专利4,761,406；和1989年3月14日公布的Uchtman的美国专利4,812,311中描述的那些，所有这些专利都引入本文以供参考。
以下非限制性实施例说明本发明的组合物、方法和使用。
实施例1
一个体重约60公斤且诊断患有绝经后骨质疏松的女性患者使用本发明的方法进行治疗。具体地讲，该患者每天口服30毫克的利塞膦酸盐，连续服用三十天。紧接着，该患者每周口服35毫克的利塞膦酸盐，连续服用两年。两年后进行髂嵴骨的活组织检查，检查结果显示，与她的基线活组织检查相比，重建单位中平均壁厚得到增加。
实施例2
一个体重约70公斤且诊断患有衰竭癌和高度骨转换的男性患者使用本发明的方法进行治疗。具体地讲，该患者每天服用35毫克阿仑膦酸盐，连续服用十四天。在该治疗期结束后，该患者接着每周口服70毫克维持剂量的阿仑膦酸盐，连续服用一年。
实施例3
一个体重约58公斤的女性患者诊断患有糖皮质素诱导的骨质疏松症。该受治疗个体然后使用本发明的方法进行治疗。具体地讲，受治疗个体每天口服30毫克的利塞膦酸盐，连续服用30天。30天期限后，剂量变为每两周口服35毫克的维持剂量，连续服用三年。
实施例4
一个体重约67公斤的男性患者被静脉给药；将总量9毫克的利塞膦酸盐平均分成两周的剂量(每周4.5毫克，在第1天和第8天)。3毫克维持剂量在第29天给药(在首次起始剂量之后)，接着从29天开始每两个月服用3毫克。
虽然已描述了本主题发明的特定实施方案，但对于本领域的专业人员显而易见的是，在不背离本发明的精神和范围的条件下，可对本发明进行各种更改或修改。因此，旨在在所附的权利要求中包括属于本发明范围的所有这些修改。
Claims (12)
1.用于依照治疗方案增加骨质的治疗的套盒，所述套盒包括用于起始期的双膦酸盐的单位剂量和在所述起始期后用于维持期的双膦酸盐的单位剂量，其中，所述起始期的双膦酸盐单位剂量比所述维持期的双膦酸盐单位剂量大2倍至20倍。
2.如权利要求1所述的套盒，其中所述套盒还包括使用说明、包装、分配方法、以及它们的组合。
3.如权利要求1所述的套盒，其中所述起始期为7天至180天。
4.如权利要求2所述的套盒，其中所述起始期为7天至180天。
5.如权利要求1所述的套盒，其中，所述起始期的双膦酸盐单位剂量比所述维持期的双膦酸盐单位剂量大3倍至6倍。
6.如权利要求1-5中任一项所述的套盒，其中所述双膦酸盐选自利塞膦酸盐、阿仑膦酸盐、帕米膦酸盐、替鲁膦酸盐、氯膦酸盐、斯孟膦酸盐、伊本膦酸盐和唑来膦酸盐。
7.如权利要求6所述的套盒，其中所述双膦酸盐为利塞膦酸盐或阿仑膦酸盐。
8.如权利要求7的套盒，其中口服单位剂型的利塞膦酸盐的起始剂量为每天15毫克至50毫克。
9.如权利要求7的套盒，其中所述阿仑膦酸盐的起始剂量为每天15毫克至70毫克。
10.双膦酸盐在制造药物套盒中的用途，其特征在于，所述套盒包括用于起始期的双膦酸盐的单位剂量和在所述起始期后用于维持期的双膦酸盐的单位剂量，其中，所述起始期的双膦酸盐单位剂量比所述维持期的双膦酸盐单位剂量大2倍至20倍。
11.如权利要求10所述的用途，其中所述双膦酸盐选自利塞膦酸盐、阿仑膦酸盐、帕米膦酸盐、替鲁膦酸盐、氯膦酸盐、斯孟膦酸盐、伊本膦酸盐、和唑来膦酸盐。
12.如权利要求10所述的用途，其中，所述起始期的双膦酸盐单位剂量比所述维持期的双膦酸盐单位剂量大3倍至6倍。
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| RU2315603C2 (ru) * | 2002-12-20 | 2008-01-27 | Ф.Хоффманн-Ля Рош Аг | Композиция с высокой дозой ибандроната |
| EP2283825B1 (en) * | 2004-05-24 | 2022-04-13 | Allergan Pharmaceuticals International Limited | Enteric solid oral dosage form of a bisphosphonate containing a chelating agent |
| WO2006020009A1 (en) * | 2004-07-23 | 2006-02-23 | The Procter & Gamble Company | Solid oral dosage form of a bisphosphonate containing a chelating agent |
| US20070191315A1 (en) * | 2006-02-16 | 2007-08-16 | Bengt Bergstrom | Method for administering ibandronate |
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- 2002-12-16 RU RU2004122433/14A patent/RU2294203C2/ru active
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- 2002-12-16 CN CNB028256271A patent/CN100479823C/zh not_active Expired - Lifetime
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- 2002-12-17 US US10/321,208 patent/US20030118634A1/en not_active Abandoned
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- 2002-12-20 MY MYPI20024837A patent/MY147886A/en unknown
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2003
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- 2004-05-19 IL IL162053A patent/IL162053A/en active IP Right Grant
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- 2004-07-20 NO NO20043113A patent/NO340249B1/no not_active IP Right Cessation
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2006
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2007
- 2007-03-20 US US11/725,896 patent/US20070166237A1/en not_active Abandoned
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2008
- 2008-03-20 US US12/077,623 patent/US20080214505A1/en not_active Abandoned
- 2008-06-27 US US12/163,278 patent/US20080260827A1/en not_active Abandoned
- 2008-06-27 US US12/163,155 patent/US20080261924A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5869471A (en) * | 1992-06-30 | 1999-02-09 | The Proctor & Gamble Company | Methods for the treatment of arthritis using phosphonates and NSAIDS |
| CN1146152A (zh) * | 1994-04-21 | 1997-03-26 | 麦克公司 | 二膦酸盐在矫形假体移植后在抑制骨再吸收中的应用 |
| US6008206A (en) * | 1994-09-21 | 1999-12-28 | Merck & Co., Inc. | Sodium alendronate preparation for local administration |
| WO2001015703A1 (en) * | 1999-09-02 | 2001-03-08 | Merck & Co., Inc. | Method for inhibiting bone resorption |
Non-Patent Citations (4)
| Title |
|---|
| Cyclical clodronate is effective in preventing postmenopausalbone loss: a comparative study with transcutaneous hormonereplacement therapy. PAOLO FILIPPONI et al.Journal of Bone and Mineral Research,Vol.10 No.5. 1995 |
| Cyclical clodronate is effective in preventing postmenopausalbone loss: a comparative study with transcutaneous hormonereplacement therapy. PAOLO FILIPPONI et al.Journal of Bone and Mineral Research,Vol.10 No.5. 1995 * |
| Long-lasting effect of pamidronate on bone metabolism inosteoporosis after stopping therapy. J. P. Devogelaer.J Musculoskel Neuron Interact,Vol.1 No.2. 2000 |
| Long-lasting effect of pamidronate on bone metabolism inosteoporosis after stopping therapy. J. P. Devogelaer.J Musculoskel Neuron Interact,Vol.1 No.2. 2000 * |
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