San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, United States of America; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, United States of America.
Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States of America.
Bone. 2020 Aug;137:115411. doi: 10.1016/j.bone.2020.115411. Epub 2020 May 11.
Alendronate was synthesized in 1970s in a search for inhibitors of calcification. Istituto Gentili investigators identified it as a potent inhibitor of bone resorption and obtained a patent covering its use in the treatment of osteoporosis and other disorders of excessive bone resorption in the 1980s. Merck licensed alendronate in 1988 and its pharmaceutical chemists reformulated it as a sodium salt with good solubility in a tablet that reduced its potential for esophageal irritation. Clinical trials proved that it reduced bone turnover, increased BMD and reduced the risk of vertebral fractures in postmenopausal osteoporotic women. Merck sponsored a large clinical trials that won FDA approval for treatment of osteoporosis in postmenopausal women and showed that it reduced the risk of spine and hip fractures. Its approval in the US in 1995 spurred sales of bone densitometers and BMD testing to screen for low bone mineral density and identify osteoporosis. Bone mass measurement was supported by medical society guidelines and reimbursement by Medicare and other insurers in the USA. A 70 mg weekly instead of 10 mg daily dose of alendronate produced the same effect on BMD and biochemical markers of bone remodelling with greater convenience and reduced potential for upper GI adverse events. Consequently, by 2006, about 30 million prescriptions for alendronate were written annually in the U.S. for about 15% of postmenopausal women in the U.S. Thereafter, publicity about rare but concerning atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ) along with the expiry of Merck's patent (in 2008) and cessation of their promotion of alendronate, and a decline in use of densitometry led to a steady slide in its use even among patients for whom the benefits of alendronate far outweigh its potential risks. Nevertheless, in 25 years since its regulatory approval, alendronate has undoubtedly prevented millions of fractures world-wide.
阿伦膦酸盐于 20 世纪 70 年代在寻找钙化物抑制剂的过程中被合成。Istituto Gentili 的研究人员发现它是一种强效的骨吸收抑制剂，并在 20 世纪 80 年代获得了一项涵盖其在骨质疏松症和其他过度骨吸收疾病治疗中的用途的专利。默克公司于 1988 年获得了阿伦膦酸盐的许可，并将其化学结构改为具有良好水溶性的钠盐，制成片剂，降低了其对食管的潜在刺激性。临床试验证明，它可以减少骨转换，增加骨密度，并降低绝经后骨质疏松症女性椎体骨折的风险。默克公司赞助了一项大型临床试验，该试验获得了美国食品和药物管理局（FDA）的批准，用于治疗绝经后妇女的骨质疏松症，并表明它可以降低脊柱和髋部骨折的风险。1995 年，该药在美国获得批准，刺激了骨密度仪和骨密度测试的销售，以筛查低骨矿物质密度并识别骨质疏松症。美国医学协会的指南支持骨量测量，并由医疗保险和其他保险公司报销。每周使用 70 毫克而不是每天使用 10 毫克的阿伦膦酸盐，对 BMD 和骨重塑的生化标志物产生相同的效果，而且更方便，上消化道不良事件的潜在风险更低。因此，到 2006 年，美国每年开出的阿伦膦酸盐处方约为 3000 万张，约占美国绝经后妇女的 15%。此后，关于罕见但令人担忧的非典型股骨骨折（AFF）和颌骨骨坏死（ONJ）的宣传，以及默克公司专利的到期（2008 年）以及他们停止推广阿伦膦酸盐，以及骨密度仪使用量的下降，导致其使用量稳步下降，即使是对那些使用阿伦膦酸盐的益处远远超过其潜在风险的患者也是如此。尽管如此，在获得监管批准后的 25 年里，阿伦膦酸盐无疑在全球范围内预防了数百万人的骨折。
