Mitchell Alexis, Watts Ashlee E, Ebetino Frank H, Suva Larry J
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, College Station, TX, USA.
Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.
BMC Vet Res. 2019 Jun 24;15(1):211. doi: 10.1186/s12917-019-1966-x.
Bisphosphonates (BPs) are a family of molecules characterized by two key properties: their ability to bind strongly to bone mineral and their inhibitory effects on mature osteoclasts and thus bone resorption. Chemically two groups of BPs are recognized, non-nitrogen-containing and nitrogen-containing BPs. Non-nitrogen-containing BPs incorporate into the energy pathways of the osteoclast, resulting in disrupted cellular energy metabolism leading to cytotoxic effects and osteoclast apoptosis. Nitrogen-containing BPs primarily inhibit cholesterol biosynthesis resulting in the disruption of intracellular signaling, and other cellular processes in the osteoclast. BODY: BPs also exert a wide range of physiologic activities beyond merely the inhibition of bone resorption. Indeed, the breadth of reported activities include inhibition of cancer cell metastases, proliferation and apoptosis in vitro. In addition, the inhibition of angiogenesis, matrix metalloproteinase activity, altered cytokine and growth factor expression, and reductions in pain have been reported. In humans, clinical BP use has transformed the treatment of both post-menopausal osteoporosis and metastatic breast and prostate cancer. However, BP use has also resulted in significant adverse events including acute-phase reactions, esophagitis, gastritis, and an association with very infrequent atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ).
Despite the well-characterized health benefits of BP use in humans, little is known regarding the effects of BPs in the horse. In the equine setting, only non-nitrogen-containing BPs are FDA-approved primarily for the treatment of navicular syndrome. The focus here is to discuss the current understanding of the strengths and weaknesses of BPs in equine veterinary medicine and highlight the future utility of these potentially highly beneficial drugs.
双膦酸盐（BPs）是一类具有两个关键特性的分子：它们与骨矿物质紧密结合的能力以及对成熟破骨细胞的抑制作用，从而抑制骨吸收。从化学角度可将双膦酸盐分为两类，即不含氮的双膦酸盐和含氮的双膦酸盐。不含氮的双膦酸盐会融入破骨细胞的能量代谢途径，导致细胞能量代谢紊乱，进而产生细胞毒性作用并引发破骨细胞凋亡。含氮的双膦酸盐主要抑制胆固醇生物合成，导致破骨细胞内细胞信号传导及其他细胞过程受到干扰。
双膦酸盐不仅能抑制骨吸收，还具有广泛的生理活性。实际上，已报道的活性范围包括抑制癌细胞转移、体外增殖和凋亡。此外，还报道了其对血管生成、基质金属蛋白酶活性的抑制作用，细胞因子和生长因子表达的改变以及疼痛减轻。在人类中，临床使用双膦酸盐已改变了绝经后骨质疏松症以及转移性乳腺癌和前列腺癌的治疗方式。然而，使用双膦酸盐也导致了严重的不良事件，包括急性期反应、食管炎、胃炎，以及与非常罕见的非典型股骨骨折（AFF）和颌骨坏死（ONJ）的关联。
尽管双膦酸盐在人类中的健康益处已得到充分认识，但关于其在马体内的作用却知之甚少。在马的治疗领域，只有不含氮的双膦酸盐获得了美国食品药品监督管理局（FDA）的批准，主要用于治疗舟状骨综合征。本文重点讨论目前对双膦酸盐在马兽医医学中的优缺点的认识，并强调这些潜在的高效药物的未来应用价值。
