质子泵抑制剂（PPIs）与胃H/K-ATP酶结合抑制胃酸分泌，是临床应用最广泛的药物之一，长期使用增加骨质疏松风险，机制不明。预实验发现：成骨细胞在PPIs干预后胞内Ca浓度及增殖活性均下降；计算机模拟显示PPIs可以与Na/K-ATP酶结合。我们提出假说，PPIs通过与胃H/K-ATP酶同源性较高的成骨细胞Na/K-ATP酶结合，增加Na/K交换，使胞外Na异常升高，进而促进Na/Ca交换，降低胞内Ca浓度，减弱成骨细胞活性，致骨质疏松发生。为了验证假说，拟以成骨细胞、小鼠和患者为研究对象，采用放射性同位素标记、Micro-PET/CT、膜片钳、流式细胞术、激光共聚焦扫描和siRNA转染等方法，探讨和确证PPIs在骨组织分布与结合位点，细胞膜Na/K和Na/Ca交换电流增加，胞内钙及细胞活性下降等致骨质疏松的分子离子机制。为PPIs合理用药提供理论依据，为药源性骨质疏松的治疗提供新靶点。

Proton pump inhibitors (PPIs), binding with gastric hydrogen-potassium adenosine triphosphatase (H/K-ATPase, proton pump), are one of the most popular and prevalent used medications. Long-term using of PPIs increase the risk of osteoporosis, but the mechanism is still not understandable. Our preliminary experiments show the results that: (1) Proton pump inhibitors can bind with Na/K-ATPase by using the method of computer-aided drug design. (2) Intracellular calcium concentration of mouse osteoblasts decreases when treating with PPIs by using the methods of laser confocal scanning, flow cytometry, and fluorescence microscope, and the decline extent is correlated with dosage. (3) Cell viability of mouse osteoblasts decreases when treating with PPIs by the experiment of cell counting kit-8. The mechanism deserves further investigation. In order to explore the possible mechanism of action, we propose our hypothesis that proton pump inhibitors distribute to bone tissue and bind with osteoblasts Na/K-ATPase, which displays a high sequence homology with gastric H/K-ATPase. The activation of Na/K-ATPase aggrandizes sodium-potassium exchange and leads to an abnormal increase of extracellular sodium, then activates sodium-calcium exchange and decreases intracellular calcium, as well as weakens the cell viability of osteoblasts, finally leads to high risk of osteoporosis. In order to validate the hypothesis, experiments are in planning from three levels including ossification cell lines (MC3T3-E1), mouse treated by PPIs and patients with osteoporsis. Then a series of techniques, such as radioisotopic labeling, Micro-PET/CT, patch clamp, flow cytometry, laser confocal scanning, siRNA transfection, real-time PCR, and western blot, and so on, will be used to explore the binding site of Na/K-ATPase in osteoblasts with PPIs after distributed to the bone tissue, sodium-potassium exchange and sodium-calcium exchange current on osteoblast membrane, intracellular calcium concentration, and cell viability, etc. Thus we could explore and confirm the molecular ion mechanism of osteoporosis induced by proton pump inhibitors. It will provide theoretical reference for clinical rational use of PPIs, and provide new targets for pharmaceutical in drug-induced osteoporosis.