Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow 226031, India.
Department of Chemical Engineering, Indian Institute of Technology-Bombay, Mumbai 400076, India.
Bone. 2019 Jun;123:28-38. doi: 10.1016/j.bone.2019.03.010. Epub 2019 Mar 9.
The non-selective phosphodiesterase inhibitor pentoxifylline (PTX) is used for the treatment of intermittent claudication due to artery occlusion. Previous studies in rodents have reported salutary effects of the intraperitoneal administration of PTX in segmental bone defect and fracture healing, as well as stimulation of bone formation. We determined the effect of orally dosed PTX in skeletally mature ovariectomized (OVX) rabbits with osteopenia. The half-maximal effective concentration (EC) of PTX in rabbit bone marrow stromal cells was 3.07 ± 1.37 nM. The plasma PTX level was 2.05 ± 0.522 nM after a single oral dose of 12.5mg/kg, which was one-sixth of the adult human dose of PTX. Four months of daily oral dosing of PTX at 12.5 mg/kg to osteopenic rabbits completely restored bone mineral density, bone mineral content (BMC), microarchitecture and bone strength to the level of the sham-operated (ovary intact) group. The bone strength to BMC relationship between PTX and sham was similar. The bone restorative effect of PTX was observed in both axial and appendicular bones. In osteopenic rabbits, PTX increased serum amino-terminal propeptide, mineralized nodule formation by stromal cells and osteogenic gene expression in bone. PTX reversed decreased calcium weight percentage and poor crystal packing found in osteopenic rabbits. Furthermore, similar to parathyroid hormone (PTH), PTX had no effect on bone resorption. Taken together, our data show that PTX completely restored bone mass, bone strength and bone mineral properties by an anabolic mechanism. PTX has the potential to become an oral osteogenic drug for the treatment of post-menopausal osteoporosis.
非选择性磷酸二酯酶抑制剂己酮可可碱（PTX）用于治疗因动脉阻塞引起的间歇性跛行。先前在啮齿动物中的研究报告称，腹腔内给予 PTX 对节段性骨缺损和骨折愈合具有有益作用，并能刺激骨形成。我们确定了在患有骨质疏松症的骨骼成熟去卵巢（OVX）兔中口服 PTX 的效果。PTX 在兔骨髓基质细胞中的半最大有效浓度（EC）为 3.07±1.37 nM。单次口服 12.5mg/kg 后，血浆 PTX 水平为 2.05±0.522 nM，为成人 PTX 剂量的六分之一。骨质疏松症兔每天口服 12.5mg/kg 的 PTX 持续 4 个月，可使骨密度、骨矿物质含量（BMC）、微结构和骨强度完全恢复至假手术（卵巢完整）组的水平。PTX 与假手术组之间的骨强度与 BMC 关系相似。PTX 的骨修复作用在轴向和附肢骨骼中均观察到。在骨质疏松症兔中，PTX 增加了血清氨基末端前肽、基质细胞矿化结节形成和骨的成骨基因表达。PTX 逆转了骨质疏松症兔中钙重量百分比降低和晶体排列不良的情况。此外，与甲状旁腺激素（PTH）相似，PTX 对骨吸收没有影响。总之，我们的数据表明，PTX 通过合成代谢机制完全恢复了骨量、骨强度和骨矿物质特性。PTX 有可能成为一种治疗绝经后骨质疏松症的口服成骨药物。
