Khajuria Deepak Kumar, Vasireddi Ramakrishna, Trebbin Martin, Karasik David, Razdan Rema
The Musculoskeletal Genetics Laboratory, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel; Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, India.
Hamburg Center for Ultrafast Imaging, University of Hamburg, Hamburg, Germany.
Mater Sci Eng C Mater Biol Appl. 2017 Feb 1;71:698-708. doi: 10.1016/j.msec.2016.10.066. Epub 2016 Oct 26.
Osteoporosis therapeutics has been monopolized mainly by bisphosphonates, which are potent anti-osteoporotic drugs, while they do not promote bone formation or replenish the already resorbed bone. Although strontium substituted hydroxyapatite (SrHA) has been proclaimed to improve bone properties in an osteoporotic animal model, there is no published data on direct delivery of SrHA nanoparticles by bisphosphonate-like zoledronic acid (ZOL) to the bone. Therefore, this study was designed to investigate the potential of using SrHA/ZOL nanoparticle-based drug formulation in an ovariectomized rat model of postmenopausal osteoporosis. SrHA and SrHA/ZOL nanoparticles were prepared and characterized by field-emission scanning electron microscopy (FESEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Twelve weeks after ovariectomy, rats were treated with either single intravenous dose of SrHA/ZOL (100, 50 or 25μg/kg); ZOL (100μg/kg); or SrHA (100μg/kg). Saline-treated OVX and SHAM-OVX groups served as controls. The energy-dispersive X-ray (EDX) microanalysis of bone specimen obtained from SrHA/ZOL groups yielded range between 64.3±6.7 to 66.9±6.8 of calcium weight (wt) % and 1.64±0.6 to 1.74±0.8 of calcium/phosphorus (Ca/P) ratio which was significantly higher when compared with 39.7±9.3 calcium and 1.30±0.2 Ca/P ratio for OVX group. Moreover, the strontium wt% in SrHA/ZOL group (between 3.1±0.5 and 6.8±0.4) was significantly higher than SrHA group (1.8±0.9). These results confirmed targeted delivery of SrHA nanoparticles by ZOL to the bone. Therapy with SrHA/ZOL showed significant improvements in trabecular bone microarchitecture and mechanical strength as compared to ZOL or SrHA (p<0.05). Moreover, treatment with SrHA/ZOL significantly precluded an increase in serum bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase than either ZOL or SrHA (p<0.05). These results strongly implicate that SrHA/ZOL nanoparticle-based drug formulation showed better efficacy at a much lower dose of ZOL. SrHA/ZOL drug formulation has a therapeutic advantage over ZOL or SrHA monotherapy for experimental osteoporosis.
骨质疏松症的治疗主要被双膦酸盐垄断，双膦酸盐是强效抗骨质疏松药物，但它们不会促进骨形成或补充已被吸收的骨。尽管锶取代羟基磷灰石（SrHA）已被宣称可改善骨质疏松动物模型的骨特性，但尚无关于通过类似双膦酸盐的唑来膦酸（ZOL）将SrHA纳米颗粒直接递送至骨的已发表数据。因此，本研究旨在研究在去卵巢大鼠绝经后骨质疏松症模型中使用基于SrHA/ZOL纳米颗粒的药物制剂的潜力（可能性）。制备了SrHA和SrHA/ZOL纳米颗粒，并通过场发射扫描电子显微镜（FESEM）、X射线衍射（XRD）和傅里叶变换红外光谱（FTIR）对其进行了表征。去卵巢12周后，大鼠接受单次静脉注射SrHA/ZOL（100、50或25μg/kg）；ZOL（100μg/kg）；或SrHA（100μg/kg）治疗。生理盐水处理的去卵巢组和假手术去卵巢组作为对照。对从SrHA/ZOL组获得的骨标本进行的能量色散X射线（EDX）微分析得出钙重量（wt）%在64.3±6.7至66.9±6.8之间，钙/磷（Ca/P）比在1.64±0.6至1.74±0.8之间，与去卵巢组的39.7±9.3钙和1.30±0.2 Ca/P比相比显著更高。此外，SrHA/ZOL组中的锶wt%（在3.1±0.5和6.8±0.4之间）显著高于SrHA组（1.8±0.9）。这些结果证实了ZOL将SrHA纳米颗粒靶向递送至骨。与ZOL或SrHA相比，SrHA/ZOL治疗在小梁骨微结构和机械强度方面显示出显著改善（p<0.05）。此外，与ZOL或SrHA相比，SrHA/ZOL治疗显著抑制了血清骨特异性碱性磷酸酶和抗酒石酸酸性磷酸酶的升高（p<0.05）。这些结果有力地表明，基于SrHA/ZOL纳米颗粒的药物制剂在低得多的ZOL剂量下显示出更好的疗效。SrHA/ZOL药物制剂在实验性骨质疏松症方面比ZOL或SrHA单一疗法具有治疗优势。
