title: Novel therapeutic intervention for osteoporosis prepared with strontium hydroxyapatite and zoledronic acid: In vitro and pharmacodynamic evaluation.
abstract: 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.
authors.affiliation: 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. Electronic address: deepak_kumarkhajuria@yahoo.co.in.
authors.forename: Deepak Kumar
authors.initials: DK
authors.lastname: Khajuria
authors.affiliation: Hamburg Center for Ultrafast Imaging, University of Hamburg, Hamburg, Germany.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Vasireddi
authors.affiliation: Hamburg Center for Ultrafast Imaging, University of Hamburg, Hamburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Trebbin
authors.affiliation: The Musculoskeletal Genetics Laboratory, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Karasik
authors.affiliation: Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, India.
authors.forename: Rema
authors.initials: R
authors.lastname: Razdan
mesh_terms: D000327:Adsorption; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001696:Biomechanical Phenomena / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D065546:Drug Liberation; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006882:Hydroxyapatites / Q000737:chemistry*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D010024:Osteoporosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013324:Strontium / Q000737:chemistry*; D014961:X-Ray Diffraction; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D015415:Biomarkers; D004164:Diphosphonates; D006882:Hydroxyapatites; D007093:Imidazoles; C076185:strontium hydroxyapatite; D000077211:Zoledronic Acid; D013324:Strontium
keywords: Hydroxyapatite; Osteoporosis; Rat model; Strontium; Zoledronic acid