Class of 2013 Abstract / Specific Aims: To determine whether concurrent use of a proton pump inhibitor (PPI) and a bisphosphonate represent an additional fracture risk compared with bisphosphonate use alone and to identify an increased risk of any particular fracture type. Methods: This study was a systematic review and meta-analysis of data collected from PubMed, Cochrane, OVID Medline, Google Scholar, and IPA. The authors utilized the search terms: bisphosphonate, fractures and proton pump inhibitors. Studies which met criteria of being English-language with adults 18 years of age and older were included. Main Results: The studies were cohort studies and primarily evaluated older adults. The summary effect was that use of a PPI with a bisphosphonate showed a slight increase in fracture risk when compared to bisphosphonate-only therapy (odds ratio [OR] 1.12, 95% confidence interval [CI], 1.06-1.18). Systematic review of similar studies showed varied results, making difficult any conclusion regarding fracture risk among the treatments. Conclusion: In this analysis, PPI + bisphosphonate demonstrated a slight increase in fracture rate without inference to an increase in any particular fracture type compared with bisphosphonate only. However, there is minimal data on the association or causal effect of this increase. The few studies available offered contradictory results. Additionally, database studies are subject to the possibility of residual confounding. Further research using randomized control trial (RCT) design evaluating long term use of bisphosphonates with or without PPI and their impact on fractures is needed to determine if there is an additional degree of fracture risk from the concurrent use.

This thesis is focused on the design, synthesis and characterization of magnetite-ionic copolymer complexes as nanocarriers for drug delivery and magnetic resonance imaging. The polymers included phosphonate and carboxylate-containing graft and block copolymers. Oleic-acid coated magnetite nanoparticles (8-nm and 16-nm diameters) were investigated. Cisplatin and carboplatin were used as sample drugs. The potentials of the magnetite-ionomer complexes as dual drug delivery carriers and magnetic resonance imaging agents were evaluated. An acrylate-functional poly(ethylene oxide) macromonomer and hexyl (and propyl) ammonium bisphosphonate methacrylate monomers were synthesized. Conventional free radical copolymerizations were conducted to synthesize the graft copolymers. The acrylate-functional poly(ethylene oxide) macromonomer was also used to form graft copolymers with tert-butyl acrylate. Block ionomers containing poly(tert-butyl acrylate) were synthesized via atom transfer radical polymerization, then the tert-butyl groups were removed to afford anions. All the monomers and polymers were characterized by 1H NMR to confirm their structures and assess their compositions. Phosphonate-containing polymers were also characterized by 31P NMR. Magnetite nanoparticles (8-nm diameter) were synthesized by reducing Fe(acac)3 with benzyl alcohol. The 16-nm diameter magnetite was synthesized by thermal decomposition of an iron oleate precursor in trioctylamine as a high-boiling solvent. The iron-oleate precursor was synthesized with iron (III) chloride hexahydrate and sodium oleate with mixed solvents. TEM images of the magnetite were obtained. Magnetite-ionomer complexes were synthesized by binding a portion of the anions (carboxylate or phosphonate) on the copolymers onto the surfaces the magnetite. The remainder of the anions was used to bind with cisplatin and carboplatin via chelation. Physicochemical properties of the complexes were measured by dynamic light scattering. All the complexes with different polymers and magnetite nanoparticles displayed relatively uniform sizes and good size distributions. The magnetite-ionomer complexes displayed good colloidal stabilities in simulated physiological conditions for at least 24 hours. Those graft and block copolymer-magnetite complexes may be good candidates as drug carriers for delivery applications. After cisplatin and carboplatin loading, the sizes of the complexes increased slightly and the zeta potential decreased slightly, which indicated that the loadings were successful. Minimal loss of iron was found, signaling that the binding strengths between the magnetite and the anions of the graft copolymers were strong. 8.7 wt% of platinum was found in the cisplatin loaded complexes and 6.9% in the carboplatin loaded complexes. The results indicated that the magnetite-graft ionomer complexes were capable of loading drugs. Drug release studies were performed at pH 4.6 and 7.4 to mimick endosomal conditions and the physiological environment. Sustained release of drugs was observed. This further indicated the potential for using the magnetite-ionomer complexes as drug carriers. Transverse relaxivities of the magnetite-ionomer complexes with and without drugs were measured and compared to a commercial T2-weighted iron MRI contrast agent-Feridex®. All the complexes had higher relaxivities compared to Feridex®. Thus, the magnetite-ionomer complexes are promising candidates for dual magnetic resonance imaging and drug delivery.Moreover, the aqueous dispersion of the complexes was found to heat upon exposure to an AC magnetic field, thus potentially allowing heat-induced drug release. / Master of Science

No description available.

The isoprenoid biosynthetic pathway (IBP) plays an important role in cellular metabolism. Currently there are drugs, including lovastatin and the nitrogenous bisphosphonates risedronate and zoledronate, that are used clinically to lower cholesterol levels and treat bone disease, respectively. These drugs work by inhibition of the upstream enzymes, HMG-CoA reductase and farnesyl diphosphate synthase (FDPS), respectively. The enzyme FDPS catalyzes the formation of farnesyl pyrophosphate (FPP), an important intermediate that represents a branch point in the pathway. The post-translational modification known as protein prenylation is mediated by the three prenyltransferase enzymes. Even though compounds like lovastatin, risedronate, and zoledronate indirectly disrupt protein prenylation, they also impair processes downstream from the point of inhibition. Therefore a direct approach would be desirable where downstream enzymes are targeted so that the rest of the cellular processes can continue to function. One such downstream enzyme is geranylgeranyl transferase II (GGTase II). This enzyme and it catalyzes the transfer of two hydrophobic geranylgeranyl chains from geranylgeranyl pyrophosphate (GGPP) to Rab proteins, which are essential for intracellular membrane trafficking. Inhibition of GGTase II may be a good therapeutic target for diseases such as multiple myeloma characterized by an over secretion of proteins. A known GGTase II inhibitor is the carboxy phosphonate 3-PEHPC, however millimolar concentrations are necessary to observe cellular effects with this compound. In an effort to develop more potent inhibitors of this enzyme, a family of isoprenoid triazole bisphosphonates was initially prepared by click chemistry, first as a mixture of olefin isomers due to an allylic azide rearrangement. These compounds were tested by our collaborators to determine the compounds’ activity as GGTase II inhibitors. Because some triazole bisphosphonates showed good activity as a mixture of isomers, a family of isoprenoid triazole bisphosphonates as single olefin isomers now has been prepared through the use of epoxy azides to avoid the azide rearrangement. The biological activity of these compounds has been studied and some of these triazole bisphosphonates were found to be potent and selective inhibitors of geranylgeranyl diphosphate synthase (GGDPS). While the enzyme GGDPS is upstream of the geranylgeranyltransferases, it is still downstream of the pathway’s primary branch point and provides GGPP for Rab geranylgeranylation. Two other families of triazole bisphosphonate analogues, homo- and bishomoisoprenoid triazole bisphosphonates, also have been prepared and tested by our collaborators to explore the compounds’ activity as GGDPS inhibitors, as well as the structure-activity-relationship. Previous research has shown digeranyl bisphosphonate (DGBP) and the bisphosphonate ether C-prenyl-O-geranyl bisphosphonate to be inhibitors of GGDPS. Two C-alkyl-C-homoalkyl DGBP analogues have been synthesized in order to study further the binding of these compounds to GGDPS, and dialkylated triazole bisphosphonates have been prepared to explore the effect of a triazole moiety on the analogue’s ability to inhibit GGDPS. The activity uncovered through these studies encourages further research on inhibitors of GGDPS.

Ce travail de thèse fut consacré au développement de nouvelles voies d.accès aux composés gembisphosphonates (BPs), et a été réalisé dans le cadre du Programme de Toxicologie Nucléaire et Environnementale (ToxNuc-E). Deux applications de ces composés ont été étudiées, la préparation de ligands puissants de l.ion uranyle pour un objectif de décorporation, et la préparation de nouveaux composés anti-cancéreux.<br /><br />La première de ces applications fit suite à des travaux réalisés au sein du laboratoire, ayant montré les fortes propriétés de complexation de ligands bisphosphoniques vis à vis de l.ion uranyle. Les tests in vivo réalisés sur ces composés ayant montré la tendance de ces ligands à entraîner une accumulation hépatique de l'uranium, nous avons voulu remédier à ce problème en modifiant le mode d.ancrage des fonctions bisphosphonates. Pour cela nous avons développé une nouvelle voie d.accès à ces composés utilisant une réaction d.insertion d.espèce métal-carbénoide, portant la fonction bisphosphonate, sur des plates-formes poly-ols et poly-amines.<br /><br />Concernant la préparation de BPs possédant une activité anticancéreuse, nous avons mis au point une nouvelle voie synthétique utilisant, comme étape clé, une réaction d.á-P-addition d.un pro-nucléophile phosphoré sur un alcyne porteur d.un groupement phosphonate catalysé par une phosphine. Cela nous a permis de préparer une trentaine de composés dont l.activité anti-cancéreuse a été évaluée sur deux lignées cellulaire (A431 et HuH7). Cinq de ces composés possèdent une activité équivalent à celle du composé décrit comme étant le plus actif, le Zolédronate®.

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) occurs subsequent to intravenous and oral bisphosphonate exposure in a small subset of patients. Evidence of concurrent bacterial colonization at sites of bone necrosis, previous reports of neutrophil-related complications in some patients taking bisphosphonates along with perturbed neutrophil function in bisphosphonate-treated mice suggests an innate immune role in the development of bisphosphonate-related osteonecrosis of the jaws. This study investigates neutrophil function in BRONJ patients to determine if neutrophil functional defects may serve as a potential biomarker for BRONJ susceptibility. Patients with BRONJ and patients beginning intravenous pamidronate were studied. Eighteen patients with BRONJ and five patients beginning pamidronate therapy provided oral and blood neutrophil samples. Neutrophils from the population of patients with bisphosphonate-related osteonecrosis of the jaws and from those post-pamidronate treatment showed lower reactive-oxygen species production. These data suggest that a compromise in neutrophil function may be a potential biomarker for BRONJ susceptibility.

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) occurs subsequent to intravenous and oral bisphosphonate exposure in a small subset of patients. Evidence of concurrent bacterial colonization at sites of bone necrosis, previous reports of neutrophil-related complications in some patients taking bisphosphonates along with perturbed neutrophil function in bisphosphonate-treated mice suggests an innate immune role in the development of bisphosphonate-related osteonecrosis of the jaws. This study investigates neutrophil function in BRONJ patients to determine if neutrophil functional defects may serve as a potential biomarker for BRONJ susceptibility. Patients with BRONJ and patients beginning intravenous pamidronate were studied. Eighteen patients with BRONJ and five patients beginning pamidronate therapy provided oral and blood neutrophil samples. Neutrophils from the population of patients with bisphosphonate-related osteonecrosis of the jaws and from those post-pamidronate treatment showed lower reactive-oxygen species production. These data suggest that a compromise in neutrophil function may be a potential biomarker for BRONJ susceptibility.

Indiana University-Purdue University Indianapolis (IUPUI) / Current interventions used to reduce skeletal fragility are insufficient at enhancing bone across multiple hierarchical levels. Bisphosphonates, such as Zoledronate (ZOL), treat a variety of bone disorders by increasing bone mass and bone mineral density to decrease fracture risk. Despite the mass-based improvements, bisphosphonate use has been shown to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mechanical properties by binding to collagen and increasing tissue hydration in a cell-independent manner. We hypothesized that a combination of RAL and ZOL would improve mechanical and material properties of bone more than either monotherapy alone by enhancing both quantity and quality of bone. In this study, wildtype (WT) and heterozygous (OIM+/-) male mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL, ZOL, or RAL and ZOL from 8 weeks to 16 weeks of age. Combination treatment resulted in higher trabecular architecture, cortical mechanical properties, and cortical fracture toughness in diseased mouse bone. Two fracture toughness properties, direct measures of the tissue’s ability to resist the initiation and propagation of a crack, were significantly improved with combination treatment in OIM+/- compared to control. There was no significant effect on fracture toughness with either monotherapy alone in either genotype. Following the mass-based effects of ZOL, bone volume fraction was significantly higher with combination treatment in both genotypes. Similar results were seen in trabecular number. Combination treatment resulted in higher ultimate stress in both genotypes, with RAL additionally increasing ultimate stress in OIM+/-. RAL and combination treatment in OIM+/- also produced a higher resilience compared to the control. Given no significant changes in cortical geometry, these mechanical alterations were likely driven by the quality-based effects of RAL. In conclusion, this study demonstrates the beneficial effects of using combination therapy to increase bone mass while simultaneously improving tissue quality, especially to enhance the mechanical integrity of diseased bone. Combination therapies could be a future mechanism to improve bone health and combat skeletal fragility on multiple hierarchical levels.

No description available.

Die Bisphosphonat- assoziierte Kiefernekrose (BONJ) gewinnt seit ihrer Erstbeschreibung 2003 durch die steigenden Verschreibungszahlen der Bisphosphonate stetig an Bedeutung. Da eine effektive Therapie der BONJ nach wie vor sehr schwierig ist, liegt das Hauptaugenmerk in der Prävention und frühzeitigen Erkennung der Erkrankung. Die vorliegende Arbeit beschäftigt sich daher vor allem mit dem Stellenwert der Dental- CT in der Diagnostik und Früherkennung der BONJ. Dafür wurden die nativen Dental- CT- Aufnahmen von 99 Patienten unter Bisphosphonattherapie retrospektiv nach im Vorfeld klar definierten qualitativen, quantitativen und halbquantitativen Kriterien neu beurteilt. Entgegen der Literatur und den aktuellen Empfehlungen der AWMF erwies sich die CT zur Früherkennung und stadiengerechten Dokumentation der BONJ als hervorragend geeignet. Bereits unspezifische klinische Entzündungszeichen können auf ein Frühstadium der BONJ hindeuten. Das radiologische Hauptsymptom der Hypersklerosierung stellt dabei ein Durchgangsstadium der BONJ dar. Mit Fortschreiten der Erkrankung kommt es zu einem zunehmend heterogenen Erscheinungsbild mit lokaler Hypersklerosierung, grobwabiger Spongiosastruktur, Osteolysen und Sequestern. Es ist erstmals gelungen die wichtigsten radiologischen Zeichen einer BONJ zu objektivieren und die große biologische Variabilität exakt abzubilden. Bemerkenswert war zudem ein signifikant hochgradigerer Befall der Mandibula durch die BONJ. Die Dental- CT ist damit für die Betreuung der betroffenen Patienten die Methode der 1. Wahl.:BIBLIOGRAPHISCHE BESCHREIBUNG ABKÜRZUNGSVERZEICHNIS 1. BISPHOSPHONAT- ASSOZIIERTE KIEFERNEKROSE 1.1. DEFINITION 1.2. PHARMAKOLOGISCHER HINTERGRUND 1.3. ÄTIOLOGIE 1.4. EPIDEMIOLOGIE . 1.5. STADIEN UND SYMPTOMATIK 2. RADIOLOGISCHE DIAGNOSTIK DER BISPHOSPHONAT- ASSOZIIERTEN KIEFERNEKROSE 2.1. DENTAL- COMPUTERTOMOGRAPHIE. 2.2. ORTHOPANTOMOGRAMM (OPG) 2.3. DIGITALE VOLUMENTOMOGRAPHIE (DVT) 2.4. STUDIEN MIT VERSCHIEDENEN BILDGEBENDEN VERFAHREN IM VERGLEICH 3. ZIEL DER ARBEIT 4. MATERIAL UND METHODEN 4.1. PATIENTENGUT 4.2. COMPUTERTOMOGRAPHISCHE UNTERSUCHUNG 4.3. RADIOLOGISCHE DATENERFASSUNG 4.3.1. Qualitative Datenerfassung 4.3.2. Quantitative und halbquantitative Datenerfassung 4.4. KLINISCHE KRITERIEN 4.5. STATISTISCHE AUSWERTUNG 5. ERGEBNISSE 5.1. PATIENTENKOLLEKTIV 5.2. KLINISCHE ERGEBNISSE 5.3. RADIOLOGISCHE BEFUNDE 5.3.1. Qualitative Kriterien 5.3.2. Quantitative und halbquantitative Kriterien 5.4. ERGEBNISSE IN BEZUG AUF DIE HYPOTHESEN 5.5. AUSWERTUNG DER INDIVIDUELLEN VERLAUFSSERIEN 6. DISKUSSION 6.1. DISKUSSION VON MATERIAL & METHODE 6.2. DISKUSSION DER ERGEBNISSE 7. SCHLUSSFOLGERUNGEN 8. ZUSAMMENFASSUNG DER ARBEIT 9. LITERATURVERZEICHNIS 10. ANLAGEN ABBILDUNGSVERZEICHNIS TABELLENVERZEICHNIS SELBSTSTÄNDIGKEITSERKLÄRUNG LEBENSLAUF DANKSAGUNG