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1
Roelofs, Anke. "Anti-tumour mechanisms of action bisphosphonates and bisphosphonate analogues." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436994.
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Debbabi, M., M. Othmani, and A. Aissa. "Nanocrystalline Hydroxyapatite-Bisphosphonate Composites." Thesis, Sumy State University, 2013. http://essuir.sumdu.edu.ua/handle/123456789/35199.
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The direct synthesis of hydroxyapatite─1,8-octan-bisphosphonic acid (HAp─BISPH) nanocrystals has been carried out in presence of increasing amounts of BISPH in solution, by hydrothermal method at 120 °C for 15 h. XRD, IR, NMR-MAS (31P, 1H and 13C), TEM, AFM, TGA and chemical analysis were used to characterize the structure, morphology and composition of the products. X-ray powder diffraction patterns show that the incorporation of bisphosphonate moieties induces a significant loss of the material crystallin-ity and a clear decrease of the crystallite size. TEM and AFM images show that the precipitated apatite particles prepared in the presence of this bisphosphonic acid are nanosized. The IR and NMR-MAS 1H spectroscopy show that the BISPH can replace the OH− groups of the apatitic structure.
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3
Sharma, Chakrabhavi Gundurao Dileep. "Role of Inflammation and Angiogenesis in Aetiology of Bisphosphonate-related Osteonecrosis of the Jaws." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367505.
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Bisphosphonates (BPs) are a group of anti-resorptive agents that possess high binding affinity to bone mineral. They accumulate in bone and are released during bone turnover to inhibit resorption after their internalisation by osteoclasts. This has been described as the principal mechanism of action of BPs, warranting their use in various bone depleting conditions such as osteoporosis, Paget’s disease, metastatic bone diseases (breast cancer, prostate cancer and multiple myeloma primary sites) and paediatric osteogenesis imperfecta. However, BPs are associated with a significant adverse effect that selectively occurs in jaw bones, termed Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ). While the pathogenesis of BRONJ is not yet clearly understood, recent focus of research has been on their anti-angiogenic properties that could significantly contribute to the aetiopathogenic process by which the avascular necrosis of the jaw bone ensues. The focus of this project was to explore the mechanism by which the anti-angiogenic properties of BPs can lead to the occurrence of BRONJ lesions and subsequently formulate a localised approach for prevention of this painful and debilitating condition.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Dentistry and Oral health
Griffith Health
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Duan, Ke. "Bisphosphonate-containing coatings for bone implants." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/31288.
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Bone implants are extensively used to replace joints affected by skeletal problems. Challenges remain to further improve the clinical outcomes of implants. A fast and strong implant fixation would improve the patient's quality of life and reduce implant failure risk. The service life of implants needs to be extended, particularly for the younger patients. A logical approach to these challenges is to control the peri-implant bone formation and remodeling. Bisphosphonate drugs, potent osteoclast inhibitors, are the appropriate choice for this purpose. This thesis studied bisphosphonate-containing coatings on bone implants for local drug delivery. A reproducible electrolytic deposition (ELD) process was developed to prepare calcium phosphate (CaP) coatings on Ti and Ta as bisphosphonate carrier. The ELD parameters were experimentally determined. Microporous coatings containing octacalcium-phosphate were obtained; the pore sizes were 0.5-1 μm. The ELD current showed a rapid Cottrell-type decay followed by a prolonged nearly-constant stage, corresponding to proton reduction and molecular water electrolysis, respectively. Alendronate was chemically adsorbed on the CaP coating, and the in vitro release from the coated porous Ta implant was slow, with ~10% released after 7 days. The ELD technique was extended to process solid bisphosphonate coatings. Uniform coatings of calcium-etidronate and calcium-alendronate were deposited on Ti and porous Ta. The ELD process did not alter the molecular structures of the bisphosphonates. The solubility of the coatings in a "physiological" buffer solution was 6 x 10⁻⁵ M for Ca-etidronate and 2.5 x 10⁻⁴ M for calcium alendronate. In vitro release of alendronate from the calcium-alendronate-coated porous Ta was completed within 3 days, and the alendronate concentration was below the solubility limit. To evaluate the in vivo performance, porous Ta implants coated with the bisphosphonate-containing coatings were implanted into rabbit tibial diaphyses together with control implants. Four weeks after implantation, the CaP-coated implants with chemically adsorbed alendronate showed significantly higher total new bone area and pushout strength. The implants with calcium alendronate solid coating showed similar implant fixation and new bone area to the native Ta implants. Eight weeks after implantation, the differences in push-out strength and total new bone area were not significant among different implants.Applied Science, Faculty of
Materials Engineering, Department of
Graduate
5
Stewart, Charlotte. "Structure activity relationships of bisphosphonate analogues." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=128207.
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The nitrogen-containing bisphosphonates (NBPs) are the most widely used treatment for diseases involving excessive osteoclastic bone resorption, such as osteoporosis. The clinical efficacy of NBPs is due in large part to their affinity for bone mineral, but it has been suggested that lowering affinity may have benefits due to altered distribution and duration of action possibly allowing direct anti-tumour effects. In addition, the phosphonocarboxylate (PC) analogues inhibit prenylation more selectively through a different enzyme target, Rab geranylgeranyl transferase (RGGT), which may offer additional benefits by reducing side-effects associated with farnesyl diphosphate synthase (FPPS) inhibition. Using fluorescent analogues of PCs and NBPs demonstrated that mineral affinity not only affects initial bone-binding, but also influences desorption, reattachment and penetration at the bone surface, suggesting that lower affinity compounds have lower retention and increased access to other cell types, such as tumour cells. The work presented aimed to investigate the potential of low affinity analogues by characterising their intracellular potency for inhibiting their target enzymes. The results showed that modification to the phosphonate groups to produce phosphonoalkylphosphinate analogues reduced potency for inhibiting FPPS. By contrast, removal of one of the phosphonate groups to give a monophosphonate changed the target enzyme to RGGT. Modifications to the R1 side-chain (substituting with hydrogen or a halogen) of both NBPs and PCs were studied and showed contrasting results, modifications to the R1 side-chain of NBPs affect their ability to inhibit FPPS whereas the same modification to PCs is insignificant for inhibiting RGGT. This showed the distinction between the structural requirements for inhibition of RGGT and FPPS and furthers the understanding of the structure-activity relationships of both NBPs and PCs which could guide future drug design. Within this thesis the most potent inhibitor of RGGT to date, 3-IPEHPC, was characterised which in addition to having therapeutic potential may be used as tool to investigate the importance of Rab prenylation for cellular function.
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Benford, Helena L. "Molecular pathways of bisphosphonate-induced apoptosis." Thesis, University of Aberdeen, 2000. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU602025.
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Recent studies have proposed that non-nitrogen-containing and nitrogen- containing bisphosphonate drugs inhibit osteoclastic bone resorption by different molecular mechanisms. The aim of this thesis was to investigate the molecular mechanisms of action of bisphosphonates in macrophages and osteoclasts and, in particular, the activation of caspase proteases and their role in apoptotic cell death. Apoptosis of J774 macrophages induced by nitrogen-containing bisphosphonates was found to involve the activation of caspase-3. By contrast, non-nitrogen- containing bisphosphonates did not cause caspase activation or J774 apoptosis, indicating that these bisphosphonates have different cellular effects. Further studies demonstrated that nitrogen-containing bisphosphonates induced J774 macrophage apoptosis by inhibiting the mevalonate pathway and preventing protein farnesylation and/or geranylgeranylation, since these compounds inhibited incorporation of [14 C] mevalonate into isoprenylated proteins, and addition of cell-permeable intermediates of the mevalonate pathway (FPP and GGPP) prevented bisphosphonate-induced apoptosis. Apoptosis of J774 macrophages induced by nitrogen-containing bisphosphonates or mevastatin (another inhibitor of the mevalonate pathway) was dependent on protein synthesis, since cycloheximide effectively prevented the activation of caspase-3 and prevented J774 cell apoptosis. Both nitrogen-containing bisphosphonates and non-nitrogen-containing bisphosphonates caused caspase-3 activation and apoptosis of rabbit and human osteoclasts in vitro. The active form of caspase-3 was detected in apoptotic osteoclasts by immunofluorescence staining, whilst caspase-3 activity was visualised in osteoclasts using a cell-permeable, fluorogenic substrate and detected in cell lysates using caspase-specific substrates. Bisphosphonate-induced osteoclast apoptosis involved loss of mitochondrial membrane potential and could be prevented by a specific inhibitor of caspase-3/-7. The ability of bisphosphonates to activate caspase-3 and cause apoptosis was mimicked by GGTI-298, a specific inhibitor of protein geranylgeranylation, suggesting that caspase activation and apoptosis in osteoclasts induced by bisphosphonates is the consequence of loss of geranylgeranylated proteins. Bisphosphonate-induced osteoclast apoptosis and inhibition of bone resorption in vitro was suppressed by RANK ligand. This did notappear to involve changes in Akt phosphorylation or increased expression of cIAP-1 or cIAP-2. These studies have helped to identify the molecular mechanisms of action of bisphosphonate drugs and have provided new insights into the involvement of caspases in osteoclast apoptosis.
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White, Courtney Ellen. "Characteristics of bisphosphonate elution from orthopaedic implants." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=99121.
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Bisphosphonates, drugs typically used to prevent bone loss for patients with osteoporosis, could also be used to enhance bone growth into porous implants. Since systemic administration of bisphosphonates is not appropriate for all patients, there is a need to develop a localized drug delivery system and characterize the drug release. The chemical affinity of bisphosphonates for hydroxyapatite was used to temporarily bind them to hydroxyapatite coatings on porous implants. Implants were immersed in aqueous solution and the drug elution was measured using UV spectrophotometry. With hydroxyapatite coating there was an initial burst of elution followed by more gradual drug release over several weeks. Without hydroxyapatite coating, all of the drug eluted in a maximum of three hours. This study served to demonstrate the feasibility of binding bisphosphonate compounds to hydroxyapatite coatings and characterized the elution characteristics as a function of time.
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Duan, Xuchen. "Physiological and biological mechanisms of bisphosphonate action." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:36b0439d-2f89-4c1e-8bb3-941b4e6ee847.
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Bisphosphonates (BPs) are stable analogues of pyrophosphate widely used for the treatment of bone diseases characterised by increased bone resorption. Studies over the years have shown that the pharmacological potencies of BPs are dependent both on their binding affinities for bone mineral and on their inhibitory actions on osteoclasts. In addition, potential effects on other cell types present locally in the environment of skeletal tissues have been reported. The present study systematically evaluated the relative mineral-binding affinities of individual BPs of clinically relevance in mixtures of these compounds and the changes with elution pH by using column chromatography with ceramic hydroxyapatite and fluoroapatite combined with mass spectrometric identification and quantitation of the individual BPs. The results indicate that pH has a profound effect on the ionisation of the phosphonate and R2 functional groups, with BPs having greater affinities at lower pH as shown by increased retention times. Moreover, two other approaches, namely using Langmuir adsorption isotherms and competition assays based on fluorescent BP, have been developed to assess the mineral-binding capacities and dissociation constants of BPs. These results suggest that there are substantial differences among BPs in their binding to hydroxyapatite. From the cellular aspect of my study, I present evidence for the anti-apoptotic effects of BPs in osteocytes and osteoblasts. However, the study of prosurvival signalling pathways involved in these cells needs to be optimised. The work described in this thesis provides novel insights into the physiological and biological mechanisms of BP action. My project has provided a better knowledge of the physicochemical properties of BPs, which are highly relevant to their differential distributions within bone, their biological potencies, and their durations of action. Additionally, the cell culture studies may provide new information on the cellular effects of BPs on osteocytes and osteoblasts.
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Roberts, Jacintha. "Studies on bisphosphonate elution from orthopaedic implants." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112582.
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In a 6-week rat model it was demonstrated that a small dose of peri-implant zoledronic acid (ZA) increased local bone formation 3-fold compared with controls. Ancillary in vitro studies using 14C-labeled ZA implant doses demonstrated biphasic elution profiles for implants coated with hydroxyapatite; complete ZA release occurred within one to three weeks in serum compared with only 60% ZA release after 12 weeks in water. Implants without hydroxyapatite coating showed more burst-type release profiles and full ZA elution within 24 hours of hydration in serum or water. Canine studies at 6 weeks using implants with 14C-labeled ZA showed that the compound remained localized, with the greatest ZA concentration immediately adjacent to the implant. Although there was evidence of skeletal ZA distribution via diffusion into the circulation, the levels were two orders of magnitude less than at the implant site.
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Phoebe, Erin, Jeff Pasteur, Marion Slack, and Jeannie Lee. "Fracture Risk with Bisphosphonate Use versus Concurrent Proton Pump Inhibitor and Bisphosphonate Use: A Systematic Review and Meta- Analysis." The University of Arizona, 2013. http://hdl.handle.net/10150/614271.
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Class of 2013 AbstractSpecific 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.
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Vassiliadou, Athiná. "Humane Osteoblasten und Bisphosphonate eine In-vitro-Studie des Verhaltens von humanen Osteoblasten unter dem Einfluss von Bisphosphonaten verschiedener Generationen /." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=969815018.
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Wermelin, Karin. "Surface bound bisphosphonate for implant fixation in bone." Doctoral thesis, Linköpings universitet, Ortopedi och idrottsmedicin, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-15310.
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During the surgical preparation of bone, prior to insertion of an implant, bone will be traumatized which leads to local resorption. Consequently, early implant fixation might be reduced. Impaired early fixation, as evidenced by radiostereometry, has been associated with increased risk of late loosening. Bisphosphonates are known to inhibit bone resorption by osteoclasts and have shown to increase implant fixation when administered systemically or locally directly at the bone prior to implant insertion. A method to bind bisphosphonates directly to the implant was developed. Stainless steel screws were coated with crosslinked fibrinogen, serving as an anchor for bisphosphonate attachment. The screws were inserted in the tibial metaphysis in rats and implant fixation was analyzed with pullout measurements. Bisphosphonate coated screws turned out to have 28 % higher pullout force at 2 weeks compared to control screws with the fibrinogen coating only. The next experiment was designed to measure at what stage in the healing process the strongest bisphosphonate effect was gained. Bisphosphonate coated screws were expected to reduce the resorption of the traumatized bone. However, no decreased fixation was found in the control group. Instead, the fixation increased with time, and so did the effect of the bisphosphonates. At 8 weeks, the pullout force was twice as high for screws with bisphosphonate compared to control screws. By histology at 8 weeks, a bone envelope was found around bisphosphonate coated screws but absent around control screws. Thus, the anti catabolic action of the bisphosphonate resulted in an increased amount of bone surrounding the bisphosphonate screws. Titanium is generally considered to be better fixated in bone compared to stainless steel. The coating technique was found to be applicable on titanium as well, again with improved fixation. A majority of fractures occur in osteoporotic bone. Despite the relatively low amount of bisphosphonates at the screws, the bisphosphonate coating improved implant fixation at 2 weeks also in rats made osteoporotic by ovariectomy. In conclusion, bisphosphonates bound to titanium or stainless steel screws coated with fibrinogen increased fixation in bone, in rats. These results suggest that the bisphosphonate and fibrinogen coating might improve the fixation of screw shaped implants and possibly also arthroplasties, in humans.
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Morgado, Maria isabel Afonso de Passos. "Studies on potential cellular targets for bisphosphonate drugs." Thesis, University of Sheffield, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268270.
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Savaridas, Terence. "The effects of bisphosphonate on direct fracture healing." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/25158.
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Fractures repair by two distinct mechanism; indirect fracture healing via an endochondral stage and direct fracture healing with primary bone formation via osteonal remodelling units ('cutting cones'). Bisphosphonates are recommended by national clinical guidelines to reduce the risk of osteoporotic fractures. Despite bisphosphonate therapy, osteoporotic fractures continue to occur. A proportion of these fractures require rigid fixation, whereby bone repairs by direct fracture healing. The effects of bisphosphonate therapy on direct fracture healing have not been previously reported. With indirect fracture healing, therapeutic doses of bisphosphonate led to a delay in callus remodelling and a larger callus volume without detrimental effects on the physical property of healing fractures. A model of direct fracture healing with rigid tibial plating in the rat was developed. In addition, a non-rigid model of external fixation that used the same number and size of screw holes to that of the plating model was used for comparison. Implants were designed and tested in cadavers prior to preliminary studies in rats. Within these two groups, animals were randomly allocated either to receive daily injections of bisphosphonate (Ibandronate) or saline (Control) for nine weeks. Following three weeks of injections a transverse tibial osteotomy was created and stabilised. Plain radiographs were obtained at fortnightly intervals. Animals were sacrificed at six weeks post fracture stabilisation. On sacrifice, fracture healing was assessed on contact radiographs, with a 4-point bend to failure and histologically. The mechanical properties of the uninjured diaphyseal bone in the contra-lateral limb were also assessed following bisphosphonate therapy. The mean bending stress at failure of diaphyseal bone in the uninjured limb was increased by 20% following only nine weeks of bisphosphonate treatment. The increase in strength of the uninjured diaphyseal bone has relevance when normalising the strength of fracture repair in a limb when comparing it to the unfractured limb as frequently reported in animal studies of fracture repair. In direct fracture healing bisphosphonate therapy resulted in impaired fracture healing as evident on plain radiographs based on the visibility of the fracture line. At six weeks post fracture the failure stress on application of a 4-point bend was decreased and histology revealed delayed bone healing compared to controls. Ibandronate treatment had an inhibitory effect on direct fracture healing in a rodent model. In clinical practice, the treating surgeon may need to consider using non-rigid fixation methods in patients already on bisphosphonate therapy. When rigid fixation is essential patients on bisphosphonates will need to be monitored for features of delayed or non-union and the use of fracture healing adjuncts should be considered.
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Wang, Ling. "Syntheses and applications of bisphosphonate-based biomaterials and nanomaterials /." View abstract or full-text, 2007. http://library.ust.hk/cgi/db/thesis.pl?CHEM%202007%20WANG.
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McKenzie, Kimberly. "Skeletal distribution of bisphosphonate after elution from porous implants." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86584.
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Skeletal attachment to an implant can be enhanced by locally delivering the bisphosphonate zoledronic acid from an implant. The purpose of this study was to map the skeletal distribution of locally delivered zoledronic acid.A porous tantalum implant coated with hydroxyapatite and 14C-labelled zoledronic acid was implanted into the left femur of three dogs. After one year bone samples were taken from sites near to and distant from the implant. The amount of drug in each sample was determined using liquid scintillation counting and its distribution in peri-implant bone was additionally demonstrated using autoradiography.
All distant skeletal bone samples contained 11.8 ng/g zoledronic acid or less whereas bone immediately adjacent to the implant contained 388 ng/g. There was a 10-fold to 100-fold decrease in zoledronic acid content in bone just 1 or 2 cm away from the implant. Autoradiographs of thin bone-implant sections and bone sections revealed the highest concentration of zoledronic acid within and immediately adjacent to the implant. These data demonstrated for the first time that zoledronic acid eluted from an implant remained mainly local, with minimal systemic distribution.
L'attachement squelettique à un implant peut être amélioré en apportant de l'acide zoledronique de bisphosphonate de façon locale depuis l'implant. Le but de la présente étude était d'évaluer la distribution squelettique de l'acide zoledronique localement généré.
Un implant poreux de tantale enduit d'hydroxyapatite et d'acide 14C zoledronique a été implanté dans le fémur gauche de trois chiens. Après un an, plusieurs échantillons d'os, proches et éloignés de l'implant, ont été prélevés. La quantité de médicament dans chaque échantillon a ensuite été déterminée en utilisant un comptage par scintillation liquide; la distribution dans l'os autour de l'implant a aussi été demontré par autoradiographie.
Tous les échantillons prélevés loin de l'implant contenaient 11.8 ng/g d'acide zoledronique ou moins alors que ceux prélevés immédiatement à côté de l'implant contenaient 388 ng/g. Une diminution de 10 à 100 fois dans la teneur en acide zoledronique a été notée dans l'os situé seulement à 1 ou 2 cm de l'implant. Les autoradiographies des sections minces d'os-implant et des sections d'os ont indiqué que la concentration la plus élevée en acide zoledronique se situait dans l'implant et immédiatement à côté. Ces données démontrent, pour la première fois, que l'acide zoledronique élué d'un implant reste principalement local, avec une distribution systémique minimale.
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Thompson, Keith. "Novel insights into the molecular pharmacology of bisphosphonate drugs." Thesis, University of Aberdeen, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288395.
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Nitrogen-containing bisphophonates (N-BPs) are a blockbuster class of drugs for the treatment of common metabolic bone diseases. Recently, N-BPs have been shown to inhibit FPP synthase and/or isopentenyl diphosphate (IPP) isomerase (both enzymes in the mevalonate pathway), thereby preventing the synthesis of the isoprenoid lipids farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), which are vital substrates for protein prenylation. By preventing the synthesis of FPP and GGPP, N-BPs prevent the prenylation of small GTPases and inhibit osteoclast function. This study demonstrates conclusively that the major pharmacological target of N-BPs is FPP synthase. Furthermore, minor structural modifications to the N-BPs that govern n vivo potency have a marked effect on potency for inhibition of FPP synthase in vitro. Non-N-BPs, such as clodronate and etidronate, did not inhibit FPP synthase, consistent with other studies suggesting that the non-N-BPs and N-BPs act by different molecular mechanisms. Clinically, N-BPs have been shown to exhibit marked differences in efficacy between patients and may lie resident in the skeleton for many years. J774 macrophage-like cells resistant to the effects of N-BP (J774-RES) were generated to study the possible cellular mechanisms underlying clinical resistance to treatment. The J774-RES cells accumulated N-BP to a lesser extent than parental cells and also exhibited increased expression of the MCSF receptor, although further studies are required to clarify the exact mechanism of the resistance of J774-RES cells. Finally, N-BPs have been shown to induce the proliferation of the major subset (Vg9Vd2) of g,d-T cells in humans, attributed to an agnostic effect on the g,d-T cell receptor (TCR). The findings of this study indicate that the N-BPs act indirectly, by inhibiting FPP synthase and causing the accumulation of IPP, a known agonist of the g,d-TCR. Furthermore, this proliferative effect of N-BPs could be abrogated by statins, possibly indicating a means of preventing the acute-phase response, the major side effect to intravenously-administrated N-BPs.
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Dudakovic, Amel. "Geranylgeranyl diphosphate synthase as a novel cancer therapeutic target." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/795.
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The isoprenoid biosynthetic pathway is targeted in the treatment of several diseases, including hypercholesteremia and bone related disorders. Farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP) are isoprenoid biosynthetic pathway intermediates that are utilized during post-translational modification of proteins termed farnesylation and geranylgeranylation, respectively, together known as prenylation. The Ras and Rho GTPase family members are examples of proteins that are prenylated. Prenylation is essential for proper membrane localization and function of these small GTPases. Activating mutations or over-expression of these proteins promote oncogenic events, such as increased proliferation and migration.
Studies have demonstrated that farnesyl transferase inhibitors and geranylgeranyl transferase inhibitors possess anti-cancer effects in humans and animal models of cancer, respectively. An alternative way to impair protein prenylation is through the depletion of FPP and GGPP. Statins and nitrogenous bisphosphonates (NBPs) deplete FPP and GGPP leading to impaired protein prenylation by inhibiting HMG-CoA Reductase (HMGCR) and FPP synthase (FDPS), respectively. These drugs have been shown to induce apoptosis, inhibit cancer cell migration, and induce cell cycle arrest. The anti-cancer effects of statins and NBPs can be prevented by GGPP addition, suggesting that GGPP depletion may be the mechanism by which these agents interfere with cancer cell survival.
We and our collaborators have developed bisphosphonate inhibitors of GGPP synthase (GGDPS), an enzyme that produces GGPP from the substrates FPP and isopentenyl pyrophosphate.
The goal of this research was to identify novel GGDPS inhibitors and to assess the effects of specific inhibition of GGDPS on cancer cell survival and function. Two aromatic bisphosphonates were identified as potent inhibitors of GGDPS in enzyme and cellular assays. Apoptosis hallmarks such as PARP cleavage and DNA fragmentation demonstrated that GGDPS inhibition induces apoptosis in K562 chronic myeloid leukemia cells through GGPP depletion and FPP accumulation. Isobologram analysis and enhanced impairment of protein geranylgeranylation showed that GGDPS inhibition is synergistic with the inhibition of HMGCR. Migration assays, transwell assay and large scale digital cell analysis system microscopy, demonstrated that GGDPS inhibition interferes with MDA-MB-231 breast cancer cell migration. Increased LC3-II expression showed that FDPS and GGDPS inhibition induces autophagy in PC3 prostate and MDA-MB-231 breast cancer cells. Inhibition of autophagy enhances the toxic effects of GGDPS inhibition as measured by MTT assay. Propidium iodine staining of DNA and immunostaining of cell cycle proteins such as p27 did not show significant effects of GGDPS inhibition on cell cycle progression. Importantly, exogenous addition of GGPP prevented most of the effects observed with GGDPS inhibition, suggesting specific inhibition of GGDPS by our bisphosphonate inhibitors. The data obtained herein suggest that GGDPS can be targeted to interfere with the progression of cancer cells.
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Koivukangas, A. (Antti). "Effects of long-term clodronate administration on bone and on fracture healing in rat, with special reference to methodological aspects." Doctoral thesis, University of Oulu, 2002. http://urn.fi/urn:isbn:9514267052.
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Abstract
Bisphosphonates (BPs) are used in the treatment of osteoporosis. However, their effects, especially long-term effects, on
bone and bone healing are not fully known. Clodronate (dichloromethylene bisphosphonic acid) is a first-generation BP.
The thesis was based on two animal experiments. The first, with 199 rats on long-term clodronate treatment, was divided into
four separate substudies. The effects of long-term administration of clodronate to rats were investigated after 32 weeks of
treatment. The effects on the femoral shaft, femoral neck and vertebra in normal, non-osteoporotic skeleton were described in two
publications. The evaluations were made by biomechanical, densitometric, histological, hematological and electron-microscopic
investigations. Fracture healing was investigated in rats after 24 weeks of clodronate treatment. The tibia was fractured, and the
effects of treatments were evaluated at 4 and 8 weeks after the fracture. Radiographs and densitometric pQCT in the evaluation of
experimental fracture healing were compared. In the other experiment with 30 mice, a mouse immobilisation osteoporosis model for
further studies was investigated.
Long-term administration of clodronate at therapeutic dosage had no harmful impacts but rather some beneficial effects on
normal, non-osteoporotic bone. However, long-term high-dose clodronate treatment resulted in a decrement of tibial length but did
not have any other significant or adverse effects. In the evaluation of fracture healing, pQCT proved to be better than radiographs
in differentiating the total mineralised cross-sectional area of callus and the area of compact bone. Clodronate treatment does not
seem to prolong the fracture healing process, even when administered on a long-term basis before the fracture. Clodronate increased
the size of callus, but had only a minor effect on its biomechanical properties. Three weeks of hind limb immobilization caused
local osteopenia in the tibia when compared to its contralateral leg.
In conclusion, this thesis suggests that long-term administration of clodronate at therapeutic dosage has no harmful, but
rather some beneficial effects on normal, non-osteoporotic bone. However, a fivefold dose of clodronate causes a slight decrease in
the growth of tibial length. Healing of fractures during or after clodronate treatment is not inhibited.
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Smits, Jacqueline Patricia. "Synthesis and evaluation of novel bis-and trisphosphonates." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/2772.
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Phosphorus is an essential element for life, observed in all biological systems usually as inorganic phosphate and various organic phosphate esters. Phosphonates are a metabolically stable analogues of natural phosphorus containing compounds and have been used in a variety of industrial and medicinal applications. Bisphosphonates have been found to be especially good inhibitors of enzymes in the isoprenoid biosynthetic pathway. A screen of bisphosphonates against the enzyme squalene synthase (SQS) resulted in the identification of a lead target. The lead compound was resynthesized via a new method along with two other analogues. It was determined that although the lead bisphosphonate had potent and selective activity against SQS and resulted in the reduction of cholesterol, use of this drug in combination with either a statin (lovastatin) or a nitrogenous bisphosphonate (zolendronate) had an even greater impact. Furthermore co-treatment of cells with the lead compound and either lovastatin or zoledronate significantly prevented a reduction of cell viability caused by lovastatin or zoledronate alone. The combination of an SQS inhibitor with either an HMGCR or FDPS inhibitor may be beneficial for reducing cholesterol synthesis while preventing non-sterol isoprenoid depletion.
A series of stilbenoid bisphosphonates has been developed to afford potential inhibitors of enzymes in the isoprenoid biosynthetic pathway, a potential target for cancer therapies. Although the new compounds had limited activity against major enzymes in the isoprenoid biosynthetic pathway, it was determined that one of the targets had modest activity in a screen of inhibitors for decaprenyl diphosphate synthase, an enzyme vital to synthesis and maintenance of cell walls in mycobacteria. A second generation synthesis of stilbenoid bisphosphonates that contain a para-substituted electron withdrawing group was initiated, resulting in the identification of a more potent inhibitor of decaprenyl diphosphate synthase. The use of novel bisphosphonate inhibitors could have an impact on treatment of bacterial diseases such as tuberculosis. The development of novel phosphorus containing compounds could provide new inspiration for industrial and medicinal products. The á-trisphosphonic acid esters provide a unique spatial arrangement of three phosphonate groups, and may represent an attractive motif for inhibitors of enzymes that utilize di- or triphosphate substrates. A general route to alkyl derivatives of the parent system has been developed through phosphinylation and subsequent oxidation of tetraethyl alkylbisphosphonates, and the reactivity of these new compounds has been studied in representative reactions that afford additional examples of this functionality. During the course of synthesis of the parent trisphosphonate system, an unusual oxidized bisphosphonate phosphate was discovered, and the methods to synthesize this species have been investigated.
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Grodde, Katharina. "Bisphosphonat- assoziierte Kiefernekrose (BONJ) im Dental- CT." Doctoral thesis, Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-215530.
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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.
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Chan, Ka Lok. "Synthesis and bioactivites of new conjugates of bisphosphonate and porphyrin /." View abstract or full-text, 2007. http://library.ust.hk/cgi/db/thesis.pl?CHEM%202007%20CHAN.
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Zhu, Yinghua, and 朱穎華. "Establishment of osteolysis model in rabbit and evaluation of bisphosphonate intervention." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B31246369.
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Li, Chunlei, and 李春蕾. "Role of periodontal diseases in bisphosphonate-related osteonecrosis of the jaws." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208556.
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Saoji, Nachiket A. "Effect of bisphosphonate on osteogenic differentiation of pulp and PDL cells." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2009r/saoji.pdf.
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Pfannkuchen, Nina [Verfasser]. "Chelator-konjugierte Bisphosphonate : Synthese, Radiomarkierung und in vivo-Evaluierung / Nina Pfannkuchen." Mainz : Universitätsbibliothek Mainz, 2018. http://d-nb.info/1149977523/34.
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Kamble, Sumedh. "Bisphosphonates for Bone Targeting and Cancer Therapy." Thesis, The University of Sydney, 2020. https://hdl.handle.net/2123/22013.
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Bisphosphonates (BPs) are a class of bone binding and bone anti-resorptive drugs used in the management of osteoporosis, and skeletal related events (SREs) in cancer. BPs selectively and rapidly bind to the bones, where they inhibit osteoclasts and osteoclast mediated bone resorption. Apart from their anti-osteoclastic activity in bones, BPs have also shown surprising anti-tumour effects outside the bone. This thesis investigates the versatility of BPs as a bone targeting molecule and a therapeutic agent for cancer and bone infection applications. In Chapter 2, we describe the formulation of bone targeting micelles encapsulating curcumin as a model anticancer agent for bone metastasis. Micelles were generated by covalently conjugating the amino BP alendronate (ALN) to the carboxyl termini of a modified Pluronic F127 blockcopolymer. The chemistry for modification of Pluronic F127 and subsequent ALN conjugation, and technology to produced monodispersed bone targeting micelles was developed and optimised. The formulated ALN conjugated micelles were of an ultra-small size, exhibited rapid binding to bone mineral and an ideal drug loading capacity. Thus, it is hypothesized that BPconjugated Pluronic F127 micelles could be a vehicle for the therapeutically effective delivery of curcumin for bone metastases. Bone-targeted micelles are also expected to reduce the systemic toxicity of cytotoxic chemotherapeutic drugs due to selective bone targeting. Chapter 3 builds upon the concept of covalently conjugating ALN to provide bone targeting. We developed a method for the conjugation of amino-BP through carbodiimide chemistry to produce a novel drug. CSA-90 and ALN were covalently conjugated via a peptide bond using a heterobifunctional PEG linker to create a bone binding antimicrobial (BBA-1). There is considerable utility for such a drug in the prevention of osteomyelitis (bone infection). A detailed characterization was performed on BBA-1. It retained the potent antibacterial action of parent CSA-90 roughly at an equimolar concentration. BBA-1 exhibited a profoundly robust and rapid affinity for bone mineral in hydroxyapatite binding/retention assay. In an osteoblast cell culture model, BBA-1 retained the pro-osteogenic activity previously reported for parental compound CSA-90. In contrast, western blot analysis of protein lysate from J774.2 macrophage cells showed no effect of BBA-1 on protein prenylation in contrast to ALN alone. In Chapter 4, an injectable sustained release formulation of BP was tested in INA-6 Tu1 human plasmacytoma xenograft murine model. While BPs are extensively used for bone metastases, it was speculated chronic exposure of non-skeletal tumours to BPs could impair growth or even induce cancer cell apoptosis. It was found by initial studies that SAIB:ethanol depots previously used for BMP/BP release were able to attain a sustained release profile of fluorescently-labelled BP compared to conventional bolus dosing in C57Bl6 mice. Analysis of long bones from these mice demonstrated an increase in fluorescently-labelled BP binding to bone when delivered with slow release SAIB:ethanol formulation compared to bolus subcutaneous injection. Moreover, two-photon and Li-COR infrared imaging showed fluorescently-labelled BP released from SAIB depot in vivo also accumulated in subcutaneous INA-6 Tu1 tumours in NOD-scid (NSG™) mice. In vivo tumour associated macrophages (TAMs) labelling and subsequent two-photon imaging of tumour explants revealed co-localization of fluorescently-labelled BP and F4/80+ TAMs, suggesting internalization of BP by TAMs. Treatment with potent zoledronic acid (ZOL) in SAIB:ethanol formulation caused inhibition of protein prenylation in INA-6 tumors in vivo. Notably, isolation of the CD11b+ (mostly TAMs) and CD11b- (mostly cancer cells) from the tumour homogenate of ZOL treated mice confirmed that BPs primarily impaired protein prenylation in CD11b+ TAMs rather than in tumour cells. In summary, this works illustrates the profound versatility of BPs both as targeting moieties and therapeutic agents for conditions outside of bone. While BPs are widely used in the treatment of osteoporosis and metabolic bone disorders, there is scope for BP-derived compounds to be used to provide new functionality to existing compounds such as antibiotics, or to treat non-skeletal tumours. Further development is required to validate the in vivo efficacy of BBA-1 in models of bone infection, as a prelude to production of GMP-quality compound and undertaking clinical trials. The findings of the anticancer effects of BPs outside the bone are very encouraging and the identification of macrophages as targets for circulating BPs is highly novel.
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Linderbäck, Paula. "Improved titanium and steel implants : Studies on bisphosphonate, strontium and surface treatments." Doctoral thesis, Linköpings universitet, Institutionen för fysik, kemi och biologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-71289.
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Purpose: The general aim of this thesis was to increase the understanding of biomaterial surface modifications and local delivery of osteoporosis drugs for bone integration. We therefore (i) characterised and investigated model surface coatings for controlled drug delivery in a rat tibia screw model (ii) elucidated the effect of surface treatment for activation of complement system in vitro. Materials and methods: Bisphosphonate was immobilised directly to implant surfaces by two methods. In the first method, bisphosphonate was bound via a crosslinked fibrinogen layer to titanium surfaces. In the second method, stainless steel screws were first dip coated in a TiO2 solgel, and thereafter incubated in simulated body fluid (SBF). The so prepared thin calcium phosphate layer on titania bound then bisphosphonate directly with high affinity. The drug release kinetics was determined in vitro by 14C marked alendronate that was quantified with scintillation techniques. The screws were inserted in the metaphysis of rat tibia and the mechanical fixation monitored by screw pullout measurements after 2 or 4 weeks of implantation. In order to compare two different osteoporosis drugs, bisphosphonate and strontium ranelate, stainless steel and PMMA screws were inserted in the tibial metaphysis of rat for 4 and 8 weeks. Bisphosphonate was then delivered subcutaneously and strontium ranelate orally during the whole implantation period. The mechanical fixation was analysed by pullout force measurements, and bone architecture studied by micro-computed tomography (μCT). The immune complement activation on sol-gel- and smooth titanium surfaces was analysed in human blood plasma before and after annealing of titanium at 100-500ºC or upon UVO-treatment for up to 96 hours. Results: Bisphosphonate coated screws enhanced the screw pull out force after 2 weeks of implantation by more than 30% (fibrinogen coating) and by 93% after 4 weeks (sol-gel derived TiO2 coating). Systemically administered bisphosphonate enhanced the mechanical screw fixation after 4 weeks by more than 96% and after 8 weeks by more than 55% as compared to strontium ranelate treated animals (p = 0.00). Strontium ranelate treatment did not show significant improvement of screw pullout force after 4 and 8 weeks, compared to control. The immune complement surface deposition from blood plasma vanished irreversibly after Ti heat treatment at 250-300 ºC during 30 minutes or after UVO exposure for 24 hours or longer. Tentatively, changes in surface water/hydroxyl binding upon heat- and UVO treatments were observed by XPS and infrared spectroscopy. Conclusions: The results show that fixation at short implantation time (weeks) of orthopaedic implant can be enhanced by immobilised bisphosphonate on stainless steel or titanium implants. Systemic delivery of strontium ranelate showed no significant effect on implant fixation in rat tibia, and we hypothesise therefore that strontium ranelate will not become a power tool to increase the early implant fixation, but may be beneficial at longer times. Heat annealing or UVO-treatment of titanium surfaces change the surface hydroxylation, leading to decreased immune complement deposition from blood plasma.
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Conners, Christopher. "Bisphosphonate Functionalized Gold Nanoparticles for the Study and Treatment of Osteoporotic Disease." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6818.
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The use of nanoparticles for disease treatment is an increasingly popular area of research. The potential for multi-functionality allows nanoparticles to be used as transport and delivery vehicles for drugs and as diagnostic aides, among other applications, to address the unmet needs of many disease treatments. One such class of disease is osteoporosis including severe disorders, like Paget’s disease, Osteogenesis Imperfecta and Legg Calve Perthes disease. In this dissertation, we discuss a nanoparticle system consisting of gold nanoparticles surface functionalized with primary amine bisphosphonates, which is a classification of pharmaceuticals that is common in the treatment of osteoporosis. Functionalized nanoparticles allow for greater intracellular concentrations of pharmaceutical, while the properties of the gold nanoparticles provide the ability to track the pharmaceutical and enhance imaging.
We have synthesized and characterized bisphosphonate functionalized gold nanoparticles of controlled size of approximately 15 nm, which are suitable for cellular uptake, and functionalized the surface using self-assembly with pamidronate and alendronate. In one major finding of this study, inductively coupled plasma mass spectrometry was used to estimate approximate surface density of the bisphosphonates on the gold nanoparticles. This resulted in concentrations of approximately 0.65 molecules per nm2 (approximately 154 Å2/molecule) for pamidronate functionalized on gold, and approximately 2.6 molecules per nm2 (approximately 39 Å2/molecule) for alendronate functionalized on gold. This allows for more accurate estimates of pharmaceutical concentrations, during in vitro and in vivo studies.
Additionally, we investigated the effects of bisphosphonate functionalized gold nanoparticles on the viability and morphology of osteoclast and osteoblast cells in vitro. We found that attaching the bisphosphonates to the surface of the nanoparticles leads to increased apoptotic effects of the bisphosphonates on the osteoclast cells compared to free bisphosphonates. Further, we showed bisphosphonate functionalized gold nanoparticles may have an effect on nuclei morphology that may provide an additional means of modulating bone resorption rather than just through influencing viability. Further we showed that it may be possible to target concentrations that are safe for osteoblasts, which is critical in determining potential treatment concentrations. These viability results bring to light a number of potential considerations into the optimization of potential treatments, such as dosing concentrations.
Finally, detailed results are given on effects of bisphosphonate functionalized gold nanoparticles on important behavior and activity of osteoclast and osteoblast cells in vitro. We showed that while using concentrations below the toxicity threshold, some of the normal activity of the cells could be maintained. RANKL and ALP expression in osteoblasts were maintained when removing viability as a variable. Additionally, bone nodule formation was also maintained for osteoblasts and co-cultured in vitro systems. Finally, we showed that the introduction of bone in the in vitro studies adds a new degree of consideration as to the interaction of the bisphosphonates with the hydroxyapatite surface. This strong interaction with bone is an important consideration in further developing potential treatments for osteoporotic disease.
This dissertation provides insights into the use of bisphosphonate functionalized gold nanoparticles as a potential treatment and means of study for bone remodeling disorders.
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Girard, Bruno. "Exploring high dose effects of a bisphosphonate, HEBP, on osteogenesis in vitro." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0018/MQ53412.pdf.
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Stürmer, Stephanie [Verfasser]. "Immunhistochemische Untersuchungen zur Differenzierung unterschiedlicher Knochenreaktionen auf Bisphosphonate in Humanpräparaten / Stephanie Stürmer." Bonn : Universitäts- und Landesbibliothek Bonn, 2013. http://d-nb.info/1043699953/34.
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Eichelberg, Anne-Christine [Verfasser]. "Bisphosphonate in der Therapie von Patienten mit Multiplem Myelom / Anne-Christine Eichelberg." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1067098887/34.
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Yamazaki, Toru. "Incidence, risk and risk factors of bisphosphonate-related osteomyelitis of the jaw." Kyoto University, 2013. http://hdl.handle.net/2433/180463.
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Gardina, Christopher. "Bone Mass Preservation and Fracture Risk Assessment with Bisphosphonate Therapy During Spaceflight." DigitalCommons@CalPoly, 2008. https://digitalcommons.calpoly.edu/theses/5.
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Space exploration and microgravity have substantial negative effects on the human body. Symptoms of space explorers include cardiovascular deconditioning, bone loss, muscular atrophy, and impairment of neurovestibular and sensory function. The great loss of bone due long-duration spaceflight increases fracture risk, jeopardizing the success of the mission and postflight recovery. Bisphosphonates may be able to counteract this bone loss by altering the remodeling process. These drugs increase bone mass, thus reducing fracture risk, but also lead to increased levels of fatigue microdamage. Fracture risk can be lowered by increasing both bone mass (quantity) and bone quality.
The purpose of this study was to create a computer model to simulate bisphosphonate treatment on astronauts while traveling in space in order to examine the ability of bisphosphonates to maintain bone mass in a microgravity environment and reduce fracture risk of bone upon return to Earth. Various bisphosphonate treatment potencies and bone balance ratios given at different time points (either at or before spaceflight) were examined. Flight duration was also varied to examine short-term (10 days) to long-term (1 year) effects of microgravity on bone mineral density (BMD), a measure commonly used to estimate bone strength, and damage accumulation. The model predicted bisphosphonate treatments with low to intermediate suppression of remodeling activation and that create higher bone balance ratios cause reductions in fracture risk. The simulation also predicted significant changes to BMD and damage upon return to Earth as the remodeling response readjusted to higher stress conditions. For treatments highly suppressing remodeling activation, these predicted postflight changes included decreased BMD and increased damage accumulation. Low levels of remodeling suppression led the model to predict substantial increases in BMD and small increases in damage postflight. Postflight changes were minimal for treatments with intermediate suppression.
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Silva, Jonathan Ribeiro da [UNESP]. "Prevenção da Osteonecrose dos Maxilares Induzida por Medicamentos com a utilização de enxerto Xenógeno e β- trifosfato de cálcio (β-TCP)." Universidade Estadual Paulista (UNESP), 2018. http://hdl.handle.net/11449/154852.
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Outra
Objetivo: Avaliar a prevenção da OMIM em ratos em risco de desenvolvimento de osteonecrose na região em que foi realizada a exodontia utilizando apenas coágulo, enxerto de osso xenógeno, e enxerto de β- trifosfato de cálcio (β-TCP). Métodos: Foram utilizados 20 Ratos Wistar machos com 3 meses de idade, pesando 350 – 450g, submetidos a indução da Osteonecrose por uso de ácido zoledrônico (0,04mg/kg) durante 05 semanas. Na 7a semana foi realizado a cirurgia de exodontia dos molares superiores direito e preenchimento do alvéolo com coágulo (controle), enxerto xenógeno (Grupo 2), e β- trifosfato de cálcio (β-TCP) (Grupo 3). A eutanásia foi realizada na 15a semana. Foram realizadas análises morfométrica, estereológica, e imunohistoquímica, onde aplicou-se os testes estatísticos ANOVA e Tukey, considerando-se um nível de significância de 5%. Resultados: Durante a análise macroscópica não houve manifestação clínica da OMIM nos grupos experimentais. A análise quantitativa demonstrou que o Grupo 3 (BTCP) apresentou menor formação de lacunas ósseas e maior formação de tecido ósseo sadio quando comparado com os grupos 1 e 2 (p<0,05). Não houve diferença estatística entre os grupos durante análise de formação de tecido epitelial. Na análise imunohistoquimica, o grupo experimental apresentou maior atividade de remodelação óssea. Conclusão: Os resultados deste trabalho demonstraram que os grupos experimentais apresentaram maior atividade de remodelação óssea, e ausência de manifestação clínica da OMIM. O grupo BTCP ainda demonstrou menor quantidade de lacunas e maior quantidade de osso formado durante analise histológica. No entanto, mais estudos necessitam ser realizados até o desenvolvimento de um protocolo de prevenção desta complicação
Objective: To evaluate the bone formation in rats with osteonecrosis in the region where the extraction was performed using only clot, xenogen bone graft, and calcium β-triphosphate (β-TCP) graft. METHODS: Twenty male Wistar rats weighing 350-450 g were submitted to osteonecrosis induction for the use of zoledronic acid (0.2 mg / kg) for 5 weeks. In the 7th week, the maxillary right molar extraction and filling of the alveolus with clot (control), xenogene graft (Group 2) and calcium β-triphosphate (β-TCP) were performed (Group 3). Euthanasia was performed in the 15th week. Morphometric and stereological analyzes were performed. The ANOVA and Tukey statistical tests were used, considering a level of significance of 5%. Results: During the macroscopic analysis there was no clinical manifestation of the OMIM in the experimental groups. Quantitative analysis showed that Group 3 (BTCP) presented less bone formation and greater formation of healthy bone tissue when compared to groups 1 and 2 (p <0.05). There was no statistical difference between groups during analysis of epithelial tissue formation. In the immunohistochemical analysis no difference was found in the bone remodeling process between the groups. Conclusion: The results of this work were favorable for the use of BTCP for guided bone regeneration and prevention of the clinical manifestation of OMIM in rats. However, more studies need to be performed until the development of a protocol to prevent this complication
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Zhang, Rui. "Ionic Copolymer-Magnetite Complexes for Magnetic Resonance Imaging and Drug Delivery." Thesis, Virginia Tech, 2015. http://hdl.handle.net/10919/73648.
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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
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Neudert, Marcus, Christian Fischer, Burkhard Krempien, Markus J. Seibel, and Frieder Bauss. "A Rapid Histological Score for the Semiquantitative Assessment of Bone Metastases in Experimental Models of Breast Cancer." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-134931.
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Background: Using a nude rat model of site-specific metastatic bone disease (MBD), we developed a semiquantitative histological score for rapid assessment of lytic lesions in bone. This provides additional information to conventional histological measurement by clarifying the extent and location of metastatic infiltration and the tumor growth pattern. The score can also be used to assess the action of bisphosphonates on bone metastases. Materials and Methods: Male nude rats (n = 12 per group) were inoculated with the human breast cancer cell line MDA-MB-231 via the femoral artery. Following appearance of radiographically visible osteolytic lesions on day 18, the animals received phosphate-buffered saline (PBS; controls) or ibandronate (IBN, 10 µg P/kg) daily until day 30. Whole body radiographs were obtained on days 18 and 30, and osteolytic areas (OA) were determined by radiographic computer-based analysis (CBA). On day 30, MBD was assessed in both tibias using conventional histological CBA and the new scoring system. Results: Metastatic tumor area correlated with the total sum of the new score in both PBS- (r = 0.762) and IBN-treated animals (r = 0.951; p < 0.001). OA correlated well with the total sum in both groups (r = 0.845 and 0.854, respectively; p < 0.001). Conclusion: Significant reduction of bone marrow and cortical infiltration of tumor cells with IBN suggested local control of metastasesHintergrund: Mit Hilfe eines etablierten Tiermodells zur Erzeugung lokalisationsspezifischer Knochenmetastasen in der Nacktratte wurde ein semiquantitatives histologisches Graduierungssystem zur schnellen Bewertung osteolytischer Knochenmetastasen entwickelt. Das Graduierungssystem liefert hinsichtlich der Metastasenlokalisation, deren Ausmaß und Infiltrationsmuster wertvolle Zusatzinformationen zu den konventionellen histologischen Untersuchungsmethoden. Damit kann beispielsweise auch die pharmakologische Wirkung von Bisphosphonaten auf die Knochenmetastasierung beurteilt werden. Material und Methoden: Männlichen Nacktratten (n = 12 pro Gruppe) wurden Zellen der humanen Brustkrebszellinie MDA-MB-231 in die Oberschenkelarterie inokuliert. Ab dem Auftreten radiologisch erkennbarer Osteolysen 18 Tage nach Inokulation erhielten die Tiere bis zum Studienende (Tag 30) täglich entweder eine subkutane Applikation einer Phosphat-Puffer-Lösung (Kontrollgruppe) oder Ibandronat (IBN, 10 µg P/kg; Behandlungsgruppe). Konventionelle Röntgenaufnahmen wurden an den Tagen 18 und 30 nach Tumorinokulation angefertigt und die Osteolysenflächen mittels Computerauswertung bestimmt. Nach Studienende wurde der Metastasenbefall in beiden Tibiae sowohl konventionell histologisch als auch mittels des neuen Graduierungssystems ausgewertet. Ergebnisse: Die Metastasenfläche korrelierte mit der kummulativen Punktsumme des Graduierungssystems sowohl in der Kontrollgruppe (r = 0,762; p < 0,001) als auch in der Ibandronat- Gruppe (r = 0,951; p < 0,001). Ebenso war die Osteolysenfläche eng mit der Punktesumme in beiden Gruppen korreliert (r = 0,845 und 0,854; p < 0,001). Schlussfolgerung: Die signifikante Reduktion von Knochenmark- und Kortikalisbefall durch IBN deuten auf eine gute lokale Kontrolle des Metastasenwachstums hin
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Kelley, Leslie K. "Effectiveness of Statin and Bisphosphonate Treatment in a 3NP model of Huntington’s Disease." ScholarWorks@UNO, 2015. http://scholarworks.uno.edu/td/1993.
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Huikko, Katri. "Capillary electrophoresis- and microchip-mass spectrometry interfaces and their utilization in bisphosphonate analysis." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/mat/farma/vk/huikko/.
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Wills, Veronica Sue. "Synthesis of geminal bisphosphonates as potential inhibitors of GGDPS." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1933.
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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.
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Callard, Jason Scott. "Effect of Zoledronic Acid on Maxillary Alveolar Bone Coverage in Rice Rats With and Without Dental Trauma." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366108637.
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Frith, Julie C. "Studies into the mechanism of action of clodronate." Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299577.
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Gardina, Christopher Hazelwood Scott James. "Bone mass preservation and fracture risk assessment with bisphosphonate therapy during spaceflight : a thesis /." [San Luis Obispo, Calif. : California Polytechnic State University], 2008. http://digitalcommons.calpoly.edu/theses/5/.
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Thesis (M.S.)--California Polytechnic State University, 2008.Major professor: Scott Hazelwood, Ph.D. "Presented to the faculty of California Polytechnic State University, San Luis Obispo." "In partial fulfillment of the requirements for the degree [of] Master of Science in Engineering with a specialization in Biomedical Engineering." "June 2008." Includes bibliographical references (leaves 46-49). Also available online. Also available on microfiche (2 sheets).
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Ward, Jonathan Joseph. "RELATIONSHIPS OF LONG-TERM BISPHOSPHONATE TREATMENT WITH MEASURES OF BONE MICROARCHITECTURE AND MECHANICAL COMPETENCE." UKnowledge, 2014. http://uknowledge.uky.edu/cbme_etds/26.
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Oral bisphosphonate drug therapy is a common and effective treatment for osteoporosis. Little is known about the long-term effects of bisphosphonates on bone quality. This study examined the structural and mechanical properties of trabecular bone following 0-16 years of bisphosphonate treatment. Fifty-three iliac crest bone samples of Caucasian women diagnosed with low turnover osteoporosis were identified from the Kentucky Bone Registry. Forty-five were treated with oral bisphosphonates for 1 to 16 years while eight were treatment naive. A section of trabecular bone was chosen from a micro-computed tomography (Scanco µCT 40) scan of each sample for a uniaxial linearly elastic compression simulation using finite element analysis (ANSYS 14.0). Morphometric parameters (BV/TV, SMI, Tb.Sp., etc.) were computed using µCT. Apparent modulus, effective modulus and estimated failure stress were calculated. Biomechanical and morphometric parameters improved with treatment duration, peaked around 7 years, and then declined independently of age. The findings suggest a limit to the benefits associated with bisphosphonate treatment and that extended continuous bisphosphonate treatment does not continue to improve bone quality. Bone quality, and subsequently bone strength, may eventually regress to a state poorer than at the onset of treatment. Treatment duration limited to less than 7 years is recommended.
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Pagano, Stefanie L. "The Effect of Varying Bisphosphonate Treatment on Changes in Bone Microdamage in Osteoporotic Women." UKnowledge, 2016. http://uknowledge.uky.edu/cbme_etds/40.
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Bisphosphonates (BPs) are used for the treatment of osteoporosis. This study evaluated changes in bone microdamage with BP treatment duration. Fifty-one iliac crest biopsies were obtained from Caucasian women, ages 41 to 87 years, who were previously diagnosed and treated for osteoporosis with oral BPs for 1-16 years duration. Patients diagnosed with any disease, drug, or substance abuse that may affect bone metabolism were excluded.
Bone samples were sectioned, stained, and histologically examined using light and fluorescence microscopy. Bone area, number and length of microcracks were quantified. Following adjustment for age, BMD, BV/TV, trabecular thickness, and turnover, regression analysis revealed a relationship between microcrack density and treatment duration (p=0.018). No significant relationship was observed between microcrack length and treatment duration.
This study provides novel data relating microdamage with varying BP treatment duration in human bone. Given information from other studies showing that microdamage amounts are related to changes in bone biomechanics, the BP treatment duration related changes in microdamage shown offer new information that may help optimize osteoporosis treatment.
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Tardoski, Sophie. "Traitement des métastases osseuses par association d’un bisphosphonate avec des ultrasons de faible intensité." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10162/document.
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Les métastases osseuses sont une complication majeure des cancers du sein. Les bisphosphonates (BPs) bloquent la progression des lyses osseuses. Des effets anti-tumoraux ont été mis en évidence mais à des doses importantes incompatibles avec un usage clinique. La forte affinité des BPs pour le minéral osseux limite leur biodisponibilité et amoindrit donc leur potentiel antitumoral in vivo. Mon travail de thèse s'est inscrit dans le cadre de la potentialisation des effets anti-tumoraux des BPs. Les BPs ont été combinés avec des ultrasons de faible intensité (LIUS) dont le rôle est d'induire une stimulation mécanique et une augmentation modérée de la température du milieu insonifié sans effet de cavitation. Les LIUS favorisent la pénétration des BPs dans des cellules tumorales en augmentant le phénomène d'endocytose. In vivo, un traitement répété aux LIUS associé à une dose clinique de BPs entraine une diminution des lyses osseuses ainsi que de la masse tumorale. L'accumulation d'un marqueur, retrouvé dans les moelles des souris traitées aux LIUS, suggère que la pénétration des BPs a été favorisée sous l'effet des LIUS. L'effet de l'association BPs avec les LIUS a ensuite été évalué sur un modèle de tumeur sous-cutanée mammaire. Un ralentissement de la croissance tumorale lors des premiers jours de traitements a été mis en évidence. Une étude menée avec de la doxorubicine et des BPs a permis d'élargir le champ d'application des LIUS pour le traitement du cancer du sein. En conclusion, ces travaux montrent que les LIUS apparaissent comme une solution d'intérêt pour augmenter la pénétration de drogues dans des tumeurs osseuses et mammaires et augmenter leur potentiel antitumoralBone metastases are common complications of advanced breast cancer. They increase morbidity of patients and alter their quality of life. Bisphosphonates (BPs) stop the progression of osteolysis. However, BPs do not affect the tumor burden located inside the bone marrow cavity. Antitumoral effects have been shown but with high doses incompatibles with a clinical use. BPs bind also avidly to bone mineral which limits their bioavailability and reduce their antitumoral potential in vivo. This work is incorporated within the framework of the enhancement of antitumoral effects of BPs. BPs were combined with low intensity ultrasound (LIUS), which are known to induce a mechanical stimulation and a slight increase of temperature without involving cavitationnal effect. Initially, LIUS were found to increase the penetration of BPs inside several mammary tumor cell lines without affecting their viability by increasing endocytosis. In vivo, a daily repeated treatment of LIUS associated with a single and clinical dose of BPs lead to a decrease in osteolysis as well as tumor burden. The accumulation of unprenylated Rap1A form was found in bone marrow of mice suggesting that LIUS promote BPs penetration inside cells of the bone cavity. The effect of BPs and LIUS was evaluated in a subcutaneous mammary tumor xenograft. Tumor growth was slowed during the first days of LIUS treatment. A study was performed using doxorubicin and BPs leading to a better penetration of both compounds when LIUS were used. This last result allows increasing the field of application of LIUS for breast cancer treatment. In conclusion, this work showed that LIUS are an interesting method to enhance the penetration of drugs inside bone and mammary tumors leading to an increase of their antitumoral activity
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Mattos, Ana Carolina Lopes. "Osteonecrosis of the jaw in association to bisphosphonates." Thesis, Boston University, 2008. https://hdl.handle.net/2144/41446.
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Thesis (M.A.)--Boston University, 2008.The use of bisphosphonate has become more widespread for the treatment of bone metastasis, multiple myeloma, osteoporosis, Paget's disease and other bone malignancies. Osteonecrosis of the jaw (ONJ) has been recently recognized as a possible complication of the use of bisphosphonate therapy. This study includes a review of the literature on the mechanism of action of bisphosphonate and its potential association to the development of osteonecrosis of the jaw. The inhibitory effects of bisphosphonates on osteoclasts and its antiangiogenic properties have been examined as possible mechanisms to induce osteonecrosis of the jaw. The incidence of ONJ in osteoporosis patients receiving bisphosphonate treatment is <1 in 100,000, and in between 1% and 10% in patients with malignancy (Hess et al., 2008). The results of this study suggest a higher incidence of osteonecrosis of the jaw in patients under long term use of nitrogen containing bisphosphonate. The incidence of bisphosphonate associated ONJ in the first 4 to 12 months of therapy was of 1.5% and it increased to 7.7% after 37 to 48 months [Bamias] Additional risk factors include dental extractions, invasive dental procedures and trauma. It is not yet clear, however, if other drugs that affect bone turnover may induce similar complications. This study suggests an association of bisphosphonates to the development of osteonecrosis of the jaw. There is no evidence that bisphosphonates cause osteonecrosis of the jaw. An evaluation of the published data indicates that more research is necessary to understand the relationship of bisphosphonates and osteonecrosis of the jaw.
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Lecercle, Delphine. "Synthèse et application de composés gem-bisphosphonates, de puissants complexants de métaux." Phd thesis, Université Paris Sud - Paris XI, 2007. http://tel.archives-ouvertes.fr/tel-00359912.
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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.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.
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®.
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Vanderpoorten, K. J. "Design, synthesis of biologically interesting dinucleotides : ADPR, c ADPR and NAD⺠alkyne (bisphosphonate) analogues." Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426911.
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Neudert, Marcus, Christian Fischer, Burkhard Krempien, Markus J. Seibel, and Frieder Bauss. "A Rapid Histological Score for the Semiquantitative Assessment of Bone Metastases in Experimental Models of Breast Cancer." Karger, 2008. https://tud.qucosa.de/id/qucosa%3A27606.
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Background: Using a nude rat model of site-specific metastatic bone disease (MBD), we developed a semiquantitative histological score for rapid assessment of lytic lesions in bone. This provides additional information to conventional histological measurement by clarifying the extent and location of metastatic infiltration and the tumor growth pattern. The score can also be used to assess the action of bisphosphonates on bone metastases. Materials and Methods: Male nude rats (n = 12 per group) were inoculated with the human breast cancer cell line MDA-MB-231 via the femoral artery. Following appearance of radiographically visible osteolytic lesions on day 18, the animals received phosphate-buffered saline (PBS; controls) or ibandronate (IBN, 10 µg P/kg) daily until day 30. Whole body radiographs were obtained on days 18 and 30, and osteolytic areas (OA) were determined by radiographic computer-based analysis (CBA). On day 30, MBD was assessed in both tibias using conventional histological CBA and the new scoring system. Results: Metastatic tumor area correlated with the total sum of the new score in both PBS- (r = 0.762) and IBN-treated animals (r = 0.951; p < 0.001). OA correlated well with the total sum in both groups (r = 0.845 and 0.854, respectively; p < 0.001). Conclusion: Significant reduction of bone marrow and cortical infiltration of tumor cells with IBN suggested local control of metastases.Hintergrund: Mit Hilfe eines etablierten Tiermodells zur Erzeugung lokalisationsspezifischer Knochenmetastasen in der Nacktratte wurde ein semiquantitatives histologisches Graduierungssystem zur schnellen Bewertung osteolytischer Knochenmetastasen entwickelt. Das Graduierungssystem liefert hinsichtlich der Metastasenlokalisation, deren Ausmaß und Infiltrationsmuster wertvolle Zusatzinformationen zu den konventionellen histologischen Untersuchungsmethoden. Damit kann beispielsweise auch die pharmakologische Wirkung von Bisphosphonaten auf die Knochenmetastasierung beurteilt werden. Material und Methoden: Männlichen Nacktratten (n = 12 pro Gruppe) wurden Zellen der humanen Brustkrebszellinie MDA-MB-231 in die Oberschenkelarterie inokuliert. Ab dem Auftreten radiologisch erkennbarer Osteolysen 18 Tage nach Inokulation erhielten die Tiere bis zum Studienende (Tag 30) täglich entweder eine subkutane Applikation einer Phosphat-Puffer-Lösung (Kontrollgruppe) oder Ibandronat (IBN, 10 µg P/kg; Behandlungsgruppe). Konventionelle Röntgenaufnahmen wurden an den Tagen 18 und 30 nach Tumorinokulation angefertigt und die Osteolysenflächen mittels Computerauswertung bestimmt. Nach Studienende wurde der Metastasenbefall in beiden Tibiae sowohl konventionell histologisch als auch mittels des neuen Graduierungssystems ausgewertet. Ergebnisse: Die Metastasenfläche korrelierte mit der kummulativen Punktsumme des Graduierungssystems sowohl in der Kontrollgruppe (r = 0,762; p < 0,001) als auch in der Ibandronat- Gruppe (r = 0,951; p < 0,001). Ebenso war die Osteolysenfläche eng mit der Punktesumme in beiden Gruppen korreliert (r = 0,845 und 0,854; p < 0,001). Schlussfolgerung: Die signifikante Reduktion von Knochenmark- und Kortikalisbefall durch IBN deuten auf eine gute lokale Kontrolle des Metastasenwachstums hin.
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