Thesis (M.S.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Background: In 2001 an assessment tool for predicting fracture risk in postmenopausal women was developed. An index based on a small number of risk factors that are easily assessed was developed called the Fracture Index. The value of this index ranges from 0-13 with higher number associated with higher five year probability of fracture. The magnitude of the morbidity and mortality associated with osteoporosis makes it valuable for health care professionals to know if a treatment to prevent fractures is cost effective or not. Objective: To investigate at what Fracture Index value it becomes cost effective to treat postmenopausal women with alendronate to prevent hip fractures. The focus is on Icelandic women. Design: A Markov model was developed to model the disease progression for women 65 years of age to 85 years of age which is the average life expectancy for women in Iceland. Cost effectiveness of alendronate vs. no treatment was assessed by transitioning women in the model every six months between different health states. In the base-case five year treatment with alendronate was assumed. Results: At Fracture Index 1-2 the incremental cost effectiveness ratio (ICER) was 27,467,073 ISK (238,844$) which is not considered to be cost effective. At Fracture Index 3-4 the ICER was 4,349,2511SK (37,820$) which has a 59% probability of being cost effective if the per capita GOP (4,800,000 ISK) for Iceland is used as a threshold for cost effectiveness. However cost effectiveness for Fracture Index 3-4 depends largely on the assumptions made in the model, some of which are uncertain such as drug cost, drug efficacy and appropriate discount rate. Treatment with Alendronate is cost effective for Fracture Index 5 and variation in the model's assumptions does not change that result. Conclusions: The results of this study indicate that treating osteoporotic women with alendronate to prevent hip fractures becomes cost effective at Fracture Index 5 with a 1.9% five year probability of hip fracture. / 2031-01-01

Class of 2013 Abstract / Specific Aims: To determine efficacy of alendronate (ALN) and risedronate (RIS) for treatment of osteoporosis and osteopenia in men. Methods: Literature search was primarily via PubMed. Inclusion criteria were: randomized controlled trials or observational studies assessing treatment of osteoporosis in men, either of primary or secondary etiology. Exclusion criteria were: minority population with baseline osteoporosis, inclusion of women, lack of control group. Primary outcomes were bone mineral density (BMD) of femoral neck (FN) and lumbar spine (LS); secondary outcomes were vertebral or non-vertebral fractures incidence. Data were synthesized using a random effects meta-analysis. Main Results: Eleven ALN and six RIS studies were included; most provided LS and FN data, but trials longer than 1-year were infrequent (ALN 3, RIS 4) as were fracture data (ALN 4, RIS 3). For both FN and LS BMD, both drugs showed significant treatment effects at one and two-years (p<0.001). For FN BMD, 2-year treatment effects were ALN: SDM= 0.638, p<0.001; RIS: SDM= 0.391, p<0.001; heterogeneity was insignificant (p> 0.05). For LS BMD, treatment effects were: 2-year ALN: SDM= 1.206, p<0.001; 1-year RIS: SDM= 0.0.574; p<0.001; heterogeneity was insignificant (p>0.05). For fracture, both drugs showed significant treatment effects at vertebral sites: ALN: OR 0.450, p<0.05; RIS: OR 0.423, p=0.001; heterogeneity was insignificant (p>0.05). RIS also showed a promising effect at non-vertebral sites (p<0.05), however only two studies provided data at this site. Conclusion: Both ALN and RIS are effective to increase BMD and decrease vertebral fracture occurrence in men with osteoporosis or osteopenia.

Os bisfosfonatos têm sido indicados para o tratamento de doenças ósseas líticas. Atualmente, seu emprego terapêutico aumentou e com ele os efeitos adversos, sendo um dos mais importante a indução da osteonecrose dos maxilares, uma complicação de difícil tratamento e solução. Até o presente, não se sabe ao certo qual o mecanismo de desenvolvimento da osteonecrose e nem qual deve ser o melhor tratamento estabelecido perante essa manifestação. Este trabalho teve como objetivo avaliar o efeito do alendronato sódico sobre a viabilidade e proliferação de osteoblastos e fibroblastos em cultura. Foram utilizados osteoblastos-símile linhagem OSTEO 1 e fibroblastos de mucosa bucal humana linhagem FMM1. Após serem submetidos aos testes de citotoxicidade com concentrações do alendronato sódico variando de 10-2M a 10-8M os fibroblastos apresentaram diminuição significante de viabilidade celular apenas na concentração de 10-2M (p<0,01). Os osteoblastos demonstraram viabilidade celular no grupo controle significantemente maior que todos os demais grupos; o grupo tratado com o alendronato na concentração de 10-4M apresentou viabilidade celular semelhante a de todos os grupos, exceto o grupo de concentração 10-2M e a viabilidade celular dos demais grupos foi semelhante entre si (p<0,01). As concentrações de alendronato sódico superiores a 10-5M impediram a proliferação dos osteoblastos. Foi possível concluir que o alendronato sódico é citotóxico para células osteoblastos-símile e fibroblastos em cultura em função de sua concentração. Os fibroblastos são menos sensíveis a concentrações maiores de alendronato sódico que os osteoblastos. / Bisphosphonates have been therapeutically used for the management of lytic bone diseases. Their use has been increased nowadays and besides that associated adverse effects have been amplified. Jaw osteonecrosis induced by this drug is perhaps the most important complication because of the great morbidity and difficulty to deal with. Until now the physiopathology of osteonecrosis remains unclear and the treatment that should be established is uncertain. This study aimed to evaluate the effect of sodium alendronate a bisphosphonate used for the treatment of osteoporosis on the viability and proliferation of osteoblasts and fibroblasts in culture. Osteoblast-simile from the lineage OSTEO1 and a human oral mucosa fibroblasts from the lineage FMM1 were used. After being subjected to tests with concentrations of sodic alendronate ranging from 10-8M to 10-2M fibroblasts showed a significant decrease in cell viability at the concentration of 10-2M (p < 0.01). Osteoblasts showed that the cell viability in the control group was significantly higher than all other groups, the group treated with alendronate at a concentration of 10-4M had similar cell viability with all groups except the group of 10-2M concentration and the cell viability of other groups was similar between groups (p < 0.01). The concentrations of alendronate greater than 10-5M prevented the proliferation of osteoblasts. It was possible to conclude that alendronate is cytotoxic to osteoblast-símile cells and fibroblasts in culture due to its concentration. The fibroblasts are less sensitive to higher concentrations of alendronate than osteoblasts.

Made available in DSpace on 2014-06-11T19:32:40Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-04-02Bitstream added on 2014-06-13T18:43:56Z : No. of bitstreams: 1 conteneto_n_dr_arafo.pdf: 2202392 bytes, checksum: 01fbaf12627344e98845ce270560a0f0 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O objetivo deste projeto foi desenvolver, em ratos, modelos experimentais de osteonecrose induzida pelos bisfosfonatos por meio da combinação de uma série de fatores de risco para esta doença, como o uso prolongado de altas doses de alendronato por via parenteral, procedimentos cirúrgicos operatórios e o estresse crônico. Os parâmetros foram estabelecidos por meio de análise histológica descritiva e por escores, análise radiográfica de alvéolos dentais, estereometria de alvéolos dentais e implantes, torque de remoção dos implantes e avaliação de marcadores do metabolismo ósseo e do estresse. No primeiro e segundo estudos foram administradas altas doses diárias ou semanais de alendronato, respectivamente, associado a exodontias dos primeiros molares inferiores. No terceiro e quarto estudos foram administradas altas doses semanais de alendronato, associado à indução de estresse crônico e instalação de implantes osseointegráveis na maxila e/ou na metáfise tibial. De um modo geral, os resultados dos estudos demonstraram que a terapia com alendronato foi associada à supressão significativa do metabolismo ósseo. Nos estudos 1 e 2, após as extrações dentais, observou-se o desenvolvimento de áreas de exposição e necrose óssea, associadas à presença de infecção significativa, especialmente na região de septo inter-dental. No estudo 3 observou-se que a indução de estresse crônico apresentou efeitos negativos sobre o metabolismo e volume do tecido ósseo neoformado nas espiras dos implantes tibiais, os quais não foram observados nos animais tratados com alendronato. Ao contrário, nestes animais, observou-se uma melhora significativa nos parâmetros de osseointegração. Já o estudo 4 demonstrou que a administração de alendronato resultou no desenvolvimento expressivo de áreas... / This study aimed to develop, in rodents, experimental models of bisphosphonatesinduced osteonecrosis through the association of several risk factors to this disease, including the long-term therapy with high dosages of alendronate by parenteral route, surgical procedures and chronic stress. The parameters were established by descriptive and scored histological analysis, radiographic evaluation of alveolar sockets, stereometry of alveolar sockets and implants, torque removal of implants and biomarkers of bone metabolism and stress. In the first and second studies, it was administered daily or weekly high doses of alendronate, respectively, associated to the lower first molar extractions. In the third and fourth studies it was administered weekly high doses of alendronate plus chronic stress induction and osseointegrated implants in the maxillae and/or tibia. In general, the outcomes of this study demonstrated that alendronate therapy was associated to a markedly bone turnover suppression. In the first and second studies, after tooth extraction, it was observed the development of exposed and necrotic bone associated to a significant infectious process, especially at the inter-radicular area. In the study three the chronic stress was related to deleterious effects on the bone metabolism and volume among tibial implants threads, which weren’t presented in animals treated with alendronate. On the contrary, in these animals, it was observed a markedly increase in the osseointegration parameters. On the other hand, the fourth study showed that the alendronate treatment resulted in the substantial development of osteonecrosis regions associated to infection at lateral areas of maxillary bone implant cavity, even with absence of exposed bone areas. In this way, we conclude that the alendronate therapy suppress significantly the bone... (Complete abstract click electronic access below)

Os bisfosfonatos têm sido indicados para o tratamento de doenças ósseas líticas. Atualmente, seu emprego terapêutico aumentou e com ele os efeitos adversos, sendo um dos mais importante a indução da osteonecrose dos maxilares, uma complicação de difícil tratamento e solução. Até o presente, não se sabe ao certo qual o mecanismo de desenvolvimento da osteonecrose e nem qual deve ser o melhor tratamento estabelecido perante essa manifestação. Este trabalho teve como objetivo avaliar o efeito do alendronato sódico sobre a viabilidade e proliferação de osteoblastos e fibroblastos em cultura. Foram utilizados osteoblastos-símile linhagem OSTEO 1 e fibroblastos de mucosa bucal humana linhagem FMM1. Após serem submetidos aos testes de citotoxicidade com concentrações do alendronato sódico variando de 10-2M a 10-8M os fibroblastos apresentaram diminuição significante de viabilidade celular apenas na concentração de 10-2M (p<0,01). Os osteoblastos demonstraram viabilidade celular no grupo controle significantemente maior que todos os demais grupos; o grupo tratado com o alendronato na concentração de 10-4M apresentou viabilidade celular semelhante a de todos os grupos, exceto o grupo de concentração 10-2M e a viabilidade celular dos demais grupos foi semelhante entre si (p<0,01). As concentrações de alendronato sódico superiores a 10-5M impediram a proliferação dos osteoblastos. Foi possível concluir que o alendronato sódico é citotóxico para células osteoblastos-símile e fibroblastos em cultura em função de sua concentração. Os fibroblastos são menos sensíveis a concentrações maiores de alendronato sódico que os osteoblastos. / Bisphosphonates have been therapeutically used for the management of lytic bone diseases. Their use has been increased nowadays and besides that associated adverse effects have been amplified. Jaw osteonecrosis induced by this drug is perhaps the most important complication because of the great morbidity and difficulty to deal with. Until now the physiopathology of osteonecrosis remains unclear and the treatment that should be established is uncertain. This study aimed to evaluate the effect of sodium alendronate a bisphosphonate used for the treatment of osteoporosis on the viability and proliferation of osteoblasts and fibroblasts in culture. Osteoblast-simile from the lineage OSTEO1 and a human oral mucosa fibroblasts from the lineage FMM1 were used. After being subjected to tests with concentrations of sodic alendronate ranging from 10-8M to 10-2M fibroblasts showed a significant decrease in cell viability at the concentration of 10-2M (p < 0.01). Osteoblasts showed that the cell viability in the control group was significantly higher than all other groups, the group treated with alendronate at a concentration of 10-4M had similar cell viability with all groups except the group of 10-2M concentration and the cell viability of other groups was similar between groups (p < 0.01). The concentrations of alendronate greater than 10-5M prevented the proliferation of osteoblasts. It was possible to conclude that alendronate is cytotoxic to osteoblast-símile cells and fibroblasts in culture due to its concentration. The fibroblasts are less sensitive to higher concentrations of alendronate than osteoblasts.

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / Periodontal disease is an infectious-inflammatory disease, and drugs have been studied as modulators of this inflammatory process. In this context, this thesis, constituted by 3 articles had by objective: (1) Perform a review about the effect of Bisphosphonates (BPs) on periodontal disease; (2) Investigate the effect of Alendronate (ALD) on Bone-specfic Alkaline Phosphatase (BALP) on alveolar bone loss (ABL) in rats; (3) Evaluate the effect of ALD and Atorvastatin (ATV) combination on ABL in rats. On study 1, we sought in data basis, using the keywords âBisphosphonatesâ and âPeriodontitisâ, pre-clinical and clinical studies, published in English and Portuguese, in the last 10 years. On study 2, 36 Wistar male rats, submitted to ligature-induced periodontitis, received 0.9% Saline (SAL) or ALD on the doses of 0.01; 0.05; 0.25 mg/kg-s.c., 30 min before ligature placement and daily during 11 days. It was evaluated: ABL (morphometry and histology) serum levels of Bone-specific Alkaline Phosphatase (BALP), transaminases, and Total Alkaline Phosphatase (TAP); and leukogram and corporal mass. On study 3, 78 Wistar male rats, submitted to ligature-induced periodontitis, received prophylactically (P): SAL or ALD (0.01; 0.25 mg/kg-s.c) or ATV (0.3; 27 mg/kg-v.o.) or the combination ALD+ATV (0.25+27; 0.01+0.3; 0.25+0.3; 0.01+27 mg/kg), 30 min before ligature and daily for 11 days; or the combination ALD+ATV (0.01+0.3 mg/kg) administered therapeutically (T), from the 5th day after ligature until the sacrifice. It was evaluated: ABL [morphometry, histology, histometry; immunohistochemistry for tartrate resistant acid phosphatase (TRAP); myeloperoxidase (MPO); BALP, transaminases; Leukogram and corporal mass]. The study 1 showed that BPs presented anti-resorptive and anti-inflammatory effects, reduced FAO and Telopeptide N-terminal of type I collagen (NTx) and improved periodontal clinical parameters. On article 2, ALD (0.25 mg/kg) prevented BALP and ABL reduction, and did not alter transaminases serum levels, but reduced TAP serum levels (p<0.05), it reduced neutrophilia and lymphomonocytosis (p<0.05), without causing important loss of weight. On the 3rd study, the isolated treatments in high doses, and all combinations controlled ABL (p<0.05). Low doses combination of ALD+ATV controlled ABL (P [38.96%] or T [53.53%]). The histological, histometric (p<0.05) and immunohistochemical analysis corroborated macroscopical findings. The low dose combination of ALD+ATV reduced MPO activity, prevented BALP reduction, reduced neutrophilia and lymphomonocytosis (p<0.05), without altering transaminases serum levels and without causing loss of weight. In this way, we can conclude that BPs presented anti-resorptive and anti-inflammatory effects reduced levels of biochemical markers of bone metabolism and improved periodontal parameters. ALD, administered isolated prevented BALP and ABL reduction, without causing systemic problems, and the combination of ALD+ATV, in low doses, reduced ABL and periodontal inflammation, without causing important systemic alterations as well. / A doenÃa periodontal à uma desordem infecto-inflamatÃria, e fÃrmacos tÃm sido estudados como moduladores deste processo inflamatÃrio. Neste contexto, esta tese, constituÃda por 3 artigos, teve por objetivo: (1) Realizar uma revisÃo sobre o efeito de Bisfosfonatos (BFs) na doenÃa periodontal; (2) Investigar o efeito do Alendronato (ALD) nos nÃveis de Fosfatase Alcalina Ãssea (FAO) na perda Ãssea alveolar (POA) em ratos; (3) Avaliar o efeito da combinaÃÃo entre ALD e Atorvastatina (ATV) na POA em ratos. No estudo 1 buscou-se, em bases de dados, utilizando as palavras chave: âBisphosphonatesâ e âPeriodontitisâ, estudos prÃ-clÃnicos e clÃnicos, publicados em lÃngua Inglesa ou Portuguesa, nos Ãltimos 10 anos. No estudo 2, 36 ratos Wistar machos, submetidos à periodontite induzida por ligadura, receberam soluÃÃo Salina (SAL) 0,9% ou ALD nas doses de 0,01; 0,05; 0,25 mg/kg-s.c, 30 min antes da colocaÃÃo do fio e diariamente por 11 dias. Avaliou-se: POA (morfometria e histologia); nÃveis sÃricos de FAO, transaminases e Fosfatase Alcalina Total (FAT); Leucograma e Peso. No estudo 3, 78 ratos Wistar machos, submetidos à periodontite induzida por ligadura, receberam de forma profilÃtica (P): SAL ou ALD (0,01; 0,25 mg/kg-s.c) ou ATV (0,3; 27 mg/kg-v.o.) ou a combinaÃÃo ALD+ATV (0,25+27; 0,01+0,3; 0,25+0,3; 0,01+27 mg/kg), 30 min antes da ligadura e diariamente por 11 dias; ou ainda a combinaÃÃo ALD+ATV (0,01+0,3 mg/kg) na forma terapÃutica (T), ou seja administrada a partir do 5 dia apÃs ligadura, atà o sacrifÃcio. Avaliou-se: POA [morfometria, histologia, histometria; imunohistoquÃmica para fosfatase Ãcido tÃrtaro resistente (TRAP); mieloperoxidase (MPO); FAO, transaminases; Leucograma e Peso]. O artigo 1 mostrou que BFs apresentaram efeitos antirreabsortivo e anti-inflamatÃrio, reduziram FAO e TelopeptÃdeo N-terminal de colÃgeno tipo I (NTx) e melhoraram os parÃmetros clÃnicos periodontais. No artigo 2, o ALD (0,25 mg/kg) preveniu a reduÃÃo de FAO e POA, nÃo alterou nÃveis de transaminases, mas nÃo preveniu reduÃÃo dos nÃveis de FAT (p<0,05), preveniu neutrofilia e linfomonocitose (p<0,05), sem causar perda de peso importante. No 3 estudo, os tratamentos isolados, em altas doses, e todas as combinaÃÃes avaliadas controlaram POA (p<0,05). A combinaÃÃo de ALD+ATV em baixas doses controlou POA (P [38,96%] ou T [53,53%]). As anÃlises histolÃgicas, histomÃtricas (p<0,05) e imunohistoquÃmicas corroboraram os achados macroscÃpicos. A combinaÃÃo de ALD+ATV em baixas doses reduziu a atividade de MPO, preveniu reduÃÃo de FAO, reduziu neutrofilia e linfomonocitose (p<0,05), sem alterar os nÃveis de transaminases e causar perda de peso. Desta forma conclui-se que os BFs apresentaram efeitos antirreabsortivo e anti-inflamatÃrio, reduziram nÃveis de marcadores bioquÃmicos do metabolismo Ãsseo e melhoraram os parÃmetros clÃnicos periodontais. O ALD, administrado isoladamente, preveniu reduÃÃo de FAO, POA, sem repercussÃes sistÃmicas e a combinaÃÃo de ALD+ATV, em baixas doses, reduziu POA e inflamaÃÃo periodontal, tambÃm sem causar alteraÃÃes sistÃmicas importantes.

A periodontite é uma doença de natureza multifatorial e infecciosa, que resulta na inflamação e perda dos tecidos de suporte dos dentes. Essa inflamação é causada por bactérias associadas ao biofilme, causando a perda progressiva de inserção. Os bisfosfonatos são fármacos com capacidade de inibir a reabsorção óssea, atuando nas células clásticas. O presente estudo teve como objetivo investigar os efeitos do alendronato, um bisfosfonato nitrogenado com grande potência antireabsortiva, na evolução da doença periodontal induzida em ratos, bem como a possível presença de necrose óssea no processo alveolar. Foram utilizados 48 ratos Wistar albinos, do sexo masculino, com 3 meses de vida e peso médio de 250g. Os animais foram divididos aleatoriamente em dois grupos: Alendronato (ALN) e Controle (CON). A periodontite foi induzida com a inserção de um fio de seda 4.0 no sulco gengival do segundo molar superior. Os ratos do grupo ALN, receberam doses diárias de 2,5 mg/kg durante 7 dias antes e 7, 14, 21 e 30 dias após a indução da doença; o grupo CON recebeu solução salina estéril. Nos tempos citados as maxilas foram fixadas, descalcificadas e incluídas em parafina ou resina Spurr. Os cortes foram corados com HE, para análise morfológica, e histomorfométrica. Alguns cortes foram submetidos à imuno-histoquímica para detecção de RANKL e OPG. Foi utilizado o método TRAP, marcador de osteoclastos e microscopia eletrônica de transmissão para análise ultraestrutural. O ALN inibiu a reabsorção da crista alveolar de todos os grupos tratados. As células clásticas apresentaram-se em estado latente. No grupo controle a crista alveolar foi reabsorvida e o TRAP revelou clastos ativos, achados confirmados pela microscopia eletrônica de transmissão. A expressão de RANKL, molécula ativadora da célula clástica, não foi inibida pela droga. A expressão de OPG foi aumentada nos animais tratados. Os animais do grupo tratado durante 21 e 30 dias, apresentaram sinais de osteonecrose na crista alveolar, como lacunas de osteócitos vazias e regiões exposta de osso. Os resultados demonstraram que o uso de alendronato durante a doença periodontal inibe a reabsorção óssea e que durante tempos prolongados pode gerar osteonecrose na região da crista óssea. / Periodontitis is an infectious disease of multifactor nature that results in the inflammation of the tissues supporting the teeth. This inflammation is caused by accumulation of biofilm and causes progressive insertion and bone loss. The bisphosphonates are drugs with the capability to inhibit the activity of clastic cells. The aim of this study was to investigate the effects of alendronate, a nitrogenated bisphosphonate with high antiresorptive power on experimental periodontal disease, and to analyze the possible presence of osteonecrosis in the rat alveolar process. Forty-eight male Wistar rats, three months old, with 250g weight were used. The animals were randomly divided into two groups: Alendronate (ALN) and Control (CON). The periodontitis was induced with a 4.0 silk wire inserted into the gingival sulcus around the right upper second molar. The ALN rats, received daily doses of 2.5 mg/kg alendronate (ALN) for 7 days before the induction of periodontitis; the treatment continued for additional 7, 14, 21 or 30 days. The CON rats, received sterile saline solution. In the time points cited, the maxillae were fixed, decalcified and embedded in Spurr resin or paraffin. The specimens were morphologically analyzed in HE stained sections, after which histomorphometry was carried out. Some stained sections were used for immunolabeling for RANKL and OPG. The osteoclasts were marker by tartrate-resistant acid phosphatase (TRAP) histochemistry. The ultrathin sections were examined in a transmission electron microscope. ALN reduced the activity of osteoclasts and significantly decreased the resorption of the alveolar crest. In the control group the alveolar crest appeared resorbed, while TRAP showed active osteoclasts, findings confirmed by transmission electron microscopy. The expression of RANKL, an osteoclast-activating molecule, was not inhibited by the drug. The expression of OPG was increased in the treated animals. The animals of the group treated for 21 and 30 days showed signs of osteonecrosis of the alveolar crest, as empty osteocyte lacunae in the exposed bone regions. The results showed that the use of ALN for periodontal disease inhibited bone resorption; when it was administered for prolonged periods it can cause osteonecrosis in the bone crest area.

Made available in DSpace on 2014-06-11T19:30:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-09-29Bitstream added on 2014-06-13T21:01:51Z : No. of bitstreams: 1 canettieri_acv_dr_sjc_prot.pdf: 1776887 bytes, checksum: 80a7e878725233d8cf3256bd1985da11 (MD5) / Este trabalho avaliou a ação local do alendronato sódico, da hidroxiapatita e da associação alendronato com hidroxiapatita na reparação de defeitos ósseos em fêmures de ratas ovariectomizadas. Noventa e oito animais foram divididos em sete grupos: controle (C), amido (Am), alendronato 1mol (A1), alendronato 2moles (A2), hidroxiapatita 1 mol (HA1), hidroxiapatita 2moles (HA2) e associação alendronato e hidroxiapatita (A+HA). As ratas pesando, aproximadamente, 250g foram ovariectomizadas e, após trinta dias, os defeitos ósseos, medindo 2,5mm de diâmetro, foram confeccionados nos fêmures esquerdos. Os defeitos foram preenchidos com alendronato sódico, hidroxiapatita e/ou com ambos, sendo que o grupo C não recebeu material de preenchimento e o grupo Am apenas o amido. Os animais foram sacrificados sete e 21 dias após a cirurgia. Foram realizadas análise histológica e histomorfométrica da área do defeito ósseo e os resultados submetidos à análise estatística. Histologicamente, as principais diferenças ocorreram após 21 dias. Os grupos C, Am, HA1 e HA2 apresentaram fechamento linear do defeito ósseo em todos espécimes e a maioria dos animais dos grupos A1, A2 e A+HA não exibiu neoformação óssea na região central do defeito, permanecendo este preenchido por tecido conjuntivo fibroso. No período de sete dias não houve diferença estatística significante entre todos os grupos experimentais em relação a neoformação óssea e, após 21 dias, o grupo HA2 apresentou a maior quantidade de osso neoformado. Estatisticamente, não houve diferença entre os grupos A1, A2 e A+HA nos dois períodos de estudo. Concluiu-se que o alendronato sódico, isolado ou associado com a hidroxiapatita, prejudicou a reparação óssea neste modelo experimental e a hidroxiapatita utilizada mostrou-se biocompatível e osteocondutora, com os melhores resultados observados no grupo HA2. / This work evaluated the action of sodium alendronate, of hydroxyapatite and the association alendronate with hydroxyapatite in the repair of bone defects in ovariectomized rats femurs. Ninety eight animals were divided into seven groups: control (C), starch (Am), alendronate 1mol (A1), alendronate 2moles (A2), hydroxyapatite 1 mol (HA1), hydroxyapatite 2 moles (HA2) and the association alendronate and hydroxyapatite (A+HA). The rats weighing, approximately, 250g were ovariectomized and, after thirty days, bone defects, measuring 2,5mm, were created in the lefts femurs. The bone defects were filled with alendronate, hydroxyapatite or with both, but the group C not received none material, and the group Am, only starch. The animals were sacrified at seven and 21 days after surgery. Histological and histomorphometric analyses were performed and the results obtained were submitted to statistical analysis. Histologically, the principal differences occurred after 21 days, with the groups C, Am, HA1 and HA2 showing a linear closure of bone defect in every specimen. The most of animals of the groups A1, A2 and A+HA did not show central bone neoformation in bone defects, and there was fibrous connective tissue in this region. After seven days, there was not significance statistical difference among all experimental groups in relation to bone neoformation and, after 21 days, the group HA2 showed the most quantity of new bone formation. Statistically, there were no differences among the groups A1, A2 and A+HA in both studied period. It was concluded that the sodium alendronate, alone or combinated with hydroxyapatite, harmed the bone repair in this experimental model and the hydroxyapatite was biocompatible and osteoconductive, with the best results in group HA2.

Orientador: Graziela Garrido Mori Panucci / Banca: Wilson Roberto Poi / Banca: Sônia Regina Panzarini Barioni / Banca: Karina HelgaTúrcio de Carvalho / Banca: Roberto Brandão Garcia / Resumo: O uso de substâncias que inibem o processo reabsortivo pode ser uma alternativa para o aumento do sucesso nos casos de reimplante tardio. O alendronato sódico é um conhecido inibidor da reabsorção, sendo que sua utilização em forma de pasta, como curativo intracanal, poderia aumentar os índices de sucesso em dentes susceptíveis à reabsorção. Frente a isso, este trabalho teve como objetivo avaliar comparativamente o efeito das pastas de alendronato sódico e hidróxido de cálcio como medicação intracanal em dentes de ratos reimplantados tardiamente. Para isso, foram utilizados 24 incisivos superiores direitos de ratos. Os dentes foram extraídos e permaneceram a seco por 30 minutos, após isso tiveram a superfície radicular tratada com hipoclorito de sódio a 1% e fluoreto de sódio a 2%. Na sequência, os dentes foram divididos em 2 grupos: no grupo I, os canais radiculares foram limpos e preenchidos com a pasta experimental a base de alendronato sódico. No grupo II, usou-se a pasta de hidróxido de cálcio, após os procedimentos citados anteriormente. Em seguida, os dentes foram reimplantados em seus respectivos alvéolos. Passados 15 e 60 dias do reimplante dentário, os animais sofreram eutanásia e as peças obtidas processadas em laboratório para análise microscópica e morfométrica. Os resultados demonstraram que em ambos os grupos a ocorrência da anquilose foi baixa, assim como a reabsorção inflamatória e por substituição. A presença de cemento sobre a superfície radicular foi alta e constante. No grupo I, o tecido conjuntivo formado no espaço do ligamento periodontal mostrou-se disposto de forma paralela, sendo que em alguns espécimes, o tecido estava inflamado e com presença de placa bacteriana, sugerindo a formação de bolsa periodontal. No grupo II, houve a formação de tecido conjuntivo paralelo na maioria... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The search for substances that may increase the success in cases of replantation is a priority. The use of substances that inhibit root resorption may be an alternative for the control of root resorption, especially in cases of delayed replantation. Sodium Alendronato is a unhibitor of bone resorption and it is used as dressing the intracanal in form of paste. This substance increased success rates in case of tooth replantation. So the objective of this study was to evaluated the effect of an experimental paste with alendronate basis used as intracanal dressing in late reimplanted rat teeth. There were used 24 right rats incisors. The teeth were avulsed and kept dry for 30 minutes, after which root surfaces were treated with sodium hypochlorite 1% and sodium fluoride 2%. The roots canal were instrumented and filled with Aledronate sodium paste (Grou I) and calcium hydroxide paste (Group II). In group II, we used the calcium hydroxide paste. Teeth were replanted in their respective sockets. After 15 and 60 days after tooth replantation, the animals were killed and the specimens were processed for morphometric and microscopic analysis The results showed that in group I there were less ankylosis, inflammatory reporotion and replacement comparing to group II. The connective tissue formed in the periodontal ligament space was found to be inflamed by the presence of plaque and periodontal pocket formations. The connective tissue arranged in parallel to the root surface was constant in group I. However this tissue in group II had a significant increase over time. The cement was absent in small proportions and similarly in all experimental groups. The number of gaps of inflammatory resorption was low in both groups. The same happened with the shortcomings of replacement resorption Thus, these findings contraindicate the use of this folder of alendronate for the treatment of intracanal late reimplanted teeth / Doutor

Bisphosphonates (BPs) have been used clinically as anti-resorptive/cancer agents with confounded clinical outcomes and uncertain/conflicting biological understanding. This study was designed to evaluate the impact of clinically used anti-resorption drug alendronate (ALN) on cancer-bone metastasis and bone biology using novel 3D cancer-bone interaction model systems. To test the effects of ALN on the cancer-bone metastasis/interactions and bone biology we have utilized a novel 3D Co-cultures of live mouse neonatal calvarial bone organs with oral squamous cancer cells in a roller tube model systems (Curtin et al, 2012) in the absence and presence of ALN. These model systems under bone resorption and formation conditions were evaluated by chemical, biochemical, and histological analyses of the used media and calvarial bones. At the end of 8 days, the calvarial bones co-cultured with oral cancer cell lines in the absence and presence of ALN were processed for histological observations, TRAP and ALP enzyme activities, and neutral red staining. These studies were complemented by the effects of ALN on oral cancer cells under 2D classic cell culture conditions. In 3D-bone organ cultures under resorption conditions, oral cancer cells induce differentiation of osteoclasts and bone resorption and inclusion of ALN inhibited cancer-induced bone resorption. However, in both bone resorption and formation models the oral cancer cells colonized the bone and while treatment with ALN inhibits bone resorption, no effect on bone colonization was evident. Contrary to those under 2D cell culture conditions exposure to ALN of confluent and non-confluent oral cancer cells in the absence of live bone impacted oral cancer cells significantly in a dose dependent manner. Our studies using live bone organ cultures with oral cancer cells under specific dissociated bone remodeling stages, viz., resorption or formation only, revealed major and significant biological events which led to the conclusions that: (a) In the absence of bone in 2D cultures oral cancers are sensitive to ALN treatment whereas in the 3D live bone microenvironment tumors are resistant to ALN drug therapy, and (b) oral cancer-bone metastasis is independent of bone remodeling stage.