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Fragility fractures caused by loss of bone mass due to postmenopausal osteoporosis represent a growing morbidity worldwide. Bisphosphonates are first-line medications for fracture treatment and prevention. In the first phase, we updated a Cochrane systematic review of randomized controlled trials on alendronate, assessing its efficacy for five types of fracture prevention, quality of life, and various safety outcomes. In the second phase, we combined indirect and direct evidence to perform a network meta-analysis including alendronate and nine other bisphosphonates evaluating the comparative efficacy and safety of these treatments. Overall, 58 studies were included in the review and 83 studies in the network. Most evidence was of moderate to high quality. Alendronate and zoledronic acid were effective for preventing the most types of fractures, while off-label and unapproved bisphosphonates showed poor efficacy. More evidence is required to evaluate long-term treatment and rare adverse events.

This review summarizes and updates data presented at recent annual Southern Medical Association conferences on postmenopausal osteoporosis. As part of any osteoporosis treatment program, it is important to maintain adequate calcium and 25-hydroxyvitamin D levels either through diet or supplementation. Among the available pharmacologic therapies, the bisphosphonates alendronate and risedronate have demonstrated the most robust fracture risk reductions- approximately 40 to 50% reduction in vertebral fracture risk, 30 to 40% in nonvertebral fracture risk, and 40 to 60% in hip fracture risk. Ibandronate, a new bisphosphonate, has demonstrated efficacy in reducing vertebral fracture risk. Salmon calcitonin nasal spray and raloxifene demonstrated significant reductions in vertebral fracture risk in pivotal studies. Teriparatide significantly reduced vertebral and nonvertebral fracture risk. Drugs on the horizon include strontium ranelate, which has been shown to reduce vertebral and nonvertebral fracture risk, and zoledronic acid, an injectable bisphosphonate that increased bone density with once-yearly administration.

A causa mais comum da osteoporose é o declínio do hormônio sexual feminino, o estrógeno, que ocorre após a menopausa. Esse hormônio regula a produção de citocinas que influenciam a proliferação dos osteoclastos, aumentando a reabsorção óssea. Os efeitos da cafeína no metabolismo ósseo são controversos e podem estar associados ao aumento significativo de doenças periodontais, fraturas, aumento do cálcio urinário e redução da densidade mineral óssea, por exercer efeitos inibidores sobre as funções dos osteoblastos. O principal objetivo deste estudo foi avaliar o efeito in vitro de diferentes concentrações de cafeína no metabolismo de células osteoblásticas da medula óssea de ratas osteoporóticas. Após aprovação pela Comissão de Ética no Uso de Animais, ratas Wistar foram divididas em dois grupos experimentais: controle (C) e submetidas à ovariectomia (OVX). Após 60 dias da cirurgia, as ratas foram sacrificadas para coleta dos fêmures e das células mesenquimais da medula óssea, que foram induzidas à diferenciação em osteoblastos com meio osteogênico com três concentrações de cafeína (1, 3 e 5 mM - grupos OVX1, OVX3 e OVX5) e cultivadas em placas de 24 poços (n = 5) para avaliação da proliferação celular, atividade de fosfatase alcalina (ALP) bioquímica e in situ, detecção e quantificação de nódulos mineralizados e análise da expressão de genes relacionados à atividade osteoblástica através de PCR em tempo real. Os ensaios foram realizados em triplicata e analisados por meio do software estatístico GraphPad Prism, com nível de significância fixado em 5%. A proliferação celular foi menor nos grupos osteoporóticos com adição de cafeína, tendo a menor queda o grupo com adição de 1mM. O método bioquímico de ALP não foi significante nos períodos analisados, entretanto, aos 10 e 14 dias, a atividade aumentou quando a concentração de cafeína era maior. Já na atividade de ALP in situ, o grupo OVX1 foi o que apresentou melhor resultado nos períodos avaliados (p < 0,05), com pico aos 14 dias. A quantificação de matriz mineralizada foi maior no grupo OVX comparado ao grupo C; entre as concentrações, a maior quantificação dos nódulos de cálcio se deu no grupo com 1mM de cafeína. Os resultados obtidos no PCR mostraram que o gene para fosfatase alcalina teve maior expressão no grupo OVX, seguido do grupo OVX1 aos 7 e 10 dias; a expressão gênica de osteocalcina foi maior para o grupo OVX1 aos 10 e 14 dias e esse grupo apresentou a maior expressão em todos os períodos para os genes Runx2 e RankL. No caso do Bmp4, o grupo OVX3 foi o mais expresso aos 10 e 14 dias. Os genes osteoprotegerina e osteopontina variaram sua expressão de acordo com o período e grupo avaliado. A expressão de osterix foi similar entre os grupos aos 7 e 10 dias, enquanto a expressão de Bsp, aos 7 e 14 dias, mostrou semelhança entre os grupos controle e OVX1. Frente aos resultados obtidos, sugere-se que a concentração de 1mM de cafeína pareceu ser a menos prejudicial ao metabolismo das células osteoblásticas neste modelo experimental de osteoporose. / The most common cause of osteoporosis is the decrease of estrogen after menopause. This hormone regulates the production of cytokines that influence osteoclast proliferation, increasing bone resorption. The effects of caffeine in bone metabolism are controversial and may be associated to periodontal disease, bone fractures, increase of urinary calcium levels and reduction of mineral bone density due to inhibition of osteoblast activities. Thus, the goal of this investigation was to evaluate the in vitro effect of different caffeine concentrations in the metabolism of bone marrow osteoblastic cells from osteoporotic rats (OVX). After Ethical Committee approval, wistar female rats were divided in two experimental groups: control (C) and submitted to ovariectomy (OVX). After 60 days of surgery, femurs were removed to isolate bone marrow mesenchymal cells, which were induced to osteoblastic differentiation in osteogenic medium along with three different concentrations of caffeine (1, 3 and 5 mM - OVX1, OVX3 e OVX5 respectively) and posteriorly seeded in 24-well plates (n = 5) to evaluate cell proliferation, alkaline phosphatase activity and its in situ detection, detection and quantification of mineralized nodules as well as assess quantitative expression of genes associated to osteoblastic activity by means of real time PCR. All the experiments were performed in triplicate and analyzed by means of the statistical software GraphPad Prism for p<0.05. Cell proliferation was diminished in the all osteoporotic groups that received caffeine, with group OVX1 being the less affected. Biochemical assay of ALP activity did not show differences among the groups in the periods analyzed; nevertheless there was a tendency to a higher activity proportional to the higher concentration of caffeine. The in situ detection of ALP showed better results in group OVX1 after 14 days of culture. Mineralized matrix quantification was higher in OVX groups when compared to control group; among the concentrations, the higher quantification of calcium nodules was in group OVX1. The results obtained with PCR showed that the gene for ALP had its highest expression in OVX group, followed by OVX1 at 7 and 10 days; expression of osteocalcin was higher in OVX1 after 10 and 14 days and this same group presented higher expression in all periods for genes Runx2 e Rankl. Analysis of Bmp4 gene showed that it was expressed in group OVX3 after 10 and 14 days. The genes that code for osteoprotegerin and osteopontin had different expression values in accordance to the period and group evaluated. The expression of osterix was similar between the groups after 7 and 10 days, whereas the expression of Bsp was similar between control and OVX1 groups after 7 and 14 days. The results suggest that the concentration of 1mM of caffeine is the most beneficial to the metabolism of osteoblastic cells in a model of osteoporosis.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

A causa mais comum da osteoporose é o declínio do hormônio sexual feminino, o estrógeno, que ocorre após a menopausa. Esse hormônio regula a produção de citocinas que influenciam a proliferação dos osteoclastos, aumentando a reabsorção óssea. Os efeitos da cafeína no metabolismo ósseo são controversos e podem estar associados ao aumento significativo de doenças periodontais, fraturas, aumento do cálcio urinário e redução da densidade mineral óssea, por exercer efeitos inibidores sobre as funções dos osteoblastos. O principal objetivo deste estudo foi avaliar o efeito in vitro de diferentes concentrações de cafeína no metabolismo de células osteoblásticas da medula óssea de ratas osteoporóticas. Após aprovação pela Comissão de Ética no Uso de Animais, ratas Wistar foram divididas em dois grupos experimentais: controle (C) e submetidas à ovariectomia (OVX). Após 60 dias da cirurgia, as ratas foram sacrificadas para coleta dos fêmures e das células mesenquimais da medula óssea, que foram induzidas à diferenciação em osteoblastos com meio osteogênico com três concentrações de cafeína (1, 3 e 5 mM - grupos OVX1, OVX3 e OVX5) e cultivadas em placas de 24 poços (n = 5) para avaliação da proliferação celular, atividade de fosfatase alcalina (ALP) bioquímica e in situ, detecção e quantificação de nódulos mineralizados e análise da expressão de genes relacionados à atividade osteoblástica através de PCR em tempo real. Os ensaios foram realizados em triplicata e analisados por meio do software estatístico GraphPad Prism, com nível de significância fixado em 5%. A proliferação celular foi menor nos grupos osteoporóticos com adição de cafeína, tendo a menor queda o grupo com adição de 1mM. O método bioquímico de ALP não foi significante nos períodos analisados, entretanto, aos 10 e 14 dias, a atividade aumentou quando a concentração de cafeína era maior. Já na atividade de ALP in situ, o grupo OVX1 foi o que apresentou melhor resultado nos períodos avaliados (p < 0,05), com pico aos 14 dias. A quantificação de matriz mineralizada foi maior no grupo OVX comparado ao grupo C; entre as concentrações, a maior quantificação dos nódulos de cálcio se deu no grupo com 1mM de cafeína. Os resultados obtidos no PCR mostraram que o gene para fosfatase alcalina teve maior expressão no grupo OVX, seguido do grupo OVX1 aos 7 e 10 dias; a expressão gênica de osteocalcina foi maior para o grupo OVX1 aos 10 e 14 dias e esse grupo apresentou a maior expressão em todos os períodos para os genes Runx2 e RankL. No caso do Bmp4, o grupo OVX3 foi o mais expresso aos 10 e 14 dias. Os genes osteoprotegerina e osteopontina variaram sua expressão de acordo com o período e grupo avaliado. A expressão de osterix foi similar entre os grupos aos 7 e 10 dias, enquanto a expressão de Bsp, aos 7 e 14 dias, mostrou semelhança entre os grupos controle e OVX1. Frente aos resultados obtidos, sugere-se que a concentração de 1mM de cafeína pareceu ser a menos prejudicial ao metabolismo das células osteoblásticas neste modelo experimental de osteoporose. / The most common cause of osteoporosis is the decrease of estrogen after menopause. This hormone regulates the production of cytokines that influence osteoclast proliferation, increasing bone resorption. The effects of caffeine in bone metabolism are controversial and may be associated to periodontal disease, bone fractures, increase of urinary calcium levels and reduction of mineral bone density due to inhibition of osteoblast activities. Thus, the goal of this investigation was to evaluate the in vitro effect of different caffeine concentrations in the metabolism of bone marrow osteoblastic cells from osteoporotic rats (OVX). After Ethical Committee approval, wistar female rats were divided in two experimental groups: control (C) and submitted to ovariectomy (OVX). After 60 days of surgery, femurs were removed to isolate bone marrow mesenchymal cells, which were induced to osteoblastic differentiation in osteogenic medium along with three different concentrations of caffeine (1, 3 and 5 mM - OVX1, OVX3 e OVX5 respectively) and posteriorly seeded in 24-well plates (n = 5) to evaluate cell proliferation, alkaline phosphatase activity and its in situ detection, detection and quantification of mineralized nodules as well as assess quantitative expression of genes associated to osteoblastic activity by means of real time PCR. All the experiments were performed in triplicate and analyzed by means of the statistical software GraphPad Prism for p<0.05. Cell proliferation was diminished in the all osteoporotic groups that received caffeine, with group OVX1 being the less affected. Biochemical assay of ALP activity did not show differences among the groups in the periods analyzed; nevertheless there was a tendency to a higher activity proportional to the higher concentration of caffeine. The in situ detection of ALP showed better results in group OVX1 after 14 days of culture. Mineralized matrix quantification was higher in OVX groups when compared to control group; among the concentrations, the higher quantification of calcium nodules was in group OVX1. The results obtained with PCR showed that the gene for ALP had its highest expression in OVX group, followed by OVX1 at 7 and 10 days; expression of osteocalcin was higher in OVX1 after 10 and 14 days and this same group presented higher expression in all periods for genes Runx2 e Rankl. Analysis of Bmp4 gene showed that it was expressed in group OVX3 after 10 and 14 days. The genes that code for osteoprotegerin and osteopontin had different expression values in accordance to the period and group evaluated. The expression of osterix was similar between the groups after 7 and 10 days, whereas the expression of Bsp was similar between control and OVX1 groups after 7 and 14 days. The results suggest that the concentration of 1mM of caffeine is the most beneficial to the metabolism of osteoblastic cells in a model of osteoporosis.

Le ranélate de strontium, prescrit dans le traitement de l'ostéoporose ménopausique, possède 2 atomes de strontium stable pouvant se fixer au minéral osseux. Le strontium a un effet dissociant sur le remodelage osseux, diminuant la résorption tout en augmentant la formation. Cependant, ses effets osseux ne sont pas complètement élucidés, en particulier ses interactions avec le minéral. Chez le singe, le strontium maintient à un niveau physiologique les propriétés intrinsèques majeures du tissu osseux, que ce soit aux niveaux tissulaire global ou des unités de remodelage. Chez la femme ostéoporotique ménopausée traitée par le ranélate de strontium, les caractéristiques du cristal d'apatite sont maintenues à un niveau physiologique. Par ailleurs, quelle que soit la durée du traitement (2 à 96 mois), le strontium est toujours distribué de façon hétérogène, présent principalement dans l'os récent formé pendant le traitement, les aires osseuses contenant du strontium augmentent progressivement mais de moins en moins avec la durée du traitement. Le contenu osseux focal en strontium est stable de 2 à 60 mois puis augmente de 60 à 96 mois, et la minéralisation secondaire est maintenue à un niveau physiologique. Enfin, après 6 et 12 mois de traitement, le ranélate de strontium maintient normaux les principaux paramètres reflétant la minéralisation secondaire, et ses effets sont similaires à ceux de l’alendronate. En conclusion, le ranélate de strontium maintient une qualité normale de la minéralisation secondaire, que ce soit à court ou à long terme, et quel que soit le modèle étudié. Le ranélate de strontium maintient également la microdureté osseuse, les caractéristiques minérales et organique tissulaires, ainsi que la structure du cristal d'apatite / Strontium ranelate, a treatment of postmenopausal osteoporosis, contains 2 atoms of stable strontium which interact with bone mineral. Strontium have a dissociating effect on bone remodeling, decreasing resorption while increasing formation. However, its bone effects are not fully clarified, in particular its interactions with mineral. In monkeys, strontium maintains the major intrinsic properties of bone at a physiological level, either at the global tissue or the bone structural units levels. In postmenopausal women treated with strontium ranelate, the characteristics of apatite crystals are maintained at a physiological level. Moreover, whatever the duration of treatment (2 to 96 months), strontium is always heterogeneously distributed, mainly present in recent bone formed during treatment, bone areas containing strontium progressively increase but less and less with the duration of the treatment. Focal bone strontium content remains stable from 2 to 60 months and then increase from 60 to 96 months, and secondary mineralization is maintained at a physiological level. Finally, after 6 and 12 months of treatment, strontium ranelate maintains normal the main parameters reflecting secondary mineralization, and its effects are similar to those of alendronate. To conclude, strontium ranelate maintains a normal quality of secondary mineralization, either after a shortterm or a long-term treatment, and whatever the model studied. Strontium ranelate also maintains bone microhardness, tissular mineral and organic characteristics, as well as the structure of apatite crystals

The purpose of this study is to further quantify adult ovine ovariectomized bone for new remodeling characteristics to obtain a better understanding of how remodeling is occurring and the effectiveness of this animal model for the study of postmenopausal osteoporosis. Postmenopausal osteoporosis is a major health concern and animal models to test new treatment options are needed. The ovine model is a good option because the ewes undergo Haversian remodeling, are a large sized animal, and have a similar hormone profile to humans. Ewes, however, do not undergo a natural menopause, so an ovariectomy surgery was conducted in the sheep to simulate the decreased levels in estrogen. Columbia-Rambouillet sheep were used in this study: some that have been ovariectomized as a model for postmenopausal osteoporosis and some that underwent a sham surgery to serve as a control. The sheep were sacrificed 12 months post operatively in the month of August, so the seasonal effects of remodeling were accounted for. The left radius was then processed into microradiographs of 6 regional cortical beams, where the cranial (tensile side) and caudal (compressive side) anatomical sections were analyzed in this study to determine regional differences in remodeling. Previous students’ theses have analyzed the similar samples for basic bone remodeling histology measurements, resulting in some significant seasonal, anatomical, and treatment differences. However, most of the results showed no particular increase in the amount of remodeled area for the ovariectomized sheep compared to the sham sheep, even though an ovariectomy is believed to cause a burst of remodeling in bone due to the decreased levels in estrogen. In this study, a new repeatable method was developed that further examines secondary bone by quantifying the extent to which secondary osteons encroach on previously-existing secondary osteons. Encroached and unencroached secondary osteons were quantified using two different methods: a point count method that measured the percentage of the area the encroached and unencroached secondary osteons inhabited and an osteon count method that measured the number of encroached and unencroached secondary osteons per area. These raw measurements were calculated into 18 parameters and 2-way repeated measures ANOVAs were run to determine the effects of surgery and anatomical region on each of the bone remodeling parameters. The results found significant effects from estrogen deletion which were different depending on if the bone region was predominately in compression or tension. The ovariectomy surgery caused an increase in remodeling, which was mostly confined on the compressive side to areas that have been previously remodeled, but on the tensile side, bone remodeling expanded into areas that used to be primary bone. The new secondary osteons, as a result of the ovariectomy surgery, were larger than in the control animals. There however, was not an increase in porosity from the ovariectomy surgery, which is one of the main characteristics of osteoporosis. The model could be further studied to determine what sheep are doing that prevents them from losing bone and that knowledge could be greatly beneficial for human treatment plans of postmenopausal osteoporosis.

Submitted by Rosangela Silva (rosangela.silva3@unioeste.br) on 2018-05-23T13:56:08Z No. of bitstreams: 2 Camila Mayumi Martin Kakihata.pdf: 1187703 bytes, checksum: 1254b570ed82583edc71e880d005902b (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-05-23T13:56:08Z (GMT). No. of bitstreams: 2 Camila Mayumi Martin Kakihata.pdf: 1187703 bytes, checksum: 1254b570ed82583edc71e880d005902b (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-02-23 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Vibratory platform vibration therapy used in the treatment of postmenopausal osteoporosis because it can promote anabolic effects on bone tissue, but the parameters of use, especially the time of application, are not established. In addition, despite the beneficial effects of vibration, it is known that it can cause peripheral nerve damage. However although mentioned, there is no scientific evidence documenting the effects of this stimulus on the peripheral nerve in parameters used in therapies. Thus, is relevant the study of the mechanical vibration during different periods on the bone tissue, besides analyzing the effects on the nervous tissue. The aim of this study was to analyze and compare the effects of mechanical vibration applied over four and eight weeks on the femur and sciatic nerve of oophorectomized Wistar rats. Sixty-six randomized rats were used in the oophorectomy (GO) and sham-oophorectomy (GP) groups (n = 32 / group). Subsequently, each group was subdivided into 4, euthanized groups in the 12th week of experiment (GP4, GO4, GPV4 and GOV4), and GPV4 and GOV4 were submitted to vibration for 4 weeks; (GP8, GO8, GPV8 and GOV8), and GPV8 and GOV8 groups were submitted to vibration for 8 weeks. The vibration was performed with frequency of 60Hz, for 10 minutes, three days a week. Nociception of the right hind paw was evaluated before the surgical procedure, at the beginning of the treatment and at the end of the treatment with vibration. After the experimental period, the animals were euthanized, and the right sciatic nerve and femur were dissected for histomorphometric analysis. Were measured in 100 fibers nerve the diameter of the fiber, axon, myelin sheath, and quotient g, also were realized the counts of smaller fibers and larger than four micrometers and of the Schwann cell nuclei, as well as the percentage of connective tissue. The femur was analyzed for femoral neck diameter, mean area of cortical bone, percentage of spongy bone, thickness measurement and percentage of cortical bone, as well as osteocyte count. From the analyzes it was observed that the nociception and morphometry of the sciatic nerve morphometry did not have a statistically significant difference; in addition, in the morphological analysis of the sciatic nerve, the groups presented similar characteristics among themselves, without altering the typical morphology. While in the femur, the vibration in the oophorectomized groups led to the increase of the bone mass, being observed the increase of the percentage of the spongy tissue, which was also evidenced in the cortical tissue, with increase of the thickness and the percentage of bone tissue, being the was able to reverse these changes. However, the variables of the mean area of the cortical bone, number of osteocytes and the diameter of the femoral neck were not altered by vibration. With this, it was concluded that the vibration during four and eight weeks promoted increase of the bone mass, whereas it did not have effects on the sciatic nerve of oophorectomized Wistar. / A terapia de vibração com plataforma vibratória é utilizada no tratamento de osteoporose pós-menopausa, pois pode promover efeitos anabólicos sobre o tecido ósseo; porém, os parâmetros de utilização, principalmente o tempo de aplicação, não estão bem estabelecidos. Além disso, apesar dos efeitos benéficos da vibração, esse estímulo pode causar lesão nervosa periférica e seus efeitos sobre o nervo periférico são ainda pouco explorado em parâmetros utilizados em terapias. Diante desses fatores, torna-se relevante o estudo da vibração mecânica durante diferentes períodos sobre o tecido ósseo, além de analisar os efeitos sobre o tecido nervoso. Sendo assim, o objetivo deste estudo foi analisar e comparar os efeitos da vibração mecânica aplicada durante quatro e oito semanas, sobre o fêmur e nervo isquiático de ratas Wistar ooforectomizadas. Foram utilizadas 64 ratas randomizadas nos grupos ooforectomia (GO) e pseudoooforectomia (GP) (n=32/grupo). Posteriormente, cada grupo foi subdividido em 4, grupos eutanasiados na 12ª semana de experimento (GP4, GO4, GPV4 e GOV4), sendo que GPV4 e GOV4 foram submetidos à vibração por 4 semanas; e os grupos eutanasiados na 16ª semana de experimento (GP8, GO8, GPV8 e GOV8), sendo que GPV8 e GOV8 foram submetidos à vibração por 8 semanas. A vibração foi realizada com frequência de 60Hz, por 10 minutos, três vezes por semana. Foi avaliada a nocicepção da pata posterior direita antes do procedimento cirúrgico, prévio e ao final do tratamento com vibração. Após o período experimental, os animais foram devidamente eutanasiados, e o nervo isquiático e o fêmur direitos foram dissecados para análise histomorfométrica. Foi mensurado em 100 fibras nervosas o diâmetro da fibra, axônio, bainha de mielina e quociente g; realizou-se a contagem de fibras menores e maiores que quatro micrometros, e dos núcleos de células de Schwann, além da porcentagem do tecido conjuntivo. O fêmur foi analisado quanto ao diâmetro do colo do fêmur, à porcentagem do osso esponjoso, à mensuração da espessura, à porcentagem e área média do osso cortical, além da contagem do número de osteócitos. A partir das análises, observou-se que a variável da nocicepção e da morfometria do nervo isquiático não houve diferença estatística significativa, além disso, na análise morfológica do nervo isquiático, os grupos apresentaram características semelhantes entre si, sem alteração da morfologia típica. Enquanto que no fêmur, a vibração nos grupos ooforectomizados levou ao aumento da massa óssea, sendo observado o aumento da porcentagem do tecido esponjoso, o que também foi evidenciado no tecido cortical, com aumento da espessura e da porcentagem de tecido ósseo. Porém, as variáveis da área média do osso cortical, o número de osteócitos e o diâmetro do colo do fêmur não foram alterados pela vibração. Com isso, conclui-se que a vibração durante quatro e oito semanas promoveu aumento da massa óssea e não apresentou efeitos sobre o nervo isquiático de ratas Wistar ooforectomizadas.