O papel da infecção e inflamação na etiopatogênese da osteonecrose dos maxilares induzida por medicamentos / The role of infection and inflammation in the etiopathogenesis of medication-related osteonecrosis of the jaw

Objetivo: O objetivo desta revisão de literatura é evidenciar o papel da infecção e inflamação na etiopatogenia da osteonecrose dos maxilares induzida por medicamentos (MRONJ). Revisão da literatura: A MRONJ é uma condição rara e grave que impacta negativamente a vida dos pacientes afetados. Sua etiopatogenia é multifatorial e ainda não foi totalmente compreendida. Uma das hipóteses propostas para explicá-la sugere que, além da inibição do turnover ósseo pelos medicamentos antirreabsortivos, a infecção associada à exodontia e a inflamação local desempenham papel decisivo no desencadeamento da condição. O entendimento da etiopatogenia da MRONJ permite ao cirurgião-dentista a identificação dos pacientes com risco maior para a doença, assim como o auxilia no monitoramento e escolha do manejo mais adequado. No campo da pesquisa, ele pode aprimorar estudos pré-clínicos e aprofundar a investigação de biomarcadores para diagnóstico precoce de MRONJ. Considerações finais: Conhecer a contribuição da infecção e inflamação na etiopatogênese da MRONJ é fundamental para orientar a pesquisa e a adoção de estratégias preventivas para os pacientes em risco, e de manejo e monitoramento adequado para aqueles já acometidos. (AU)

Aim: The aim of this literature review is to highlight the role of infection and inflammation in the etiopathogenesis of drug-induced osteonecrosis of the jaw (MRONJ). Literature review: MRONJ is a rare and serious condition that negatively impacts the lives of affected patients. Its etiopathogenesis is multifactorial and has not yet been fully understood. One of the hypotheses proposed to explain it suggests that, in addition to the inhibition of bone turnover by antiresorptive drugs, the infection associated with tooth extraction and local inflammation play a decisive role in triggering the condition. Understanding the etiopathogenesis of MRONJ allows the dentist to identify patients at higher risk for the disease, as well as assisting in monitoring and choosing the most appropriate management. In research, it can improve preclinical studies and deepen the investigation of biomarkers for early diagnosis of MRONJ. Conclusion: Knowing the contribution of infection and inflammation in the etiopathogenesis of MRONJ is essential to guide research and the adoption of preventive strategies for patients at risk, and adequate management and monitoring for those already affected.(AU)

Intercellular mediators in bone remodeling regulation in the experimental renal pathology / Mediadores intercelulares de la regulación de la remodelación ósea en un modelo experimental de patología renal

Bone metabolism disorders are characterized by an imbalance of bone resorption and formation in the bone remodeling process. Glucocorticoids that are used to treat kidney diseases exacerbate these disorders. P-selectin and galectin-3 are molecules involved in the sclerotic process in kidney, whereas bone resorption is regulated by the interaction between the nuclear factor activator kappa b receptor (RANK), its ligand (RANKL) and the RANKL decoy receptor osteoprotegerin (OPG). The aim of this study was to investigate the cellular and molecular mechanisms of disruption of bone remodeling regulation processes, reflected by intercellular mediators (RANKL, OPG, P-selectin and galectin-3) in chronic kidney disease experimental model treated with glucocorticoids. Rats were divided into four groups of 10 animals each. The first group, the control group, included intact animals. The second group consisted of rats with impaired bone remodeling resulting from chronic kidney disease (experimental group (CKD). The third group was a group of animals with impaired bone remodeling due to exposure to glucocorticoids (experimental group (GCs)). The fourth group consisted of rats with impaired bone remodeling in chronic kidney disease, followed by exposure to glucocorticoids (experimental group (CKD + GCs)). The effects of CKD and glucocorticoid were evaluated biochemically, histologically and by measuring bone density. An enzymelinked immunoassay was used to measure intercellular mediator levels in the serum. The bone density in the experimental groups was reduced compared to the control group. RANKL levels in animals of three experimental groups were higher than in intact animals. Serum levels of OPG were higher in CKD and GCs groups than in intact animals. At the same time, in the animals' blood serum of the CKD + GCs group, the levels of OPG were lower, than those in animals from the control group. The levels of galectin-3 in the serum of the experimental groups GCs and CKD + GCs were lower than in intact animals. The serum levels of galectin-3 in animals of the CKD group were higher than those in animals from the control group. The levels of P-selectin were lower in the serum of the GCs group than in intact animals. At the same time, the levels of P-selectin were higher in the CKD and CKD + GCs groups, than those in animals from the control group. In conclusion, the study of the complex system of bone remodeling regulation, which includes many factors and their interactions, may lead to the development of new methods for treating patients with chronic kidney disease in order to prevent osteoporosis in the future. (AU)

Las enfermedades metabólicas óseas se caracterizan por un desequilibrio en el proceso de remodelación ósea en los que participan mediadores tales como receptor del activador del factor nuclear- kappa- b (RANK), su ligando (RANKL) y la osteoprotegerina (OPG). Los glucocorticoides, recuentemente empleados en el tratamiento de la enfermedad renal crónica, exacerban este desequilibrio. En la enfermedad esclerótica renal, las moléculas de adhesión celular P-selectina and galectina-3 tienen un rol fundamental. El objetivo de esta trabajo fue estudiar las alteraciones en los mediadores de la remodelación ósea (RANKL, OPG, P-selectina and galectina-3) en un modelo de enfermedad renal crónica con tratamiento glucocorticoideo. Ratas Wistar hembras fueron divididos en 4 grupos: control (C); enfermedad renal crónica con afección de la remodelación ósea (ERC); animales con afección de la remodelación ósea expuestos a glucocorticoides (GC); enfermedad renal crónica con afección de la remodelación ósea tratados con glucocorticoides (ERC+GC). Los efectos de la ERC y los GC fueron evaluados bioquímicamente, histológicamente y por medición de la densidad ósea. RANKL, OPG, Pselectina and galectina-3 se cuantificaron en muestras de sangre venosa empleando enzimoinmuno análisis. En los 3 grupos experimentales la densidad ósea se evidenció reducida y los niveles séricos de RANKL elevados respecto al grupo control. Los niveles de OPG en los grupos ERC y GC fueron superiores mientras que en el grupo ERC+GC menores respecto a los animales controles. Galectina 3 plasmática en GC y ERC+GC se encontró reducida y aumentada en los animales ERC, en comparación con los animales controles. La concentración sérica de P-selectina sérica fue mayor en los grupos ERC y ERC+GC, y menor en los animales GC respecto a los niveles plasmáticos de los animales intactos. El avance del conocimiento sobre la regulación de la remodelación ósea a través de la interacción de mediadores sistémicos, en un futuro, puede conducir al desarrollo de nuevas estrategias terapéuticas para la prevención de la osteoporosis en pacientes con enfermedad renal crónica. (AU)

Efecto de Vitamina E y Alendronato sobre la Densidad Mineral en Hueso Maxilar de Ratas / Effect of Vitamin E and Alendronate on Mineral Density in Rat Maxillary Bone

RESUMEN: El balance óseo está mediado por una regulación inmunoendócrina, siendo éste un complejo proceso. Entre las acciones llevadas a cabo para mantener la densidad y estructura del esqueleto son variadas las farmacoterapias utilizadas. Diversos estudios han demostrado que tanto Alendronato (AL) y Vitamina E (E) contribuyen a la inhibición de la reabsorción ósea. El objectivo de este trabajo fue estudiar el efecto de la administración combinada de (AL) por vía subcutánea y (E) se administró tres veces por semana también por vía subcutánea con una dosificación de 20 mg/kg de peso corporal. La fórmula farmacéutica fue de 0,5 mg/kg de peso corporal para AL, y 20 mg/kg de vitamina E. El efecto se evaluó en ratas machos Wistar (n=108), de 90 ± 20 g, divididas en 4 grupos. Se realizó la exodoncia de los primeros molares inferiores. La droga se inyectó en forma subcutánea en tiempos 0, 7, 15 y 30 días post cirugía. Las imágenes de las mandíbulas fueron adquiridas mediante radiovisiógrafo, en cada tiempo experimental y fueron analizadas con el Software Image ProPlus versión 4,1 de Media Cibernetics. Estudios estadísticos: no paramétrico: prueba de Kruskal-Wallis Resultados: El grupo C (que registró la media de intensidad más baja), se diferenció significativamente de los grupos E y A-E (p<0,001), no así del grupo que utilizó únicamente Al (p=0,070; p>0,05). Los grupos Al, E y el combinado Al-E no se diferenciaron significativamente entre sí (p>0,05 en todos los casos). Los datos evaluados sirven para mostrar una tendencia favorable en relación al efecto beneficioso de la combinación de AL y vitamina E.

ABSTRACT: The bone balance is mediated by an immunoendocrine regulation, this being a complex process. A number of pharmacotherapies are used among the actions taken to maintain the density and structure of the skeleton. Several studies have shown that both Alendronate (AL) and Vitamin E (E) contribute to the inhibition of bone resorption. Objective: To study the effect of combined administration of (LA) subcutaneously and (E) was administered three times per week also subcutaneously with a dosage of 20 mg / kg body weight. The pharmaceutical formulation was 0.5 mg / kg body weight for AL and 20 mg / kg vitamin E. The effect was evaluated in male Wistar rats (n = 108), 90 ± 20 g, divided into 4 groups. Extraction of the first lower molars was performed. The drug was injected subcutaneously at time 0, 7, 15 and 30 days post-surgery. The images of the jaws were acquired by radiovisiography, at each experimental time and were analyzed with Image ProPlus Software version 4.1 of Media Cibernetics. Statistical studies: non-parametric: Kruskal-Wallis test Group C (which recorded the lowest mean intensity) was significantly different from the E and AE groups (p <0.001), but not from the group that used only Al (P = 0.070, p> 0.05). The Al, E and combined Al-E groups did not differ significantly from each other (p> 0.05 in all cases). The data evaluated serve to show a favorable trend in relation to the beneficial effect of the combination of AL and vitamin E.

The effect of graft application and simvastatin treatment on tibial bone defect in rats. A histological and immunohistochemical study

Abstract Purpose: To evaluate histologically and immunohistochemically the bone regeneration after application of simvastatin on tibial bone defects in rats. Methods: Sixty Wistar albino rats were divided into 3 groups as control (6 mm tibial bone defect), defect + graft (allograft treatment), and defect + graft + simvastatin (10 mg/kg/day) for 28 days. Results: Histopathological examination revealed inflammation in control group (defect group), congestion in blood vessels, and an increase in osteoclast cells. In defect + graft group, osteoclastic activity was observed and osteocyte cells were continued to develop. In defect + graft + simvastatin group, osteocytes and matrix formation were increased in the new bone trabeculae. Osteopontin and osteonectin expression were positive in the osteclast cells in the control group. Osteoblasts and some osteocytes showed a positive reaction of osteopontin and osteopontin. In defect + graft + simvastatin group, osteonectin and osteopontin expression were positive in osteoblast and osteocyte cells, and a positive expression in osteon formation was also seen in new bone trabeculae. Conclusion: The simvastatin application was thought to increase bone turnover by increasing the osteoinductive effect with graft and significantly affect the formation of new bone.

Influence of antiretroviral therapy on bone metabolism of patients with chronic hepatitis B: a review

Abstract Hepatitis B is a major public health problem worldwide and associated with significant mortality. To prevent or delay the deleterious effects of chronic infection by the hepatitis B virus, patients should be carefully followed, and antiviral therapy indicated according to specific recommendations. Currently, available drugs inhibit viral replication and slow or stop the progression of inflammation and fibrosis of the liver. However, the drugs for oral use in the treatment of hepatitis B, jointly referred to as nucleoside/nucleotide analogs, are indicated for prolonged use and have potential side effects. The reduction in bone mineral density was associated with the use of tenofovir, already evaluated in patients infected with HIV because the drug is also part of the therapeutic arsenal for this viral infection. There are few studies on the effects of tenofovir in patients with mono hepatitis B. Therefore, this literature review proposes to examine how hepatitis B acts in the body and the mechanisms by which antiretroviral drugs (especially tenofovir) can affect bone metabolism.

Potencial of different hydroxyapatites as biomaterials in the bone remodeling

Abstract Purpose: To analyze the therapeutic potentials of different hydroxyapatites used for the correction of bone defects in rats. Methods: Forty rats, male, albino wistar, were distributed in 4 groups. They were submitted to a 3.5 mm defect in tibia. They received low purity hydroxyapatite, Strontium hydroxyapatite and hydroxyapatite doped with gallium, having a seven day evaluation time. Histopathology slides were stained with hematoxylin-eosin, for morphological evaluation. Were analyzed inflammatory processes, necrosis, presence of osteoclasts and osteoblasts, presence of the material, presence of white cells, neovascularization and bone neoformation. Results: It was observed that the groups HAPSr and HAPGa, presented better results of trabecular bone, hyaline cartilage and bone marrow more organized. Conclusion: There was improvement in the repair of the bone defect produced, showing that these hydroxyapatites are effective osteoinductive, osteoconductive, osteintegrant agents and have biocompatibility, and may be indicated for use in defect repairs.

Combination therapy of curcumin and alendronate modulates bone turnover markers and enhances bone mineral density in postmenopausal women with osteoporosis

ABSTRACT Objective: This study evaluated the effects of combination therapy of curcumin and alendronate on BMD and bone turnover markers in postmenopausal women with osteoporosis. Subjects and methods: In a randomized, double-blind trial study, 60 postmenopausal women were divided into three groups: control, alendronate, and alendronate + curcumin. Each group included 20 patients. Total body, total hip, lumbar spine and femoral neck BMDs were measured by dual-energy X-ray absorptiometry (DXA) at baseline and after 12 months of therapy. Bone turnover markers such as bone-specific alkaline phosphatase (BALP), osteocalcin and C-terminal cross-linking telopeptide of type I collagen (CTx) were measured at the outset and 6 months later. Results: Patients in the control group suffered a significant decrease in BMD and increased bone turnover markers at the end of study. The group treated with only alendronate showed significantly decreased levels of BALP and CTx and increased levels of osteocalcin compared to the control group. The alendronate group also showed significant increases in the total body, total hip, lumbar spine and femoral neck BMDs at the end of study compared to the control group. In the curcumin + alendronate group, BALP and CTx levels decreased and osteocalcin levels increased significantly at the end of study compared to the control and alendronate groups. BMD indexes also increased in four areas significantly at the end of study compared to the control and alendronate groups. Conclusion: The combination of curcumin and alendronate has beneficial effects on BMD and bone turnover markers among postmenopausal women with osteoporosis. Arch Endocrinol Metab. 2018;62(4):438-45

Levetiracetam and lamotrigine effects as mono- and polytherapy on bone mineral density in epileptic patients / Efeitos do levetiracetam e lamotrigina, em mono e politerapia, na densidade mineral óssea de pacientes epilépticos

ABSTRACT The purpose of this study was to determine the effect of lamotrigine (LTG) and levetiracetam (LEV) as mono- and polytherapy on biochemical markers of bone turnover and bone mineral density in Egyptian adult patients with epilepsy. Methods Forty-eight patients were divided into four groups: two received monotherapy of either LTG or LEV, and the other two groups received polytherapy comprising (valproate [VPA] + LTG or VPA + LEV). Thirty matched healthy participants were included in the study. Participants completed a nutritional and physical activity questionnaire. Biochemical markers of bone and mineral metabolism and bone mineral density of the lumbar spine were measured at baseline and at six months. Results In the LEV monotherapy group, the bone formation markers showed a significant decrease in serum alkaline phosphatase and serum osteocalcin levels while the bone resorption marker showed a significant increase in urinary deoxypyridinoline levels. After six months of treatment, bone mineral density showed a significant decrease in all treated groups, while among monotherapy groups, this significant decrease was more prevalent in the LEV monotherapy group compared with the LTG monotherapy group. Furthermore, there was significant negative correlation between urinary deoxypyridinoline levels and bone mineral density in the LEV monotherapy group. Conclusion Using new generation antiepileptics, LEV monotherapies and polytherapy showed harmful effects on bone but LTG did not.

RESUMO O objetivo deste estudo foi determinar o efeito da lamotrigina (LTG) e levetiracetam (LEV) como mono e politerapia em marcadores bioquímicos de remodelação óssea e densidade mineral óssea em pacientes adultos egípcios com epilepsia. Métodos Quarenta e oito pacientes foram divididos em quatro grupos: dois grupos receberam monoterapia de LTG ou LEV e os outros dois grupos receberam politerapia (valproato [VPA] + LTG ou VPA + LEV). Trinta participantes saudáveis controle foram incluídos no estudo. Os participantes preencheram um questionário nutricional e de atividade física. Marcadores bioquímicos do metabolismo ósseo e mineral e densidade mineral óssea da coluna lombar foram medidos no início e aos seis meses. Resultados No grupo de monoterapia LEV, os marcadores de formação óssea mostraram uma diminuição significativa nos níveis séricos de fosfatase alcalina e osteocalcina sérica, enquanto o marcador de reabsorção óssea mostrou um aumento significativo nos níveis de desoxipiridinolina urinária. Após seis meses de tratamento, a densidade mineral óssea mostrou uma diminuição significativa em todos os grupos tratados, enquanto entre os grupos de monoterapia, esta diminuição significativa foi mais prevalente no grupo de monoterapia LEV em comparação com o grupo de monoterapia LTG. Além disso, houve correlação negativa significativa entre os níveis de desoxipiridinolina urinária e densidade mineral óssea no grupo de monoterapia LEV. Conclusão Utilizando antiepilépticos de nova geração, as monoterapias LEV e a politerapia mostraram efeitos prejudiciais no osso, mas a LTG não.

Strontium ranelate as a possible disease-modifying osteoarthritis drug: a systematic review

Considering that osteoarthritis (OA) is the most prevalent joint disease worldwide, multiple pharmacological treatments have been proposed to alter the articular structure with potential benefit in the progression of the disease. The so-called disease-modifying OA drugs have been frequently investigated but conclusive findings are rare. Strontium ranelate (SrRan) is a drug usually prescribed to treat osteoporosis, with proven effects in decreasing the risk of fractures and possible effect in reducing the progression of OA. The objective of this review was to demonstrate the current panorama of knowledge on the use of SrRan in clinical and experimental models, clarifying its mechanisms of action and describing possible anti-nociceptive and anti-inflammatory effects. The systematic review was based on the PRISMA statement and included articles that are indexed in scientific databases. Fifteen studies were included: seven pre-clinical and eight clinical studies. Despite the limited number of studies, the results suggest a positive effect of SrRan in patients with OA, through changes in functional capacity and reduction of progression of morphological parameters and joint degradation, with moderate quality of evidence for those clinical outcomes. Novel studies are necessary to elucidate the molecular targets of SrRan, focusing on anti-inflammatory effects and histological changes promoted by SrRan, which seemed to reduce the progression of OA in the experimental and clinical studies.

Effects of continual intermittent administration of parathyroid hormone on implant stability in the presence of osteoporosis: an in vivo study using resonance frequency analysis in a rabbit model

Abstract Objective: This study aimed to evaluate the effects of continual intermittent administration of parathyroid hormone (PTH) on implant stability in the presence of osteoporosis, using rabbit models. Material and Methods: Fifteen female New Zealand white rabbits underwent ovariectomy and were administered glucocorticoids to induce osteoporosis, following which they were divided into three groups. The first group received intermittent subcutaneous PTH for 4 weeks until implant placement (PTH1), while the second and third groups received PTH (PTH2) and saline (control), respectively, for 4 weeks before and after implant placement. After intermittent administration of PTH or saline, titanium implants were inserted into the left femoral epiphyses of all animals, and the implant stability quotient (ISQ) was measured immediately after placement to assess the primary stability and at 2 and 4 weeks after implant placement to assess osseointegration. At 4 weeks after implant placement, histological and histomorphometric evaluations were conducted and the bone area around the implant socket was measured as a ratio of the total bone area to the total tissue area. Results: Regarding primary stability, the ISQ values for the PTH1 and PTH2 groups were significantly higher than those for the control group (p<0.05). Concerning osseointegration, the ISQ values at 2 and 4 weeks were significantly higher for the PTH2 group than for the PTH1 and control (p<0.05) groups. Histological assessments showed a thicker and more trabecular bone around the implant sockets in the PTH2 specimens than in the PTH1 and control specimens. The bone area around the implant socket was significantly greater in the PTH2 group than in the PTH1 and control groups (p<0.05). Conclusions: Our results suggest that continual intermittent PTH administration before and after dental implant placement is effective for the achievement of favorable stability and osseointegration in the presence of osteoporosis.

Desarrollo de un modelo experimental de osteonecrosis de maxilar asociada al tratamiento crónico con aminobisfosfonatos / Experimental model of osteonecrosis of the jaw associated to chronic treatment with aminobisphosphonates

La osteonecrosis de maxilar asociada a aminobisfosfonatos (BRONJ) constituye un efecto secundario del tratamiento crónico con los más potentes. Un modelo experimental permitiría determinar la patogenia de dicha alteración. La oveja presenta características orales y del metabolismo óseo similar al humano y permite realizar manipulaciones bucales. Se evaluaron cambios clínicos, remodelación ósea y masa ósea maxilar en ovejas hembras adultas tratadas con zolendronato (ZOL), durante 22 meses y utilizando dosis equivalente al tratamiento de neoplasias. Seis ovariectomizadas (OVX) recibieron ZOL; 5 OVX y 4 SHAM (control) recibieron solución fisiológica. Al inicio, 4 y 22 meses se evaluó calcemia, fosfatemia, crosslaps (CTX) y fosfatasa alcalina ósea. Al final, se evaluó contenido mineral óseo de la hemimandíbula superior (CMO: mg/cm2). Al final del estudio, CTX disminuyó significativamente en ZOL (p<0,05) sin diferencias entre SHAM y OVX. En maxilar, los contenidos de Ca y P (g/g tejido) y CMO (g/cm2 ) disminuyeron en OVX vs. SHAM (p<0,05) y solo Ca y CMO respecto de ZOL (p<0,05). ZOL incrementó el contenido de Ca y CMO, mientras que el de P permaneció significativamente disminuido respecto de SHAM. La sobrevida en SHAM y OVX fue del 100% y en ZOL 77% (2 muertes); 2 ovejas del grupo ZOL presentaron necrosis de maxilar. Conclusiones: fue posible obtener desarrollo de BRONJ por tratamiento crónico con ZOL, el cual redujo notablemente la resorción y, según la relación Ca/P, posiblemente haya afectado la mineralización ósea. (AU)

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a complication of chronic treatment with the most powerful aminobisphosphonates (BPs). An experimental animal model would allow to determine the pathogenesis of this complication. Ewes exhibit similar oral cavity characteristics and bone metabolism as humans, and they are suitable for oral cavity interventions. We examined herein the clinical manifestations, bone remodeling status, and maxillary bone mass in adult female ewes treated with zoledronate (ZOL) for 22 months. Six ovariectomized (OVX) ewes received ZOL; and 5 OVX and 4 SHAM animals received saline solution. At the start of the experiment, and at the 4 and 22 month-time points serum Ca, P, crosslaps (CTX), and bone alkaline phosphatase were measured. Bone mineral content (BMC) of the superior hemimandible was measured at the end of the experiment. At this time point, CTX was significantly decreased only in the ZOL group (p<0.05). Ca and P content (g/g tissue) and BMC in the mandible were significantly decreased in the OVX group compared to SHAM animals (p<0.05) and only Ca content and BMC were decreased when compared to ZOL (p<0.05). ZOL treatment increased the Ca content and BMC, whereas the P content remained low compared to the SHAM group (p<0.05). All ewes from the SHAM and OVX groups and 77% of the animals from the ZOL group survived until the end of the experiment, whereas two ewes of ZOL group exhibited BRONJ. Conclusion: under our experimental conditions, it was possible to induce BRONJ by the chronic ZOL administration, which in turn induced a high reduction in bone resorption as well as possibly impaired bone mineralization, based on the Ca/P ratio in the mandible. (AU)

Modulation of in vitro osteoclast activity mediated by different doses of parathyroid hormone / Modulación in vitro de la actividad osteoclástica mediada por diferentes dosis de hormona paratiroidea

Bone remodeling is a process regulated by the interaction between cells and various molecules such as parathyroid hormone (PTH). The aim of the study was to evaluate the effect of different doses of PTH on osteoclast activity in a culture model of bone organs. Six-day-old male C57BL/6 mice (n=14) were euthanized and the calvariae were dissected and sectioned in the middle, keeping the periosteal and endosteal. The bone fragments were divided into three groups: Group I (control - without adding PTH), Group II (addition of 3 nM PTH) and Group III (30 nM PTH), all cultured in aMEM for up to 72 h osteoclast activity was evaluated by biochemical quantification of calcium released in the culture medium at intervals of 24, 48, and 72 h and by histomorphometric analysis of bone resorption lacunae at 72 h our results show that group II exhibited significantly higher values of calcium levels in the medium compared to group I (p<0.05) in all intervals, also being higher for group III at 24 hours (p<0.05). Group II promoted a greater demineralization area (22068 ± 2193 mm2) than those found in group I (2084 ± 38 mm2) and group III (8952 ± 246 mm2), with statistically significant difference (p<0.001) among all groups. We concluded that in culture model of bone organs PTH promotes higher bone resorption when administered in lower doses.

La remodelación ósea es un proceso regulado por la interacción entre las células y varias moléculas como la hormona paratiroidea (PTH). El objetivo de este estudio fue evaluar el efecto de diferentes dosis de PTH sobre la actividad de los osteoclastos en un modelo de cultivo de órganos óseos. Se sacrificaron ratones C57BL/6 machos, de 6 días de edad (n = 14), y se disecaron y seccionaron las calvarias, manteniendo el periostio y endostio. Los fragmentos óseos se dividieron en tres grupos: Grupo I (control - sin adición de PTH), Grupo II (adición de 3 mM de PTH) y Grupo III (30 nM de PTH), todos cultivados en aMEM hasta 72 horas. La actividad de los osteoclastos se evaluó mediante la cuantificación bioquímica de calcio liberado en medio de cultivo, a intervalos de 24, 48 y 72 horas, y por análisis histomorfométrico de las lagunas de resorción ósea a las 72 horas. Nuestros resultados muestran que el grupo II exhibió valores significativamente más altos de calcio en el medio, comparado con el grupo I (p <0.05) en todos los intervalos, siendo también más alto para el grupo III a las 24 horas (p <0.05). El grupo II promovió una mayor área de desmineralización (22068 ± 2193 mm2) que los encontrados en el grupo I (2084 ± 38 mm2) y en el grupo III (8952 ± 246 mm2), con diferencia estadísticamente significativa (p <0,001) entre todos los grupos. Concluimos que en el modelo de cultivo de órganos óseos la PTH promueve una mayor resorción ósea cuando se administra en dosis más bajas.

Hepatic Osteodystrophy: The Mechanism of Bone Loss in Hepatocellular Disease and the Effects of Pamidronate Treatment

OBJECTIVES: The present study was designed to evaluate the bone phenotypes and mechanisms involved in bone disorders associated with hepatic osteodystrophy. Hepatocellular disease was induced by carbon tetrachloride (CCl4). In addition, the effects of disodium pamidronate on bone tissue were evaluated. METHODS: The study included 4 groups of 15 mice: a) C = mice subjected to vehicle injections; b) C+P = mice subjected to vehicle and pamidronate injections; c) CCl4+V = mice subjected to CCl4 and vehicle injections; and d) CCl4+P = mice subjected to CCl4 and pamidronate injections. CCl4 or vehicle was administered for 8 weeks, while pamidronate or vehicle was injected at the end of the fourth week. Bone histomorphometry and biomechanical analysis were performed in tibiae, while femora were used for micro-computed tomography and gene expression. RESULTS: CCl4 mice exhibited decreased bone volume/trabecular volume and trabecular numbers, as well as increased trabecular separation, as determined by bone histomorphometry and micro-computed tomography, but these changes were not detected in the group treated with pamidronate. CCl4 mice showed increased numbers of osteoclasts and resorption surface. High serum levels of receptor activator of nuclear factor-κB ligand and the increased expression of tartrate-resistant acid phosphatase in the bones of CCl4 mice supported the enhancement of bone resorption in these mice. CONCLUSION: Taken together, these results suggest that bone resorption is the main mechanism of bone loss in chronic hepatocellular disease in mice.

Lamivudine, Entecavir, or Tenofovir Treatment of Hepatitis B Infection: Effects on Calcium, Phosphate, FGF23 and Indicators of Bone Metabolism

ABSTRACT Background. Patients with chronic hepatitis B virus (HBV) are often treated with nucleoside/nucleotide antiviral agents and metabolic bone toxicity is a possible concern. Objective. To determine the relationships between fibroblast growth factor 23 (FGF23), a phosphaturic hormone, bone mineral density (BMD), and bone biochemical abnormalities in these patients. Material and methods. This is a cross-sectional observational study comparing HBV-infected subjects treated for at least one year with tenofovir (TDF), lamuvidine (LVD), entacavir (ETV), or not treated (CON). Patients with abnormalities in either calcium (Ca), phosphate (PO4), intact parathyroid hormone (iPTH) or FGF23 were further evaluated with BMD by DXA. Results. No difference in liver enzymes or renal function seen among groups, but hypophosphatemia was seen in all groups with the highest incidence with TDF treatment (14%). FGF 23 levels were found to be elevated in 11.1% of TDF patients, 2.77% amongst controls. No elevations were found in the LVD or ETV groups. Among a subset of subjects (FGF23, PO4, and/or Ca abnormalities) who underwent further evaluation, 67% had insufficient 25-OH vitamin D, and 30% had elevated 24 h urinary Ca or PO4 excretion. No patients with FGF23 abnormalities had urine abnormalities. 40% had low DXA Z-score (<-2) at spine or hip but there was no difference between control and antiviral treatment groups and the mean FRAX score was 2.33% for major osteoporotic fractures and 0.29% for hip fracture. Conclusion. Abnormalities in bone metabolism, particularly involving vitamin D insufficiency, in HBV-treated subjects were observed with a small increased likelihood in TDF treated patients.

Estudio radiográfico de la asociación de antioxidantes y bifosfonatos en remodelación ósea peri-Implantaria / Radiographic antioxidants association and biphosphonates study in bone remodeling peri-implant

Estudios previos han demostrado que los bisfosfonatos son potentes inhibidores de la resorción ósea. El aceite de oliva (O) es rico en ácidos grasos monoinsaturados con potentes propiedades anti-oxidantes. El objetivo de este estudio fue estudiar el efecto del tratamiento de alendronato (AL) y pamidronato (PA) y de O sobre la regeneración tisular. Las fórmulas se dosificaron 0,5 mg/kg de peso para AL, y de 0,6 mg/kg de peso para PA. El O se administró en la dieta, 50 g/ Kg. Cincuenta y cuatro ratas macho de la línea Wistar se dividieron en 6 grupos. El grupo control (C), recibió semanalmente 0,3 ml/100g de peso corporal de solución salina vía subcutánea. El grupo (AL) recibió semanalmente por vía subcutánea en el miembro posterior izquierdo. El grupo (PA) se colocó igual que el grupo anterior. El grupo (O) fue tratado en la alimentación y en las áreas de la cirugía recibieron inyección subcutánea con solución fisiológica. El grupo (ALO) recibió tratamiento combinado con AL y O. El grupo (PAO) se trató igual al anterior. La cirugía consistió en una incisión longitudinal en las tibias realizando un defecto circular en la parte plana de cada tibia hasta llegar al hueso medular. Se tomaron radiografías a los 0, 7, 15, 30, 60 y 90 días y fueron analizadas con el Software Image Pro Plus. Los estudios estadísticos se realizaron a través del análisis de la variancia a dos y tres criterios de clasificación. Se evidencio un incremento en la densidad mineral ósea promedio (DMO) conforme avanza el tiempo en todos los grupos, siendo evidentes con PA a los 60 días. El tratamiento O mostró eficacia en la remodelación ósea, observándose un pico a los 60 días. Esto sugiere que O representa una opción terapéutica para el tratamiento de las patologías óseas.

Previous studies have shown that bisphosphonates are potent inhibitors of bone resorption. Olive oil (O) is rich in monounsaturated fatty acids with potent anti-oxidant properties. The objective of this work was to study the effect of alendronate treatment (AL) and pamidronate (PA) and O on tissue regeneration. Formulas 0.5 mg / kg for AL dosed, and 0.6 mg / kg for PA. O was administered in the diet, 50 g / kg. Fifty-four male rats Wistar were divided into 6 groups. The control group (C) received weekly 0.3 ml / 100g body weight of saline subcutaneously. The group (AL) received a weekly dose subcutaneously in the left posterior limb. The group (PA) was placed as the previous group. The group (O) was treated in food and in the areas of surgery received subcutaneousinjection with saline. The group (ALO) received combined treatment with Al and O. The group (PAO) was treated the same as before. Surgery consisted of a longitudinal incision in the warm using a circular on the flat side of each tibia until the medullary bone defect. X-rays at 0, 7, 15, 30, 60 and 90 days were taken and analyzed with Image Pro Plus Software. Statistical studies were conducted through analysis of variance to two and three classification criteria. Results: an increase in the average bone mineral density (BMD) was evident as time progresses in all groups, with PA still evident at 60 days. Or treatment showed efficacy in bone remodeling observed a peak at 60 days. Conclusions: This suggests that O represents a therapeutic option for the treatment of bone disease.

Raloxifene neutralizes bone brittleness induced by anti-remodeling treatment and increases fatigue life through non-cell mediated mechanisms / El raloxifeno invierte fragilidad ósea inducida por el tratamiento anti-remodelación y aumenta la resistencia a la fatiga a través de mecanismos mediados no celulares

Pre-clinical data have shown that tissue level effects stemming from bisphosphonateinduced suppression of bone remodeling can result in bone that is stronger yet more brittle. Raloxifene has been shown to reduce bone brittleness through non-cellular mechanisms. The goal of this work was to test the hypothesis that raloxifene can reverse the bone brittleness resulting from bisphosphonate treatment. Dog and mouse bone from multiple bisphosphonate dosing experiments were soaked in raloxifene and then assessed for mechanical properties. Mice treated with zoledronate in vivo had lower post-yield mechanical properties compared to controls. Raloxifene soaking had significant positive effects on select mechanical properties of bones from both vehicle and zoledronate treated mice. Although the effects were blunted in zoledronate bones relative to vehicle, the soaking was sufficient to normalize properties to control levels. Additional studies showed that raloxifene-soaked bones had a significant positive effect on cycles to failure (+114%) compared to control-soaked mouse bone. Finally, raloxifene soaking significantly improved select properties of ribs from dogs treated for 3 years with alendronate. These data show that ex vivo soaking in raloxifene can act through non-cellular mechanisms to enhance mechanical properties of bone previously treated with bisphosphonate. We also document that the positive effects of raloxifene soaking extend to enhancing fatigue properties of bone. (AU)

Los datos preclínicos han demostrado que los efectos a nivel de tejido que se derivan de la supresión del remodelado óseo inducida por bifosfonatos puede dar como resultado un hueso que es más fuerte pero más frágil. Está comprobado que el raloxifeno reduce la fragilidad ósea a través de mecanismos no celulares. El objetivo de este trabajo fue probar la hipótesis de que el raloxifeno puede revertir la fragilidad ósea resultante del tratamiento con bifosfonatos. Se emplearon huesos de perro y ratón de múltiples experimentos con diferentes dosis de bifosfonatos los cuales fueron sumergidos en raloxifeno y luego se evaluaron sus propiedades mecánicas. Ratones tratados con zoledronato in vivo mostraron propiedades mecánicas post-rendimiento más bajas en comparación con los controles. Luego de sumergirlos en raloxifeno se observaron efectos positivos significativos en algunas propiedades biomecánicas tanto en los huesos de ratones tratados con vehículo como con zoledronato. Aunque los efectos se atenuaron en los huesos tratados con zoledronato en relación con los tratados con vehículo, el raloxifeno fue suficiente para normalizar las propiedades a niveles basales. Estudios adicionales mostraron que los huesos sumergidos en raloxifeno tuvieron un efecto positivo significativo en los ciclos de fractura (+ 114%) en comparación con los huesos de ratón sumergido en vehículo. Finalmente, el raloxifeno mejoró significativamente las propiedades de costillas de perros tratados durante 3 años con alendronato. Estos datos muestran que la inclusión ex vivo en raloxifeno puede actuar a través de mecanismos no celulares para mejorar las propiedades mecánicas de huesos previamente tratado con bifosfonatos. También documentamos que los efectos positivos del raloxifeno mejoran las propiedades de fatiga del hueso. (AU)

Using agents that suppress bone remodeling to treat or prevent joint disease: quo vadis?

Treatment of osteoarthritis (OA) with antiremodeling agents has had a mixed record of results. It is likely that remodeling suppression is only effective when used in the early phases of OA, before significant progression. Animal and human studies largely bear this out. Treatment of young mice with a RANKL inhibitor suppresses bone resorption and prevents OA progression. Likewise, bisphosphonate treatments in rodents and rabbits with induced injury or inflammatory arthritis, reduced cartilage degeneration when administered preemptively, but later administration did not. The increased prevalence of OA in women after the menopause, and presence of estrogen receptors in joint tissues, suggests that treatment with estrogens or Selective Estrogen Receptor Modulators may be effective. However, in clinical trials of knee and hip, results show decreased or increased risk for OA, or no effect. Raloxifene had positive effects in animal models, but no effect in human studies. More recent potential treatments such as strontium ranelate or cathepsin-K inhibitors may be effective, but may work directly on the cartilage rather than through their well-known effects on bone. The conclusion from these studies is that anti-remodeling agents must be administered pre-emptively or in the very early stages of disease to be effective. This means that better imaging techniques or identification of early structural changes in bone that occur before progressive cartilage destruction must be developed. (AU)

Utilidad del tratamiento secuencial con teriparatide y denosumab en la osteoporosis de alto riesgo: nuestra experiencia asistencial / Benefits of sequential treatment of high risk osteoporosis with teripartide and denosumab: our experience

El tratamiento de las formas graves de osteoporosis representa un desafío en la práctica asistencial. Reportamos tres pacientes con formas graves de osteoporosis tratadas en el Instituto de Diagnóstico e Investigaciones Metabólicas con un esquema secuencial de teriparatide 20 µg/día durante 18 meses, seguidos de 12 meses de denosumab 60 mg semestral. Luego de 18 meses de tratamiento con teriparatide la densidad mineral ósea en columna aumentó 5,86±1,01% y en cuello femoral 1,92±3,10%; al finalizar los doce meses de tratamiento con denosumab se constató un aumento total en columna de 10,45±1,70% y en cuello femoral 9,28±3,86%. El tratamiento con teriparatide se acompañó de un aumento en los niveles plasmáticos de telopéptidos del colágeno óseo (CTX) y en el período de tratamiento con denosumab dichos valores disminuyeron de manera significativa, mostrando el impacto de estos fármacos sobre el remodelado óseo. Concluimos que el tratamiento secuencial con teriparatide y denosumab en dosis convencionales resultó beneficioso en las tres pacientes tratadas. Sería de utilidad ampliar esta experiencia en un trabajo prospectivo. (AU)

High risk osteoporosis treatment is a challenge in daily medical practice. We report three patients that attended our institution with severe osteoporosis who received sequentially teriparatide (20 ug daily) for eighteen months followed by denosumab (60 mg every six months) for twelve months. After teriparatide treatment bone mineral density increased 5.86±1.01% at lumbar spine and 1.92±3.10 % at femoral neck, while after denosumab it continued increasing to reach a total of 10.45±1.70% at lumbar spine and 9.28±3.86% at femoral neck. Teriparatide treatment increased bone resorption evidenced by high serum CTX while after denosumab it fell abruptly, showing the impact of these two drugs on bone turnover. We conclude that sequential treatment with teriparatide and denosumab in approved doses was beneficial for these three patients. Prospective studies are needed. (AU)

Bone health in cerebral palsy and introduction of a novel therapy / A saúde do osso na paralisia cerebral e a introdução de uma nova terapia

ABSTRACT Objective To assess the bone health status of children with cerebral palsy and the therapeutic effect of denosumab in a subgroup of children with cerebral palsy and decreased bone mass. Methods Children with cerebral palsy were evaluated according to their motor disability score (classification system gross motor functions III to V), bone density and bone turnover markers. Dual X-ray energy absorption was used to measure the lumbar spine, and total body, except the head. Thereafter a group of children with cerebral palsy and osteoporosis was treated with denosumab, a fully human monoclonal antibody. Bone turnover markers were measured before and three months after treatment. Results Reduction in bone mineral density was observed, particularly in children with greater impairment evaluated by the motor score. Decreased bone turnover markers were found in a selected group of children three months after exposure to denosumab. Conclusion Bone loss was present in children with significant impairment of motor function, as well as decreased serum levels of bone resorption markers with new forms.

RESUMO Objetivo Avaliar o estado de saúde dos ossos em crianças com paralisia cerebral e o efeito terapêutico do denosumabe em um subgrupo de crianças com paralisia cerebral e redução da massa óssea. Métodos Crianças com paralisia cerebral foram avaliadas de acordo com seu escore de incapacidade motora (sistema de classificação para funções motoras grossas, de III a V), e marcadores de turnover ósseo. Dual de absorção de energia de raios X foi utilizado para medir a coluna lombar e total do corpo menos cabeça. Posteriormente, um grupo de crianças com paralisia cerebral e osteoporose foi tratado com denosumabe, um anticorpo monoclonal totalmente humano. Marcadores de remodelação óssea foram medidos antes e três meses após o tratamento. Resultados Houve uma redução da densidade óssea, particularmente em crianças com maior comprometimento do escore motor; os marcadores de remodelação óssea diminuíram em um grupo selecionado de crianças três meses depois de terem sido expostas ao denosumabe. Conclusão A perda óssea esteve presente em crianças com importante comprometimento das funções motoras, além da redução nos níveis séricos de marcadores de reabsorção óssea com novos tratamentos.

Experimental evidence of pharmacological management of anchorage in Orthodontics: A systematic review

Introduction: Orthodontic anchorage is one of the most challenging aspects of Orthodontics. Preventing undesired movement of teeth could result in safer and less complicated orthodontic treatment. Recently, several reviews have been published about the effects of different molecules on bone physiology and the clinical side effects in Orthodontics. However, the effects of local application of these substances on the rate of orthodontic tooth movement have not been assessed.Objectives: The aim of this research was to analyze the scientific evidence published in the literature about the effects of different molecules on orthodontic anchorage.Methods: The literature was systematically reviewed using PubMed/Medline, Scopus and Cochrane databases from 2000 up to July 31st, 2014. Articles were independently selected by two different researchers based on previously established inclusion and exclusion criteria, with a concordance Kappa index of 0.86. The methodological quality of the reviewed papers was performed.Results: Search strategy identified 270 articles. Twenty-five of them were selected after application of inclusion/exclusion criteria, and only 11 qualified for final analysis. Molecules involved in orthodontic anchorage were divided into three main groups: osteoprotegerin (OPG), bisphosphonates (BPs) and other molecules (OMs).Conclusions: Different drugs are able to alter the bone remodeling cycle, influencing osteoclast function and, therefore, tooth movement. Thus, they could be used in order to provide maximal anchorage while preventing undesired movements. OPG was found the most effective molecule in blocking the action of osteoclasts, thereby reducing undesired movements.

Introdução: a ancoragem ortodôntica é um dos aspectos mais desafiadores da Ortodontia. A prevenção de movimentos dentários indesejados poderia resultar em um tratamento ortodôntico mais seguro e menos complexo. Recentemente, foram publicadas várias revisões de literatura sobre os efeitos de diferentes substâncias na fisiologia do tecido ósseo e os efeitos colaterais clínicos na Ortodontia. Porém, os efeitos da aplicação local dessas substâncias no grau de movimentação dentária ortodôntica não foram avaliados.Objetivos: o objetivo da presente pesquisa foi analisar a evidência científica publicada na literatura sobre os efeitos de diferentes substâncias na ancoragem ortodôntica.Métodos: a literatura foi sistematicamente revisada utilizando-se as bases de dados PubMed/Medline, Scopus e Cochrane, de 2000 a 31 de julho de 2014. Os artigos foram selecionados, de maneira independente, por dois pesquisadores diferentes, tendo como base critérios de inclusão e exclusão previamente estabelecidos, com um índice Kappa de concordância de 0,86. A qualidade metodológica dos artigos revisados foi analisada.Resultados: a estratégia de pesquisa identificou 270 artigos; 25 artigos foram selecionados após a aplicação dos critérios de inclusão e exclusão, mas apenas 11 foram qualificados para a análise final. As substâncias envolvidas na ancoragem ortodôntica foram divididas em três grupos principais: osteoprotegerina (OPG), bisfosfonatos (BFs) e outras substâncias (OSs).Conclusões: diferentes substâncias são capazes de alterar o ciclo de remodelação óssea, influenciando na função dos osteoclastos e, portanto, na movimentação dentária. Sendo assim, essas substâncias podem ser utilizadas para promover o máximo de ancoragem e prevenir movimentos indesejados. A OPG foi a substância mais eficaz no bloqueio da ação dos osteoclastos, reduzindo os movimentos indesejados.