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1.
J Nanobiotechnology ; 19(1): 83, 2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33766057

RESUMEN

BACKGROUND: Chemokine therapy with C-C motif chemokine ligand 25 (CCL25) is currently under investigation as a promising approach to treat articular cartilage degeneration. We developed a delayed release mechanism based on Poly (lactic-co-glycolic acid) (PLGA) microparticle encapsulation for intraarticular injections to ensure prolonged release of therapeutic dosages. However, CCL25 plays an important role in immune cell regulation and inflammatory processes like T-cell homing and chronic tissue inflammation. Therefore, the potential of CCL25 to activate immune cells must be assessed more thoroughly before further translation into clinical practice. The aim of this study was to evaluate the reaction of different immune cell subsets upon stimulation with different dosages of CCL25 in comparison to CCL25 released from PLGA particles. RESULTS: Immune cell subsets were treated for up to 5 days with CCL25 and subsequently analyzed regarding their cytokine secretion, surface marker expression, polarization, and migratory behavior. The CCL25 receptor C-C chemokine receptor type 9 (CCR9) was expressed to a different extent on all immune cell subsets. Direct stimulation of peripheral blood mononuclear cells (PBMCs) with high dosages of CCL25 resulted in strong increases in the secretion of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-1ß (IL-1ß), tumor-necrosis-factor-α (TNF-α) and interferon-γ (IFN-γ), upregulation of human leukocyte antigen-DR (HLA-DR) on monocytes and CD4+ T-cells, as well as immune cell migration along a CCL25 gradient. Immune cell stimulation with the supernatants from CCL25 loaded PLGA microparticles caused moderate increases in MCP-1, IL-8, and IL-1ß levels, but no changes in surface marker expression or migration. Both CCL25-loaded and unloaded PLGA microparticles induced an increase in IL-8 and MCP-1 release in PBMCs and macrophages, and a slight shift of the surface marker profile towards the direction of M2-macrophage polarization. CONCLUSIONS: While supernatants of CCL25 loaded PLGA microparticles did not provoke strong inflammatory reactions, direct stimulation with CCL25 shows the critical potential to induce global inflammatory activation of human leukocytes at certain concentrations. These findings underline the importance of a safe and reliable release system in a therapeutic setup. Failure of the delivery system could result in strong local and systemic inflammatory reactions that could potentially negate the benefits of chemokine therapy.


Asunto(s)
Quimiocinas CC/farmacología , Quimiocinas CC/uso terapéutico , Preparaciones de Acción Retardada/farmacología , Preparaciones de Acción Retardada/uso terapéutico , Inflamación/tratamiento farmacológico , Quimiocina CCL2/metabolismo , Quimiocinas/farmacología , Quimiocinas/uso terapéutico , Humanos , Interferón gamma , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Leucocitos Mononucleares , Ligandos , Macrófagos/metabolismo , Monocitos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Receptores CCR/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
2.
Z Rheumatol ; 75(5): 459-65, 2016 Jun.
Artículo en Alemán | MEDLINE | ID: mdl-27117306

RESUMEN

BACKGROUND: Osteoporosis in men is an important public health problem with more than 1 million cases in Germany. Although osteoporotic fractures have a much higher mortality in men than in women, male patients are still underdiagnosed and undertreated. OBJECTIVE: Epidemiology of male osteoporosis and current treatment situation, pathophysiological aspects at the hormonal level, risk factors, diagnostic work-up and therapeutic options. MATERIAL AND METHODS: Overview of data concerning male osteoporosis, recommendations for diagnostic work-up and presentation of the study situation on pharmaceutical therapies. RESULTS: As risk factors for osteoporosis are present in 50-70 % of male patients, a detailed patient history is necessary for assessment of the risk factors. Radiological imaging of the spine is primarily recommended to identify individuals with prevalent vertebral fractures, as approximately 10 % of males above the age of 50 years have suffered a vertebral fracture. Laboratory testing of relevant parameters helps to rule out other metabolic bone diseases. In Germany, specific medications available for the treatment of male osteoporosis comprise the active vitamin D analogue alfacalcidol, the oral bisphosphonates alendronate and risedronate, the intravenous biphosphonate zoledronic acid, the anti- receptor activator of NF-κB ligand (RANKL) antibody denosumab, which can be given as intravenous injection and strontium ranelate, a drug with a complex mode of action. Teriparatide, a recombinant form of the 34 N-terminal amino acid sequence of parathyroid hormone is the only anabolic agent approved for male osteoporosis. CONCLUSION: Osteoporosis in men is increasingly being recognized as an important public health problem and affected patients need to be adequately diagnosed and treated. Nowadays, a broad spectrum of well-proven therapeutic options with different modes of action allow individual treatment strategies for male osteoporosis patients.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Terapia de Reemplazo de Hormonas/estadística & datos numéricos , Osteoporosis/tratamiento farmacológico , Osteoporosis/epidemiología , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/terapia , Anciano , Anciano de 80 o más Años , Causalidad , Comorbilidad , Medicina Basada en la Evidencia , Alemania/epidemiología , Humanos , Incidencia , Masculino , Salud del Hombre/estadística & datos numéricos , Persona de Mediana Edad , Factores de Riesgo , Resultado del Tratamiento
3.
Osteoporos Int ; 26(6): 1667-71, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25868510

RESUMEN

Osteoporosis accounts for about 3 % of total European health-care spending. The low proportion of costs for the pharmacological prevention of osteoporotic fracture means that it is highly cost saving, especially in patient with severe osteoporosis or patients who cannot take certain osteoporosis medications due to issues of contraindications or tolerability. Following recent regulatory changes, strontium ranelate is now indicated in patients with severe osteoporosis for whom treatment with other osteoporosis treatments is not possible, and without contraindications including uncontrolled hypertension, established, current or past history of ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. We review here today's evidence for the safety and efficacy of strontium ranelate. The efficacy of strontium ranelate in patients complying with the new prescribing information (i.e. severe osteoporosis without contraindications) has been explored in a multivariate analysis of clinical trial data, which concluded that the antifracture efficacy of strontium ranelate is maintained in patients with severe osteoporosis without contraindications and also demonstrated how the new target population mitigates risk. Strontium ranelate is therefore an important alternative in today's management of osteoporosis, with a positive benefit-risk balance, provided that the revised indication and contraindications are followed and cardiovascular risk is monitored. The bone community should be reassured that there remain viable alternatives in patients in whom treatment with other agents is not possible and protection against the debilitating effects of fracture is still feasible in patients with severe osteoporosis.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Osteoporosis/tratamiento farmacológico , Tiofenos/uso terapéutico , Conservadores de la Densidad Ósea/efectos adversos , Aprobación de Drogas , Prescripciones de Medicamentos/normas , Humanos , Medición de Riesgo , Tiofenos/efectos adversos , Resultado del Tratamiento
4.
Osteoporos Int ; 25(11): 2507-29, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25023900

RESUMEN

UNLABELLED: This consensus article reviews the diagnosis and treatment of osteoporosis in geriatric populations. Specifically, it reviews the risk assessment and intervention thresholds, the impact of nutritional deficiencies, fall prevention strategies, pharmacological treatments and their safety considerations, the risks of sub-optimal treatment adherence and strategies for its improvement. INTRODUCTION: This consensus article reviews the therapeutic strategies and management options for the treatment of osteoporosis of the oldest old. This vulnerable segment (persons over 80 years of age) stands to gain substantially from effective anti-osteoporosis treatment, but the under-prescription of these treatments is frequent. METHODS: This report is the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores some of the reasons for this and presents the arguments to counter these beliefs. The risk assessment of older individuals is briefly reviewed along with the differences between some intervention guidelines. The current evidence on the impact of nutritional deficiencies (i.e. calcium, protein and vitamin D) is presented, as are strategies to prevent falls. One possible reason for the under-prescription of pharmacological treatments for osteoporosis in the oldest old is the perception that anti-fracture efficacy requires long-term treatment. However, a review of the data shows convincing anti-fracture efficacy already by 12 months. RESULTS: The safety profiles of these pharmacological agents are generally satisfactory in this patient segment provided a few precautions are followed. CONCLUSION: These patients should be considered for particular consultation/follow-up procedures in the effort to convince on the benefits of treatment and to allay fears of adverse drug reactions, since poor adherence is a major problem for the success of a strategy for osteoporosis and limits cost-effectiveness.


Asunto(s)
Osteoporosis/diagnóstico , Osteoporosis/tratamiento farmacológico , Accidentes por Caídas/prevención & control , Anciano de 80 o más Años , Envejecimiento/fisiología , Densidad Ósea/fisiología , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/uso terapéutico , Suplementos Dietéticos , Manejo de la Enfermedad , Humanos , Cumplimiento de la Medicación , Fracturas Osteoporóticas/prevención & control , Vitamina D/uso terapéutico
5.
Rheumatol Int ; 34(5): 727-32, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-23334374

RESUMEN

Almost 50 % of osteoporosis (OP) patients discontinue bisphosphonate (BP) therapy within 1-2 years after the start of their treatment. Denosumab's longer dosing interval with its administration every 6 months (Q6M) as a subcutaneous (sc) injection might result in a better real-life treatment adherence and persistence than weekly or monthly oral BP treatment regimen. The objectives of this open, investigator-initiated, prospective, observational, single-center study were to evaluate adherence with denosumab 60 mg sc every 6 months (Q6M) (Prolia(®)) injections in osteoporotic patients in a routine clinical care setting and to describe whether positive feedback to OP patients based on measured bone mineral density (BMD) increases and good safety profile have an impact on patients' real-life adherence. Results indicate that the rarity of adverse events and reduced dosage frequency together with the consistency of rapid and highly significant increases in BMD already after 6 months of denosumab therapy used as a positive reinforcement during doctor-patient interactions had a significant, positive impact on osteoporotic patient's adherence to continue with the 6-monthly sc denosumab injections.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Conservadores de la Densidad Ósea/administración & dosificación , Densidad Ósea/efectos de los fármacos , Cumplimiento de la Medicación , Osteoporosis/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Conservadores de la Densidad Ósea/efectos adversos , Comunicación , Denosumab , Esquema de Medicación , Retroalimentación , Femenino , Alemania , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Osteoporosis/patología , Satisfacción del Paciente , Relaciones Médico-Paciente , Estudios Prospectivos , Refuerzo en Psicología , Factores de Tiempo , Resultado del Tratamiento
6.
Osteoporos Int ; 24(1): 263-9, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22736069

RESUMEN

UNLABELLED: This study aims to estimate bisphosphonate effectiveness by comparing fracture incidence over time on therapy in glucocorticoid-induced osteoporosis (GIO). From this observational study, alendronate and risedronate decreased clinical vertebral and nonvertebral fractures over time. The effectiveness of each bisphosphonate is consistent with their efficacies demonstrated on surrogate markers in randomized controlled trials (RCTs). INTRODUCTION: This study aims to estimate bisphosphonate effectiveness by comparing fracture incidence over time on therapy with fracture incidence during a short period after starting a therapy. METHODS: The study population was a subgroup of a larger cohort study comprising two cohorts of women aged ≥65 years, prescribed with alendronate or risedronate. Within the two study cohorts, 11,007 women were identified as having received glucocorticoids. Within each cohort, the baseline incidence of clinical fractures at nonvertebral and vertebral sites was defined by the initial 3-month period after starting therapy. Relative to these baseline data, we then compared the fracture incidence during the subsequent 12 months on therapy. RESULTS: The baseline incidence of clinical nonvertebral and vertebral fractures was similar in the alendronate cohort (5.22 and 5.79/100 person-years, respectively) and in the risedronate cohort (5.51 and 5.68/100 person-years, respectively). Relative to the baseline incidence, fracture incidence was significantly lower in the subsequent 12 months in both cohorts of alendronate (33 % lower at nonvertebral sites and 59 % at vertebral sites) and risedronate (28 % lower at nonvertebral sites and 54 % at vertebral sites). CONCLUSION: From this observational study not designed to compare drugs, both alendronate and risedronate decreased clinical vertebral and nonvertebral fractures over time. The reductions observed in fracture incidence, within each cohort, suggest that the effectiveness of each bisphosphonate in clinical practice is consistent with their efficacies demonstrated on surrogate markers in randomized controlled trials.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/uso terapéutico , Glucocorticoides/efectos adversos , Osteoporosis Posmenopáusica/inducido químicamente , Fracturas Osteoporóticas/prevención & control , Administración Oral , Anciano , Alendronato/uso terapéutico , Conservadores de la Densidad Ósea/administración & dosificación , Difosfonatos/administración & dosificación , Ácido Etidrónico/análogos & derivados , Ácido Etidrónico/uso terapéutico , Femenino , Estudios de Seguimiento , Francia/epidemiología , Humanos , Incidencia , Osteoporosis Posmenopáusica/tratamiento farmacológico , Osteoporosis Posmenopáusica/epidemiología , Fracturas Osteoporóticas/inducido químicamente , Fracturas Osteoporóticas/epidemiología , Ácido Risedrónico
7.
Osteoporos Int ; 24(12): 2971-81, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23740422

RESUMEN

UNLABELLED: Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. INTRODUCTION: To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. METHODS: A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 µg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. RESULTS: PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. CONCLUSIONS: Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Glucocorticoides/efectos adversos , Osteogénesis/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Teriparatido/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Fenómenos Biomecánicos/efectos de los fármacos , Fenómenos Biomecánicos/fisiología , Densidad Ósea/efectos de los fármacos , Ácido Etidrónico/análogos & derivados , Ácido Etidrónico/uso terapéutico , Cuello Femoral/fisiopatología , Análisis de Elementos Finitos , Humanos , Vértebras Lumbares/fisiopatología , Masculino , Persona de Mediana Edad , Osteogénesis/fisiología , Osteoporosis/inducido químicamente , Osteoporosis/fisiopatología , Fragmentos de Péptidos/sangre , Procolágeno/sangre , Ácido Risedrónico , Resultado del Tratamiento
8.
Rheumatol Int ; 33(3): 637-43, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22527138

RESUMEN

Due to pleiotropic-synergistic actions on bone, muscle, gut, brain and different other non-skeletal tissues, alfacalcidol is an interesting drug for treating osteoporosis. In studies on glucocorticoid-induced osteoporosis, men have always been treated with calcitriol or this active D-hormone prodrug, but there is no study of male patients only in the literature. The AIM-Trial (Alfacalcidol In Men) is an extension of the control group (n = 158) of our former risedronate study in male osteoporosis (Ringe et al. in Rheumatol Int 29:311-315, 2009). In that study, we treated daily those controls with prevalent vertebral fractures with 1 µg alfacalcidol + 500 mg calcium (group A) and those without prevalent vertebral fractures with 1,000 IU plain vitamin D (Vit. D) + 1,000 mg calcium (group B). Subsequently, we added an additional 56 pairs of patients to these two groups: 28 with and 28 without prevalent vertebral fractures, reaching a total of 214 cases. That means with this design, we are comparing two groups with a different risk at onset. Due to the prevalent vertebral fractures and lower average bone mineral density (BMD) values, there was a higher risk of incident fractures in group A. After 2 years, we found significantly higher increases in lumbar spine BMD (+3.2 vs. +0.8 %) and total hip BMD (+1.9 vs. -0.9 %) in group A and B, respectively. Eighteen incident falls were recorded in the alfacalcidol group and 38 in the group treated with Vit. D (p = 0.041). There were significantly lower rates of patients with new vertebral and non-vertebral fractures in group A than in group B. Back pain was significantly reduced only with alfacalcidol. Concerning the incidence of new non-vertebral fractures, we found that there was a relation to renal function in the two groups. The advantage for alfacalcidol was mainly due to a higher non-vertebral fracture-reducing potency in patients with a creatinine clearance (CrCl) below 60 ml/min (p = 0.0019). There were no serious adverse events (SAE), and the numbers of mild-to-moderate adverse events (AE) were not different between groups. Despite the higher initial fracture risk in the alfacalcidol group, 2-year treatment with this active D-hormone prodrug showed a higher therapeutic efficacy in terms of BMD, falls and fractures. One important advantage of alfacalcidol may be that it is effective even in patients with mild-to-moderate renal insufficiency.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Hidroxicolecalciferoles/uso terapéutico , Osteoporosis/tratamiento farmacológico , Anciano , Densidad Ósea/efectos de los fármacos , Determinación de Punto Final , Humanos , Hidroxicolecalciferoles/efectos adversos , Riñón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Vitamina D/administración & dosificación
9.
Osteoporos Int ; 23(1): 213-21, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21953472

RESUMEN

UNLABELLED: The competitive price of generic bisphosphonates has had a marked effect on practice guidelines, but an increasing body of evidence suggests that they have more limited effectiveness than generally assumed. INTRODUCTION: The purpose of this study is to review the impact of generic bisphosphonates on effectiveness in the treatment of osteoporosis. METHODS: This study is a literature review. RESULTS: A substantial body of evidence indicates that many generic formulations of alendronate are more poorly tolerated than the proprietary preparations which results in significantly poorer adherence and thus effectiveness. Poorer effectiveness may result from faster disintegration times of many generics that increase the likelihood of adherence of particulate matter to the oesophageal mucosa. Unfortunately, market authorisation, based on the bioequivalence of generics with a proprietary formulation, does not take into account the potential concerns about safety. The poor adherence of many generic products has implications for guideline development, cost-effectiveness and impact of treatment on the burden of disease. CONCLUSIONS: The impact of generic bisphosphonates requires formal testing to re-evaluate their role in the management of osteoporosis.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/uso terapéutico , Medicamentos Genéricos/uso terapéutico , Osteoporosis/tratamiento farmacológico , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/economía , Química Farmacéutica , Análisis Costo-Beneficio , Difosfonatos/efectos adversos , Difosfonatos/economía , Costos de los Medicamentos/estadística & datos numéricos , Medicamentos Genéricos/efectos adversos , Medicamentos Genéricos/economía , Humanos , Fracturas Osteoporóticas/prevención & control
10.
Eur Heart J ; 32(17): 2168-78, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21183501

RESUMEN

AIMS: Coxsackievirus B3 (CVB3)-induced myocarditis, initially considered a sole immune-mediated disease, also results from a direct CVB3-mediated injury of the cardiomyocytes. Mesenchymal stem cells (MSCs) have, besides immunomodulatory, also anti-apoptotic features. In view of clinical translation, we first analysed whether MSCs can be infected by CVB3. Next, we explored whether and how MSCs could reduce the direct CVB3-mediated cardiomyocyte injury and viral progeny release, in vitro, in the absence of immune cells. Finally, we investigated whether MSC application could improve murine acute CVB3-induced myocarditis. METHODS AND RESULTS: Phase contrast pictures and MTS viability assay demonstrated that MSCs did not suffer from CVB3 infection 4-12-24-48 h after CVB3 infection. Coxsackievirus B3 RNA copy number decreased in this time frame, suggesting that no CVB3 replication took place. Co-culture of MSCs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis, oxidative stress, intracellular viral particle production, and viral progeny release in a nitric oxide (NO)-dependent manner. Moreover, MSCs required priming via interferon-γ (IFN-γ) to exert their protective effects. In vivo, MSC application improved the contractility and relaxation parameters in CVB3-induced myocarditis, which was paralleled with a reduction in cardiac apoptosis, cardiomyocyte damage, left ventricular tumour necrosis factor-α mRNA expression, and cardiac mononuclear cell activation. Mesenchymal stem cells reduced the CVB3-induced CD4- and CD8- T cell activation in an NO-dependent way and required IFN-γ priming. CONCLUSION: We conclude that MSCs improve murine acute CVB3-induced myocarditis via their anti-apoptotic and immunomodulatory properties, which occur in an NO-dependent manner and require priming via IFN-γ.


Asunto(s)
Infecciones por Coxsackievirus , Enterovirus Humano B , Células Madre Mesenquimatosas/fisiología , Miocarditis/terapia , Animales , Apoptosis/fisiología , Enterovirus Humano B/crecimiento & desarrollo , Humanos , Interferón gamma/farmacología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/virología , Ratones , Ratones Endogámicos C57BL , Miocarditis/fisiopatología , Miocarditis/virología , Óxido Nítrico/biosíntesis , Función Ventricular/fisiología , Replicación Viral/fisiología
11.
MMW Fortschr Med ; 154 Suppl 1: 10-21, 2012 Apr 05.
Artículo en Alemán | MEDLINE | ID: mdl-23427364

RESUMEN

BACKGROUND: The therapeutic strategy for the reduction of fracture risk in osteoporosis should not only aim to increase bone strength, but should also improve muscle function and reduce falls without increasing the risk of significant side effects. Since 2008 a combination therapy of the antiresorptive active bisphosphonatealendronate and the pleiotropic active D-hormone-prodrug alfacalcidol is licensed in Germanyfor treatment of postmenopausal osteoporosis (Tevabone). METHODS: In the review the results of numerous preclinical and clinical studies are reported, showing the efficacy of the combination of alendronate plus alfacalcidol. RESULTS: In preclinical trials with ovariectomized rats the combination has shown a significantly better effect on increased bone turnover in comparison with bisphosphonate monotherapy. Presumably the "oversuppression" of bone remodeling and the resulting risk of reduced microfracture healing, which is known to occur after long-term therapy with bisphosphonates, will be reduced by the combination. Clinical studies have shown better efficacy of the combination in the increase of bone density and reduction of fracture rate (vertebral and non-vertebral fractures). Less falls were reported compared to alendronate plus genuine vitamin D. The reduction of increased parathormone levels by the alendronate plus alfacalcidol combination compared to alendronate alone was proven to increase the responder rate of the alendronate therapy. The potential risks of alendronate-induced hypocalcemia as well as alfacalcidol-induced hypercalcemia or hypercalcuria are reduced due to the contrasting mode of action of both compounds. CONCLUSION: Treatment with the alendronate plus alfacalcidol combination meets the demands of an optimized therapy for osteoporosis.With the especially developed, self-explanatory combination package better compliance and less dispensing mistakes can be expected.


Asunto(s)
Alendronato/administración & dosificación , Medicina Basada en la Evidencia , Hidroxicolecalciferoles/administración & dosificación , Osteoporosis Posmenopáusica/tratamiento farmacológico , Anciano , Alendronato/efectos adversos , Animales , Densidad Ósea/efectos de los fármacos , Modelos Animales de Enfermedad , Combinación de Medicamentos , Interacciones Farmacológicas , Ácido Etidrónico/administración & dosificación , Ácido Etidrónico/efectos adversos , Ácido Etidrónico/análogos & derivados , Femenino , Humanos , Hidroxicolecalciferoles/efectos adversos , Cuidados a Largo Plazo , Persona de Mediana Edad , Osteoporosis Posmenopáusica/diagnóstico , Fracturas Osteoporóticas/diagnóstico , Fracturas Osteoporóticas/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Ratas , Ácido Risedrónico
12.
MMW Fortschr Med ; 153 Suppl 4: 115-8, 2011 Dec 15.
Artículo en Alemán | MEDLINE | ID: mdl-23964472

RESUMEN

Vitamin D regulates the calcium-phosphate metabolism and thereby plays an important role for the integrity and functioning of bone, muscle and nerves. Studies have shown furthermore an influence on certain types of cancer, diabetes and cardiovascular diseases. Vitamin D is mainly produced by the skin. During exposure to sunlightthe precursor7-dehydrocholesterol is transformed to colecalciferol (vitamin D3). Smaller amounts are supplied by nutrition. In our latitude vitamin D synthesis takes only place during summertime. The vitamin stored in fat tissue in generally is not sufficient for the whole winter period and accordingly insufficiency is very frequent. In a cross-sectional study all over Germany (DeViD, 2007) only about 8% of the population was vitamin D sufficient in spring time.Two prospective studies (2008) proved a correlation between vitamin D supply and overall mortality. An amelioration of vitamin D supply can be achieved either by increasing sun exposure or daily oral intake of 800-2000 IU (=20-50 microg) colecalciferol.


Asunto(s)
Causas de Muerte , Colecalciferol/deficiencia , Deficiencia de Vitamina D/mortalidad , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Colecalciferol/fisiología , Estudios Transversales , Femenino , Alemania , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Medición de Riesgo , Estaciones del Año , Factores Sexuales , Estadística como Asunto , Deficiencia de Vitamina D/fisiopatología , Adulto Joven
13.
Osteoarthritis Cartilage ; 18(4): 581-92, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20060954

RESUMEN

INTRODUCTION: Although the extracellular matrix (ECM) is the functional element in articular cartilage and its degradation is central in the pathogenetic process in osteoarthritis (OA), increasing the knowledge about the cellular OA phenotype is essential. The aim of this study is therefore to provide a more complete picture of the cellular and molecular alterations detected in OA cartilage. MATERIAL AND METHODS: Human articular cartilage biopsies were collected from donors with macroscopical and microscopical signs of OA as well as donors with no previous history of OA and with microscopically intact cartilage. RNA was isolated from the biopsies and subjected to whole genome microarray analysis. Important results from the microarray analysis were verified using real-time PCR and immunohistochemistry. RESULTS: Our results reveal several new candidate genes not previously associated with OA to display significantly higher expression in OA cartilage than in normal donor cartilage, including genes involved in bone formation (CLEC3B, CDH11, GPNMB, CLEC3A, CHST11, MSX1, MSX2) and genes encoding collagens (COL13A1, COL14A1, COL15A1, COL8A2). DISCUSSION: This study is the first to report a comprehensive gene expression analysis of human OA cartilage compared to control cartilage from donors lacking macroscopical and microscopical signs of OA using recently developed microarrays containing the whole human genome. Our results could broadly confirm previously published data on many characteristic features of OA as well as adding a panel of genes to the list of genes known to be differentially expressed in OA. Elucidation of the phenotypical alterations occurring in OA chondrocytes is important for the development of effective treatments for OA.


Asunto(s)
Cartílago Articular/metabolismo , Perfilación de la Expresión Génica , Osteoartritis/genética , Anciano , Anciano de 80 o más Años , Cartílago Articular/patología , Femenino , Humanos , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Osteoartritis/metabolismo , Fenotipo , Reacción en Cadena de la Polimerasa/métodos , ARN/análisis
14.
Osteoarthritis Cartilage ; 18(11): 1458-66, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20709179

RESUMEN

OBJECTIVE: The microfracture technique activates mesenchymal progenitors that enter the cartilage defect and form cartilage repair tissue. Synovial fluid (SF) has been shown to stimulate the migration of subchondral progenitors. The aim of our study was to determine the chemokine profile of SF from normal, rheumatoid arthritis (RA) and osteoarthritis (OA) donors and evaluate the chemotactic effect of selected chemokines on human subchondral progenitor cells. METHOD: Chemokine levels of SF were analyzed using human chemokine antibody membrane arrays. The chemotactic potential of selected chemokines on human mesenchymal progenitors derived from subchondral cortico-spongious bone was tested using 96-well chemotaxis assays. Chemokine receptor expression of subchondral progenitors was assessed by real-time gene expression analysis and immuno-histochemistry. RESULTS: Chemokine antibody array analysis showed that SF contains a broad range of chemokines. Ten chemokines that showed significantly reduced levels in RA or OA compared to normal SF or robustly high levels in all SF tested were used for further chemotactic analysis. Chemotaxis assays showed that the chemokines MDC/CCL22, CTACK/CCL27, ENA78/CXCL5 and SDF1α/CXCL12 significantly inhibited migration of progenitors, while TECK/CCL25, IP10/CXCL10 and Lymphotactin/XCL1 effectively stimulated cell migration. MCP1/CCL2, Eotaxin2/CCL24 and NAP2/CXCL7 showed no chemotactic effect on subchondral progenitors. Gene expression and immuno-histochemical analysis of corresponding chemokine receptors document presence of low levels of chemokine receptors in subchondral progenitors, with the CXCL10 receptor CXCR3 showing the highest expression level. CONCLUSION: These results suggest that SF contains chemokines that may contribute to the recruitment of human mesenchymal progenitors from the subchondral bone in microfracture.


Asunto(s)
Artritis Reumatoide/inmunología , Quimiocinas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Osteoartritis/inmunología , Líquido Sinovial/inmunología , Biomarcadores/metabolismo , Ensayos de Migración Celular , Quimiocina CXCL10/metabolismo , Quimiocinas C/metabolismo , Quimiocinas CC/metabolismo , Quimiotaxis , Humanos , Inmunohistoquímica
15.
Osteoporos Int ; 21 Suppl 2: S431-6, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20464377

RESUMEN

Osteoporosis is listed by the WHO among the ten most frequent and socio-economically important, chronic diseases of mankind. The term osteoporosis however comprises a number of different pathophysiological conditions and clinical situations of weakened bones with increased risk of fragility fractures. A modern anti-osteoporotic drug should provide qualified study results proving therapeutic efficacy over this broad range of daily clinical appearances of osteoporosis. The decision for treatment in the individual patients depends no longer only on bone mineral density. Today, the major criterion for decision making is the prospective 10-year risk for fractures. Since this risk is calculated on the basis of age, sex, bone mineral density, prevalent fractures, and a number of other contributing risk factors (Kanis et al., Osteoporos Int 12:989-995, 2001; Kanis et al., Osteoporos Int 19:385-397, 2008), it seems to be of interest to have a look whether the fracture-reducing potency of a drug is influenced by these risk factors. The purpose of this review is to analyze whether the fracture-reducing efficacy of strontium ranelate in patients with osteoporosis can be achieved independently of sex, etiology of osteoporosis, and the major diagnostically relevant risk factors.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Osteoporosis/tratamiento farmacológico , Fracturas Osteoporóticas/prevención & control , Tiofenos/uso terapéutico , Índice de Masa Corporal , Femenino , Predisposición Genética a la Enfermedad , Glucocorticoides/efectos adversos , Humanos , Masculino , Fracturas Osteoporóticas/etiología , Factores de Riesgo , Fumar/efectos adversos
16.
Osteoporos Int ; 21(6): 1021-9, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19722103

RESUMEN

SUMMARY: There are differences in the risk profile of patients prescribed alendronate, risedronate, or ibandronate. Observed reductions in fracture incidence over time suggest that the effectiveness of each bisphosphonate in clinical practice has been consistent with their efficacies demonstrated in randomized controlled trials. INTRODUCTION: Observational studies of bisphosphonate effectiveness for fracture prevention are subject to bias from unknown characteristics of baseline fracture risk at the start of therapy. The fracture incidence during the short period after starting a bisphosphonate and before any expected clinical benefit likely reflects baseline fracture risk. Bisphosphonate effectiveness may then be estimated by measuring the change in fracture incidence over time on therapy. METHODS: Administrative billing data were used to follow three cohorts of women aged 65 and older (total n = 210,144) after starting therapy either on alendronate, risedronate, or ibandronate in the USA between market introduction and 2006. Within each cohort, the baseline incidence of clinical fractures at the hip, vertebral, and nonvertebral sites was defined by the initial 3-month period after starting therapy. Relative to these baselines, we then compared the fracture incidence during the subsequent 12 months on therapy. RESULTS: At the start of therapy, the ibandronate cohort was younger and had fewer prior fractures than either the risedronate or alendronate cohorts. Accordingly, the baseline incidence of hip fractures was higher in the risedronate cohort (0.90 per 100 person-years) and in the alendronate cohort (0.77) than in the ibandronate cohort (0.64). Relative to the baseline incidence, fracture incidence was significantly lower in the subsequent 12 months in both cohorts of alendronate (18% lower at hip, 28% at nonvertebral sites, and 57% at vertebral sites) and risedronate (27% lower at hip, 21% at nonvertebral sites, and 54% at vertebral sites). In the ibandronate cohort, the fracture incidence was lower (31%) only at vertebral sites. CONCLUSIONS: Differences in the baseline fracture incidence among the cohorts may reflect differences in the risk profile of patients prescribed each bisphosphonate. The reductions observed in fracture incidence over time within each cohort suggest that the effectiveness of each bisphosphonate in clinical practice has been consistent with their efficacies demonstrated in randomized controlled trials.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/uso terapéutico , Fracturas Osteoporóticas/prevención & control , Factores de Edad , Anciano , Alendronato/uso terapéutico , Métodos Epidemiológicos , Ácido Etidrónico/análogos & derivados , Ácido Etidrónico/uso terapéutico , Femenino , Fracturas de Cadera/epidemiología , Fracturas de Cadera/prevención & control , Humanos , Ácido Ibandrónico , Osteoporosis Posmenopáusica/complicaciones , Osteoporosis Posmenopáusica/tratamiento farmacológico , Osteoporosis Posmenopáusica/epidemiología , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/etiología , Ácido Risedrónico , Estados Unidos/epidemiología
17.
Osteoporos Int ; 20(11): 1895-902, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19296144

RESUMEN

UNLABELLED: Two studies in postmenopausal women with osteoporosis provide information about the efficacy and safety of dosing oral risedronate 5 mg daily at a time other than before breakfast (i.e., 2 h before and 2 h after any food and drink other than plain water). A significant increase in lumbar spine BMD was observed for both treatment regimens in the two studies. However, smaller increases in lumbar spine BMD were observed with flexible dosing versus before-breakfast dosing. Geographic region, compliance, and consistency of dosing time appear to affect the amount of increase in BMD observed with flexible dosing. INTRODUCTION: Two studies in postmenopausal women with osteoporosis provide additional information about the efficacy and safety of dosing oral risedronate 5 mg daily at a time other than before breakfast (i.e., 2 h before and 2 h after any food and drink other than plain water). METHODS: One study, flexible dosing, was a 6-month North American study in 730 patients randomized to before-breakfast dosing or flexible dosing later in the day. A second study, IMPACT, was a large (N = 2382), 1-year multinational study in patients that chose their dosing regimen (before breakfast or later in the day). These studies were used to examine the bone mineral density (BMD) response with different dosing regimens. RESULTS: A significant increase in lumbar spine BMD was observed for both treatment regimens in the two studies. However, in both studies, the flexible dosing group had a smaller increase from baseline compared to the before-breakfast regimen (ratio of flexible dosing to before breakfast: flexible dosing study, 0.52; IMPACT study, 0.75). In addition, a relationship between geographic region and BMD response was observed with flexible dosing in both studies. Patients in the flexible dosing group who had greater dosing compliance (based on the number of times the bottle was opened) and consistency of dosing time (bottle opened within a 1.5-h window) had a greater increase in lumbar spine BMD. CONCLUSION: Results of these two studies demonstrate that overall flexible dosing of risedronate leads to smaller BMD gains compared to before-breakfast dosing. This result may be due to poorer adherence to the flexible dosing instructions that may be more pronounced in patients in certain geographic regions. If patients cannot abide by before-breakfast dosing and flexible dosing is an approved option, one can expect suboptimal BMD results with flexible dosing.


Asunto(s)
Conservadores de la Densidad Ósea/administración & dosificación , Ácido Etidrónico/análogos & derivados , Osteoporosis Posmenopáusica/tratamiento farmacológico , Anciano , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/uso terapéutico , Esquema de Medicación , Ácido Etidrónico/administración & dosificación , Ácido Etidrónico/efectos adversos , Ácido Etidrónico/uso terapéutico , Femenino , Humanos , Vértebras Lumbares/fisiopatología , Persona de Mediana Edad , Osteoporosis Posmenopáusica/fisiopatología , Cooperación del Paciente , Ácido Risedrónico , Método Simple Ciego
18.
Rheumatol Int ; 29(10): 1177-85, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19159932

RESUMEN

There are no general accepted strategies for combined drug treatments in osteoporosis, while in other important chronic diseases combinations of different medications are used as a rule to improve therapeutic results and reduce the risk of adverse events. It is suggested that the success of combined treatments is related to the different modes of action of the respective single therapies. On the other hand it was shown that a strong antiresorptive bisphosphonate is able to blunt at least in part the effects of anabolic parathyroid hormone peptides Calcitriol, the active vitamin D-hormone and its prodrug alfacalcidol lead to pleiotropic effects on bone remodelling (antiresorptive, anabolic and enhancing mineralization) and in addition to effects on other important target tissues (e.g. gut, parathyroid glands, muscle). With active D-analogs significant improvements in the therapeutic outcome of osteoporosis can be achieved by the resulting improvements of bone quality, calcium absorption and risk reduction of falling. The same beneficial effects cannot be achieved with plain vitamin D due to feedback controlled, limited renal activation or insufficient conversion in the elderly with impairment of renal function. Accordingly alfacalcidol, approved as a treatment for different forms of osteoporosis, is besides adoption as a mono-therapy an interesting candidate for combined therapies. There are interesting preclinical trials and clinical pilote studies in the literature proving that a parallel therapy with selectively anti-osteoclastic bisphophonates and pleiotropically acting D-analogs is able to optimize therapeutic results in osteoporosis. In the AAC-Trial (Alfacalcidol-Alendronate-Combined) we studied 90 patients with established osteoporosis (57 women, 33 men) over two years after alternate allocation to three treatment arms (alfacalcidol plus calcium, alendronate plus plain vitamin D and Ca, and alendronate plus alfacalcidol and Ca). During the 2-year-study we observed the significantly highest lumbar spine and hip BMD increases in the combined treatment group (p < 0.001). The number of patients with new vertebral and non-vertebral fractures after 2 years was 9 with alfacalcidol alone, 10 with alfacalcidol and plain vitamin D and 2 in the group receiving alendronate plus alfacalidol (p < 0.02). Furthermore there was a lower rate of falls and an earlier reduction in back pain in the patients treated with the active combination. This trial confirms the demonstrated highly significant advantages of this combined treatment regimen used in the pilote studies. Especially in patients with severe osteoporosis this interesting combination of two substances with complete different mechanisms of action should be taken into consideration.


Asunto(s)
Accidentes por Caídas/prevención & control , Conservadores de la Densidad Ósea/uso terapéutico , Fracturas Óseas/prevención & control , Hidroxicolecalciferoles/uso terapéutico , Anciano , Alendronato/efectos adversos , Alendronato/uso terapéutico , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/efectos adversos , Calcitriol/efectos adversos , Calcitriol/uso terapéutico , Calcio/efectos adversos , Calcio/uso terapéutico , Ensayos Clínicos como Asunto , Difosfonatos/efectos adversos , Difosfonatos/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Glucocorticoides/farmacología , Humanos , Hidroxicolecalciferoles/efectos adversos , Vértebras Lumbares/efectos de los fármacos , Masculino , Metaanálisis como Asunto , Osteoporosis/inducido químicamente , Osteoporosis/clasificación , Osteoporosis/tratamiento farmacológico , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Vitamina D/efectos adversos , Vitamina D/uso terapéutico
20.
Ann Rheum Dis ; 67(6): 741-9, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17921184

RESUMEN

OBJECTIVE: Bone marrow (BM) mesenchymal stem cells (MSCs) are being considered as potential therapeutic agents in various inflammatory autoimmune diseases for their tissue-repair and anti-inflammatory tissue-protective properties. This study investigates the reserves and function, the molecular and proteomic profile and the differentiation potential of BM MSCs in patients with active rheumatoid arthritis (RA). METHODS: We evaluated the frequency of MSCs in the BM mononuclear cell fraction using a limiting dilution assay, the proliferative/clonogenic potential and the capacity of cells to differentiate towards the osteogenic/chondrogenic/adipogenic lineages using appropriate culture conditions. We also assessed the molecular and proteomic characteristics in terms of inflammatory cytokine gene and protein expression, the relative telomere length and the survival characteristics of BM MSCs. RESULTS: MSCs from patients with RA (n = 26) and age- and sex-matched healthy individuals (n = 21) were similar in frequency, differentiation potential, survival, immunophenotypic characteristics, and protein profile. Patient MSCs, however, had impaired clonogenic and proliferative potential in association with premature telomere length loss. Transcriptome analysis revealed differential expression of genes related to cell adhesion processes and cell cycle progression beyond the G1 phase. Previous treatment with methotrexate, corticosteroids, anti-cytokine and biological agents or other disease-modifying anti-inflammatory drugs did not correlate with the clonogenic and proliferative impairment of BM MSCs. CONCLUSION: In spite of some restrictions related to the impaired clonogenic and proliferative potential, our findings support the use of autologous BM MSCs in RA and may have important implications for the ongoing efforts to repair tissue injury commonly seen in the course of the disease.


Asunto(s)
Artritis Reumatoide/patología , Células de la Médula Ósea/patología , Células Madre Mesenquimatosas/patología , Adulto , Anciano , Análisis de Varianza , Artritis Reumatoide/inmunología , Células de la Médula Ósea/inmunología , Estudios de Casos y Controles , Diferenciación Celular , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Células Clonales , Citocinas/genética , Citocinas/inmunología , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Masculino , Células Madre Mesenquimatosas/inmunología , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Telómero/ultraestructura
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