RESUMEN
Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the ß-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr. The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the ß-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis.
Asunto(s)
Tejido Adiposo/metabolismo , Adiposidad , Hormona Folículo Estimulante de Subunidad beta/antagonistas & inhibidores , Termogénesis , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo Beige/efectos de los fármacos , Tejido Adiposo Beige/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Adiposidad/efectos de los fármacos , Animales , Anticuerpos/inmunología , Anticuerpos/farmacología , Dieta Alta en Grasa/efectos adversos , Femenino , Hormona Folículo Estimulante de Subunidad beta/inmunología , Haploinsuficiencia , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/prevención & control , Osteoporosis/tratamiento farmacológico , Ovariectomía , Consumo de Oxígeno/efectos de los fármacos , Receptores de HFE/antagonistas & inhibidores , Receptores de HFE/genética , Receptores de HFE/metabolismo , Termogénesis/efectos de los fármacos , Proteína Desacopladora 1/biosíntesisRESUMEN
A variety of human cancers, including nonsmall cell lung (NSCLC), breast, and colon cancers, are driven by the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Having shown that bisphosphonates, a class of drugs used widely for the therapy of osteoporosis and metastatic bone disease, reduce cancer cell viability by targeting HER1, we explored their potential utility in the prevention and therapy of HER-driven cancers. We show that bisphosphonates inhibit colony formation by HER1(ΔE746-A750)-driven HCC827 NSCLCs and HER1(wt)-expressing MB231 triple negative breast cancers, but not by HER(low)-SW620 colon cancers. In parallel, oral gavage with bisphosphonates of mice xenografted with HCC827 or MB231 cells led to a significant reduction in tumor volume in both treatment and prevention protocols. This result was not seen with mice harboring HER(low) SW620 xenografts. We next explored whether bisphosphonates can serve as adjunctive therapies to tyrosine kinase inhibitors (TKIs), namely gefitinib and erlotinib, and whether the drugs can target TKI-resistant NSCLCs. In silico docking, together with molecular dynamics and anisotropic network modeling, showed that bisphosphonates bind to TKIs within the HER1 kinase domain. As predicted from this combinatorial binding, bisphosphonates enhanced the effects of TKIs in reducing cell viability and driving tumor regression in mice. Impressively, the drugs also overcame erlotinib resistance acquired through the gatekeeper mutation T790M, thus offering an option for TKI-resistant NSCLCs. We suggest that bisphosphonates can potentially be repurposed for the prevention and adjunctive therapy of HER1-driven cancers.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/prevención & control , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/prevención & control , Difosfonatos/farmacología , Receptores ErbB/antagonistas & inhibidores , Animales , Western Blotting , Difosfonatos/uso terapéutico , Reposicionamiento de Medicamentos/métodos , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Ratones , Ratones Endogámicos BALB C , Simulación de Dinámica Molecular , Unión Proteica , Transducción de Señal/efectos de los fármacos , Sales de Tetrazolio , Tiazoles , Ensayo de Tumor de Célula MadreRESUMEN
Bisphosphonates are the most commonly prescribed medicines for osteoporosis and skeletal metastases. The drugs have also been shown to reduce cancer progression, but only in certain patient subgroups, suggesting that there is a molecular entity that mediates bisphosphonate action on tumor cells. Using connectivity mapping, we identified human epidermal growth factor receptors (human EGFR or HER) as a potential new molecular entity for bisphosphonate action. Protein thermal shift and cell-free kinase assays, together with computational modeling, demonstrated that N-containing bisphosphonates directly bind to the kinase domain of HER1/2 to cause a global reduction in downstream signaling. By doing so, the drugs kill lung, breast, and colon cancer cells that are driven by activating mutations or overexpression of HER1. Knocking down HER isoforms thus abrogates cell killing by bisphosphonates, establishing complete HER dependence and ruling out a significant role for other receptor tyrosine kinases or the enzyme farnesyl pyrophosphate synthase. Consistent with this finding, colon cancer cells expressing low levels of HER do not respond to bisphosphonates. The results suggest that bisphosphonates can potentially be repurposed for the prevention and therapy of HER family-driven cancers.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Difosfonatos/farmacología , Receptores ErbB/antagonistas & inhibidores , Modelos Moleculares , Anisotropía , Western Blotting , Línea Celular Tumoral , Cristalografía , Difosfonatos/metabolismo , Receptores ErbB/química , Receptores ErbB/metabolismo , Fluorescencia , Humanos , Simulación de Dinámica Molecular , Unión Proteica , Conformación Proteica , Sales de Tetrazolio , TiazolesRESUMEN
BACKGROUND: The MOTION (Monthly Oral Therapy with Ibandronate for Osteoporosis Intervention) study reported that once-monthly ibandronate was noninferior to once-weekly alendronate in terms of increasing bone mineral density (BMD) at the lumbar spine and total hip over 12 months. On analysis of secondary and exploratory end points in MOTION, which included trochanter and femoral neck BMD, monthly ibandronate was found to be noninferior to weekly alendronate. The coprimary, secondary, and exploratory BMD end points from MOTION have been previously reported. OBJECTIVE: This report presents additional results from the MOTION study, including response rates in terms of lumbar spine and total hip BMD gains above baseline; findings from a comparison of serum concentrations of bone turnover markers; and tolerability analysis, including adverse events that led to withdrawal and gastrointestinal (GI) adverse events. METHODS: MOTION was a 12-month (with 15-day follow-up), randomized, multinational, multicenter, double-blind, double-dummy, parallel-group, noninferiority study in postmenopausal women aged 55 to <85 years with osteoporosis. Patients were randomly assigned to receive 150-mg-monthly oral ibandronate and weekly alendronate-matched placebo, or 70-mg-weekly oral alendronate and monthly ibandronate-matched placebo, for 12 months. At baseline, day 7 of treatment, 3 and 6 months, 6 months + 7 days, and 12 months, serum concentrations of markers of bone resorption (C-telopeptide of the a chain of type 1 collagen [sCTX]) and bone formation (serum N-terminal propeptides of type 1 collagen) were measured in a subset of the total trial population. At baseline and month 12, BMD was measured using dual-energy x-ray absorptiometry. Exploratory analyses of patients whose spine, total hip, and trochanter BMD at 12 months were above baseline (responders) were also performed. RESULTS: A total of 1760 women were enrolled (ibandronate, 887 patients; alendronate, 873). The median changes in the trough concentrations of sCTX were -75.5% with monthly ibandronate and -81.2% with weekly alendronate. The percentage of patients with mean lumbar spine and total hip BMD gains above baseline (responders) were 90% and 87%, respectively, for ibandronate and 92% and 90%, respectively, for alendronate. GI adverse events were reported in Asunto(s)
Alendronato/uso terapéutico
, Conservadores de la Densidad Ósea/uso terapéutico
, Difosfonatos/uso terapéutico
, Osteoporosis Posmenopáusica/tratamiento farmacológico
, Anciano
, Anciano de 80 o más Años
, Alendronato/administración & dosificación
, Alendronato/efectos adversos
, Densidad Ósea/efectos de los fármacos
, Conservadores de la Densidad Ósea/administración & dosificación
, Conservadores de la Densidad Ósea/efectos adversos
, Colágeno Tipo I/sangre
, Difosfonatos/administración & dosificación
, Difosfonatos/efectos adversos
, Método Doble Ciego
, Esquema de Medicación
, Femenino
, Humanos
, Ácido Ibandrónico
, Persona de Mediana Edad
, Péptidos/sangre
, Resultado del Tratamiento
RESUMEN
Recent reports suggest that bone loss begins during late perimenopause at a dramatic rate, even before estrogen levels plummet. During the ensuing 5 years, there is evidence of the beginnings of microarchitectural deterioration, which impacts bone strength and ultimately enhances its propensity to fracture. The diagnosis of osteoporosis based on T-scores alone, or through stratification for a high fracture risk by FRAX, excludes these women who are rapidly losing bone. Because all antiosteoporosis therapies, in particular bisphosphonates, reduce bone loss, we propose aggressive, likely short-term therapy with a goal to reduce bone loss, stabilize bone density, and prevent microarchitectural deterioration.
Asunto(s)
Osteoporosis Posmenopáusica/diagnóstico , Osteoporosis Posmenopáusica/tratamiento farmacológico , Densidad Ósea , Conservadores de la Densidad Ósea/uso terapéutico , Remodelación Ósea , Femenino , Fracturas Espontáneas/etiología , Fracturas Espontáneas/prevención & control , Humanos , Osteoporosis Posmenopáusica/fisiopatología , Perimenopausia , Medición de RiesgoRESUMEN
Despite a clear association between type 2 diabetes (T2D) and fracture risk, the pathogenesis of bone fragility in T2D has not been clearly elucidated. Insulin resistance is the primary defect in T2D. Insulin signalling regulates both bone formation and bone resorption, but whether insulin resistance can affect bone has not been established. On the other hand, evidence exists that bone might play a role in the regulation of glucose metabolism. This article reviews the available experimental and clinical evidence on the interplay between bone and insulin resistance. Interestingly, a bilateral relationship between bone and insulin resistance seems to exist that unites them in a biological partnership.
Asunto(s)
Huesos/fisiología , Resistencia a la Insulina/fisiología , Animales , Densidad Ósea , Resorción Ósea/etiología , Huesos/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulina/metabolismo , Osteocalcina/metabolismoRESUMEN
While initial preclinical studies provide an important starting point for dose selection, they may not provide adequate information to identify the optimal dosage for an extended treatment regimen. Determining the best dose for use in an extended dosing regimen requires ongoing development, illustrated best with the bisphosphonate, ibandronate. As mandated for regulatory purposes, the daily oral regimen of ibandronate was proven effective in significantly reducing the rate of new vertebral fractures assessed prospectively, and nonvertebral fractures in a high-risk population, assessed retrospectively. Extended dosing regimens, namely monthly and quarterly intravenous formulations, were developed subsequently to improve the convenience and enhance persistence, while maintaining or increasing efficacy. The continuing and progressive evolution of data led to the understanding that extension of drug-free interval requires higher annual cumulative skeletal exposures (ACE), which were not simply numerical multipliers of the interval and daily dose. For ibandronate, this led to dose selection for the oral monthly 150 mg (ACE 10.8 mg) and intravenous quarterly 3 mg (ACE 12 mg) formulations that proved superior in increasing bone mineral density (BMD) compared with oral daily 2.5 mg (ACE 5.5 mg) ibandronate. Pooling data from clinical trials with high ACE regimens (monthly and quarterly) led to the evolution of statistical evidence for a reduction in clinical and nonvertebral fractures with ibandronate. The ibandronate story should serve as an important future paradigm for bisphosphonate development.
Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/uso terapéutico , Osteoporosis/tratamiento farmacológico , Administración Oral , Animales , Densidad Ósea , Química Farmacéutica/métodos , Química Farmacéutica/tendencias , Ensayos Clínicos como Asunto , Esquema de Medicación , Diseño de Fármacos , Humanos , Ácido Ibandrónico , Osteoporosis Posmenopáusica/tratamiento farmacológico , Modelos de Riesgos Proporcionales , Factores de TiempoRESUMEN
Here we briefly review our studies that have unraveled an important role for the calcium- and calmodulin-sensitive enzyme calcineurin (CN) in bone remodeling. We find that the genetic deletion of the calcineurin Aalpha isoform results in osteoporosis, which is recapitulated in humans following calcineurin inhibitor therapy widely used after solid organ transplantation. Mechanistically, however, while both calcineurin inhibitors cyclosporine and tacrolimus initially stimulate osteoclastic bone resorption in humans, the predominant feature in the CNAalpha null mouse is a profound reduction in bone formation. We speculate that the so-called "calcineurin inhibitors" may interact with molecules other than calcineurin. The clinical relevance of these observations is explored.
Asunto(s)
Calcineurina/genética , Eliminación de Gen , Remodelación Ósea , Calcineurina/metabolismo , Inhibidores de la Calcineurina , Ciclosporina/farmacología , Homocigoto , Humanos , Inmunosupresores/farmacología , Osteoblastos/metabolismo , Tacrolimus/farmacologíaRESUMEN
Advances in understanding diabetes mellitus (DM) through basic and clinical research have helped clarify and reunify a disease state fragmented into numerous etiologies and subtypes. It is now understood that a common pathophysiology drives the diabetic state throughout its natural history and across its varied clinical presentations, a pathophysiology involving metabolic insults, oxidative damage, and vicious cycles that aggravate and intensify organ dysfunction and damage. This new understanding of the disease requires that we revisit existing diagnostics and treatment approaches, which were built upon outmoded assumptions. 'The Common Pathophysiologic Origins of Diabetes Mellitus and its Complications Construct' is presented as a more accurate, foundational, and translatable construct of DM that helps make sense of the hitherto ambiguous findings of long-term outcome studies.
Asunto(s)
Complicaciones de la Diabetes/etiología , Diabetes Mellitus Tipo 2/complicaciones , Animales , Complicaciones de la Diabetes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Redes y Vías Metabólicas/fisiología , Modelos Biológicos , Estrés Oxidativo/fisiologíaRESUMEN
Glucocorticoids have been the main agents for preventing organ rejection,but unfortunately they possess serious side effects. Newer immunosuppressive agents have therefore been introduced to overcome these effects and have had a dramatic impact on reducing the incidence of organ rejection, enhancing donor organ acceptance, and hence patient survival posttransplantation. However, calcineurin inhibitors (CIs), such as cyclosporine and tacrolimus, also have serious effects causing rapid and severe bone loss in animal models and humans. The mechanism accounting for this action is unclear at present, but the role of T lymphocyte action via RANKL seems to be of essence in triggering bone loss. The mechanism is complex and in vitro studies often produce results that are opposite to those seen in vivo. In addition to acute, rapid, and severe bone loss (ARSBL), the clinical picture shows an extremely high incidence of fractures at all sites, and depends upon the organ transplanted, preexisting bone disease, interval before transplantation, and the dose and duration of multiple immunosuppressive drugs. Other immune-modifying drugs, such as azathioprine, mycophenolate mofetil, and sirolimus, which are used in conjunction with glucocorticoids and CIs have not been shown to promote bone loss experimentally or clinically. With the exception of glucocorticoids, all of the agents discussed here demand further investigation with regard to their effects on bone health in the clinical setting.
Asunto(s)
Enfermedades Óseas/inmunología , Factores Inmunológicos/uso terapéutico , Inmunosupresores/farmacología , Resorción Ósea/inmunología , Huesos/efectos de los fármacos , Huesos/inmunología , Humanos , Osteoporosis/inmunología , Linfocitos T/inmunologíaRESUMEN
A previously validated kinetic-pharmacodynamic model was applied to changes in a marker of bone resorption (serum C-telopeptide cross-links of type I collagen [sCTX]) using data from a large-scale clinical trial of ibandronate (Monthly Oral iBandronate In LadiEs [MOBILE]). The model showed rapid and significant suppression of sCTX compared to baseline with daily and monthly ibandronate, and gradual recovery of sCTX levels between monthly doses. This modeled, post-dose oscillatory pattern of sCTX paralleled significant increases in BMD and was associated with an acceptable safety profile for patients in MOBILE, suggesting that the between-dose recovery of sCTX does not negatively affect the efficacy of once-monthly ibandronate.
Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Colágeno Tipo I/sangre , Difosfonatos/uso terapéutico , Osteoporosis Posmenopáusica/tratamiento farmacológico , Péptidos/sangre , Biomarcadores/sangre , Femenino , Humanos , Ácido Ibandrónico , Monitoreo Fisiológico , Osteoporosis Posmenopáusica/sangreRESUMEN
BACKGROUND: Osteoporosis is a common chronic condition in elderly women and is associated with decreased bone strength and an increased risk for fractures. As the incidence of osteoporotic fractures continues to rise, it is important to identify the most effective therapies for reducing patients' risk of fracture. OBJECTIVE: This article reviews the medication classes commonly used for treating osteoporosis and the efficacy, tolerability, and drug-interaction potential of specific medications. The evidence for the use of combination therapies is summarized, as are the agents under investigation. METHODS: Relevant articles were identified through a search of MEDLINE (August 1985-August 2005) using the terms osteoporosis, postmenopausal, fracture, and efficacy combined with drug therapy, calcium, vitamin D, estrogen, progesterone, selective estrogen modulators, calcitonin, strontium ranelate, bisphosphonates, alendronate, risedronate, ibandronate, pamidronate, parathyroid hormone, combination therapy, and zoledronic acid. The identified articles were reviewed for suitability, with priority given to meta-analyses. RESULTS: Among the therapeutic options for the treatment of osteoporosis, the bisphosphonates appear to provide the greatest antiresorptive efficacy, with some bisphosphonates providing 7% to 8% increases in bone mineral density and 60% to 70% decreases in markers of bone resorption. Bisphosphonates also may reduce the incidence of new vertebral fractures by 50% to 52%. CONCLUSIONS: Bisphosphonates are currently the first choice for the treatment of osteoporosis. Use of intermittent regimens of the newer bisphosphonates appears to be a promising alternative to administration of daily or weekly treatment.
Asunto(s)
Osteoporosis Posmenopáusica/tratamiento farmacológico , Anabolizantes/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Calcio/uso terapéutico , Difosfonatos/uso terapéutico , Quimioterapia Combinada , Terapia de Reemplazo de Estrógeno , Femenino , Humanos , Infusiones Intravenosas , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Vitamina D/uso terapéuticoRESUMEN
CONTEXT: Proton pump inhibitors (PPIs) may interfere with calcium absorption through induction of hypochlorhydria but they also may reduce bone resorption through inhibition of osteoclastic vacuolar proton pumps. OBJECTIVE: To determine the association between PPI therapy and risk of hip fracture. DESIGN, SETTING, AND PATIENTS: A nested case-control study was conducted using the General Practice Research Database (1987-2003), which contains information on patients in the United Kingdom. The study cohort consisted of users of PPI therapy and nonusers of acid suppression drugs who were older than 50 years. Cases included all patients with an incident hip fracture. Controls were selected using incidence density sampling, matched for sex, index date, year of birth, and both calendar period and duration of up-to-standard follow-up before the index date. For comparison purposes, a similar nested case-control analysis for histamine 2 receptor antagonists was performed. MAIN OUTCOME MEASURE: The risk of hip fractures associated with PPI use. RESULTS: There were 13,556 hip fracture cases and 135,386 controls. The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59). The risk of hip fracture was significantly increased among patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI, 1.80-3.90; P<.001). The strength of the association increased with increasing duration of PPI therapy (AOR for 1 year, 1.22 [95% CI, 1.15-1.30]; 2 years, 1.41 [95% CI, 1.28-1.56]; 3 years, 1.54 [95% CI, 1.37-1.73]; and 4 years, 1.59 [95% CI, 1.39-1.80]; P<.001 for all comparisons). CONCLUSION: Long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.
Asunto(s)
Antiulcerosos/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Reflujo Gastroesofágico/tratamiento farmacológico , Fracturas de Cadera/epidemiología , Inhibidores de la Bomba de Protones , Anciano , Anciano de 80 o más Años , Antiulcerosos/administración & dosificación , Resorción Ósea , Estudios de Casos y Controles , Inhibidores Enzimáticos/administración & dosificación , Femenino , Antagonistas de los Receptores H2 de la Histamina/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , RiesgoRESUMEN
The current classification system presents challenges to the diagnosis and treatment of patients with diabetes mellitus (DM), in part due to its conflicting and confounding definitions of type 1 DM, type 2 DM, and latent autoimmune diabetes of adults (LADA). The current schema also lacks a foundation that readily incorporates advances in our understanding of the disease and its treatment. For appropriate and coherent therapy, we propose an alternate classification system. The ß-cell-centric classification of DM is a new approach that obviates the inherent and unintended confusions of the current system. The ß-cell-centric model presupposes that all DM originates from a final common denominator-the abnormal pancreatic ß-cell. It recognizes that interactions between genetically predisposed ß-cells with a number of factors, including insulin resistance (IR), susceptibility to environmental influences, and immune dysregulation/inflammation, lead to the range of hyperglycemic phenotypes within the spectrum of DM. Individually or in concert, and often self-perpetuating, these factors contribute to ß-cell stress, dysfunction, or loss through at least 11 distinct pathways. Available, yet underutilized, treatments provide rational choices for personalized therapies that target the individual mediating pathways of hyperglycemia at work in any given patient, without the risk of drug-related hypoglycemia or weight gain or imposing further burden on the ß-cells. This article issues an urgent call for the review of the current DM classification system toward the consensus on a new, more useful system.
Asunto(s)
Diabetes Mellitus Tipo 1/clasificación , Diabetes Mellitus Tipo 2/clasificación , Células Secretoras de Insulina/patología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Resistencia a la InsulinaRESUMEN
Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. Properties related to bone strength include rate of bone turnover, bone mineral density, geometry, microarchitecture, and mean degree of mineralization. These properties (with or without bone density) are sometimes collectively referred to as bone quality. Antiresorptive agents may reduce fracture risk by several separate but interrelated effects on these individual properties. For example, antiresorptive agents have been reported to reduce bone turnover, stabilize or increase bone density, preserve or improve microarchitecture, reduce the number or size of resorption sites, and improve mineralization. Although changes in bone architecture and mineralization are not currently measurable in clinical practice, bone turnover is assessed easily in vivo and affects the other bone properties. Moreover, antiresorptive therapies that produce larger decreases in bone turnover markers together with larger increases in bone mineral density are associated with greater reductions in fracture risk, especially at sites primarily composed of cortical bone such as the hip. Reductions in fracture risk are the most convincing evidence of good bone quality. Data from well-designed randomized clinical trials with up to 10 years of continuous antiresorptive therapy have shown that certain antiresorptive agents effectively reduce fracture risk and (together with extensive preclinical data) suggest no deleterious effects on bone quality.
Asunto(s)
Densidad Ósea , Remodelación Ósea , Fracturas Óseas/fisiopatología , Densidad Ósea/fisiología , Remodelación Ósea/efectos de los fármacos , Remodelación Ósea/fisiología , Huesos/patología , Calcificación Fisiológica/fisiología , Toma de Decisiones , Fracturas Óseas/patología , Humanos , Menopausia/fisiología , Osteoporosis/tratamiento farmacológico , Osteoporosis/patología , Osteoporosis/fisiopatologíaRESUMEN
CD38 is an ectocyclase that converts NAD+ to the Ca2+-releasing second messenger cyclic ADP-ribose (cADPr). Here we report that in addition to CD38 ecto-catalysis, intracellularly expressed CD38 may catalyze NAD+-->cADPr conversion to cause cytosolic Ca2+ release. High levels of CD38 were found in the plasma membranes, endoplasmic reticulum, and nuclear membranes of osteoblastic MC3T3-E1 cells. More important, intracellular CD38 was colocalized with target ryanodine receptors. The cyclase also converted a NAD+ surrogate, NGD+, to its fluorescent product, cGDPr (Km approximately 5.13 microM). NAD+ also triggered a cytosolic Ca2+ signal. Similar results were obtained with NIH3T3 cells, which overexpressed a CD38-EGFP fusion protein. The Delta(-49)-CD38-EGFP mutant with a deleted amino-terminal tail and transmembrane domain appeared mainly in the mitochondria with an expected loss of its membrane localization, but the NAD+-induced cytosolic Ca2+ signal was preserved. Likewise, Ca2+ release persisted in cells transfected with the Myr-Delta(-49)-CD38-EGFP or Delta(-49)-CD38-EGFP-Fan mutants, both directed to the plasma membrane but in an opposite topology to the full-length CD38-EGFP. Finally, ryanodine inhibited Ca2+ signaling, indicating the downstream activation of ryanodine receptors by cADPr. We conclude that intracellularly expressed CD38 might link cellular NAD+ production to cytosolic Ca2+ signaling.
Asunto(s)
Antígenos CD , Antígenos de Diferenciación/fisiología , Señalización del Calcio , NAD+ Nucleosidasa/fisiología , NAD/farmacología , Células 3T3 , ADP-Ribosil Ciclasa , ADP-Ribosil Ciclasa 1 , Animales , Antígenos de Diferenciación/análisis , Antígenos de Diferenciación/genética , Línea Celular , Membrana Celular/enzimología , Núcleo Celular/enzimología , Citosol/metabolismo , Retículo Endoplásmico/enzimología , Proteínas Fluorescentes Verdes , Indicadores y Reactivos/análisis , Membranas Intracelulares/enzimología , Proteínas Luminiscentes/análisis , Proteínas Luminiscentes/genética , Glicoproteínas de Membrana , Ratones , Microscopía Confocal , Modelos Biológicos , Mutación , NAD+ Nucleosidasa/análisis , NAD+ Nucleosidasa/genética , Osteoblastos/enzimología , Proteínas Recombinantes de Fusión/análisis , Canal Liberador de Calcio Receptor de Rianodina/análisisRESUMEN
We describe a constellation of bone diseases characterized by the common feature of acute, rapid, and severe bone loss accompanied by dramatic fracture rates. These disorders are poorly recognized, resulting mainly from systemic diseases, frailty, immobilization, and immunosuppressive drugs, such as glucocorticoids and the calcineurin inhibitors. The opportunity to prevent or treat fractures is commonly missed because they are often not detected. Ideally, patients need to be identified early and preventative therapy initiated promptly to avoid the rapid bone loss and fractures. The most effective therapy at present seems to be the bisphosphonates, particularly when bone resorption is predominant. However, more severe forms of bone loss that result from an osteoblastic defect and reduced bone formation may benefit potentially more from newer anabolic agents, such as recombinant human parathyroid hormone (rhPTH).
Asunto(s)
Enfermedades Óseas Metabólicas/clasificación , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/terapia , Terapia de Reemplazo de Estrógeno , Femenino , Glucocorticoides/antagonistas & inhibidores , Humanos , Osteoporosis/inducido químicamente , Osteoporosis/etiología , Complicaciones Posoperatorias , Trasplante/efectos adversosRESUMEN
Ibandronate is a potent nitrogen-containing bisphosphonate. It has a strong affinity for bone mineral and potently inhibits osteoclast-mediated bone resorption. Ibandronate is effective for the treatment of hypercalcemia of malignancy, metastatic bone disease, postmenopausal osteoporosis, corticosteroid-induced osteoporosis, and Paget's disease. Oral ibandronate is rapidly absorbed (t(max) < 1 hour), with a low bioavailability (0.63%) that is further reduced (by up to 90%) in the presence of food. Ibandronate has a wide therapeutic index and is not metabolized and, therefore, has a low potential for drug interactions. Given its metabolic stability, ibandronate is eliminated from the blood by partitioning into bone (40%-50%) and through renal clearance (CL(R) approximately 60 mL/min). The CL(R) of ibandronate is linearly related to creatinine clearance. The sequestration of ibandronate in bone (V(D) > 90 L) results in a multiphasic elimination (t((1/2)) range approximately 10-60 hours), characterized by the slow release of ibandronate from the bone compartment. The potency of ibandronate and its sequestration into bone allow ibandronate to be developed as oral and intravenous injection formulations that can be administered with convenient extended between-dose intervals.
Asunto(s)
Difosfonatos/efectos adversos , Difosfonatos/farmacología , Difosfonatos/farmacocinética , Disponibilidad Biológica , Biotransformación , Difosfonatos/administración & dosificación , Difosfonatos/química , Relación Dosis-Respuesta a Droga , Humanos , Ácido Ibandrónico , Inyecciones Intravenosas , Absorción Intestinal , Osteoporosis/tratamiento farmacológico , Distribución TisularRESUMEN
Oral bisphosphonate dosing schedules have evolved from the original daily regimens to weekly (alendronate and risedronate) and monthly (risedronate and ibandronate) regimens. Intravenous (i.v.) bisphosphonates are administered less frequently-quarterly ibandronate injection and yearly zoledronic acid i.v. infusion. Comparative fracture efficacy among BP options is increasingly a focus of debate. The approved daily oral BPs and annual zoledronic acid infusion demonstrated vertebral fracture prevention in clinical trials; however, nonvertebral fracture prevention results varied. Nondaily regimens of licensed agents (except for zoledronic acid) were approved via "bridging trials", which compared changes in bone mineral density and bone turnover markers with the approved daily regimen and generally collected fractures as adverse events. Head-to-head antifracture efficacy trials directly comparing available BPs are unlikely because the required sample sizes, durations and costs would be prohibitively large. Observational studies and the concept of annual cumulative exposure, used recently to evaluate the efficacy of nondaily ibandronate regimens, provide alternative methods to compare BP efficacy. At this time, the available trial and meta-analysis evidence supports effective reduction of vertebral fractures and NVFs with all approved BP regimens. This article presents a comprehensive review of the key efficacy data for currently available BPs, including their nondaily regimens, to assist clinicians in assessing treatment options for NVF prevention.