Asunto(s)

Estética Dental , Sociedades Odontológicas , Europa (Continente) , Humanos

RESUMEN

Pharmaceutical innovation is increasingly risky, costly and at times inefficient, which has led to a decline in industry productivity. Despite the increased investment in R&D by the industry, the number of new molecular entities achieving marketing authorization is not increasing. Novel approaches to clinical development and trial design could have a key role in overcoming some of these challenges by improving efficiency and reducing attrition rates. The effectiveness of clinical development can be improved by adopting a more integrated model that increases flexibility and maximizes the use of accumulated knowledge. Central to this model of drug development are novel tools, including modelling and simulation, Bayesian methodologies, and adaptive designs, such as seamless adaptive designs and sample-size re-estimation methods. Applications of these methodologies to early- and late-stage drug development are described with some specific examples, along with advantages, challenges, and barriers to implementation. Because they are so flexible, these new trial designs require significant statistical analyses, simulations and logistical considerations to verify their operating characteristics, and therefore tend to require more time for the planning and protocol development phase. Greater awareness of the distinct advantages of innovative designs by regulators and sponsors are crucial to increasing the adoption of these modern tools.

Asunto(s)

Ensayos Clínicos como Asunto/estadística & datos numéricos , Farmacología Clínica/tendencias , Proyectos de Investigación/tendencias , Teorema de Bayes , Humanos , Modelos Estadísticos , Farmacología Clínica/estadística & datos numéricos , Proyectos de Investigación/estadística & datos numéricos , Tamaño de la Muestra

RESUMEN

OBJECTIVES: To evaluate the relationship between drug copayment level and persistence and the implications of non-persistence on healthcare utilization and costs among adult hypertension patients receiving single-pill combination (SPC) therapy. METHODS: Patients initiated on SPC with angiotensin receptor blocker (ARB) + calcium channel blocker, ARB + hydrochlorothiazide, or angiotensin-converting enzyme inhibitors + hydrochlorothiazide were identified in the MarketScan Database (2006-2008). Multivariate models were used to assess copayment level as a predictor of 3-month and 6-month persistence. Three levels of copayment were considered (low: ≤$5, medium: $5-30, high: >$30 for <90-day supply; low: ≤$10, medium: $10-60, high: >$60 for ≥90-day supply). Separate models examined the implications of persistence during the first 3 months on outcomes during the subsequent 3-month period, including utilization and changes in healthcare costs from baseline. National- and state-level outcomes were analyzed. RESULTS: Analyses of 381,661 patients found significantly lower 3-month and 6-month persistence to therapies with high copayments. Relative to high-copayment drugs, risk-adjusted odds ratios at 3 months were 1.29 (95% confidence interval [CI]: 1.26, 1.32) and 1.27 (95% CI: 1.24, 1.30) for low- and medium-copayment medications, respectively. The strength of the association between copayment and persistence varied across states. Non-persistent patients had significantly more cardiovascular-related hospitalizations (incidence rate ratio [IRR] = 1.36; 95% CI: 1.30, 1.43) and emergency room (ER) visits (IRR = 1.51; 95% CI: 1.43, 1.59) than persistent patients. Non-persistence was associated with significantly larger increases in all-cause medical services cost by $277 (95% CI: $225, $329), but lesser increases in prescription costs by -$81 (95% CI: -$85, -$76). LIMITATIONS: Limitations include the possibility of confounding from unobserved factors (e.g., patient income), and the lack of blood pressure data. CONCLUSIONS: High copayment for SPC therapy was associated with significantly worse persistence among hypertensive patients. Persistence was associated with substantially lower frequencies of hospitalizations and ER visits and net healthcare cost savings.

Asunto(s)

Antihipertensivos/uso terapéutico , Seguro de Costos Compartidos , Combinación de Medicamentos , Servicios de Salud/estadística & datos numéricos , Hipertensión/tratamiento farmacológico , Cooperación del Paciente , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Oportunidad Relativa

RESUMEN

BACKGROUND: Evidence is currently equivocal on the added benefits of dual blockade of the renin-angiotensin-aldosterone system with the combination of either an ACE inhibitor (ACEI) plus an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) or aliskiren, the first-in-class direct renin inhibitor, plus an ARB. OBJECTIVE: To compare the compliance, persistence, healthcare resource utilization, and healthcare costs associated with aliskiren plus ARB versus ACEI plus ARB combination therapies among adult patients diagnosed with hypertension. METHODS: Patients (aged ≥18 years) initiated on either combination therapy were identified in the MarketScan Commercial and Medicare Supplemental Databases (1 July 2007 to 30 June 2008). The ARB components considered were candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. The ACEI components included benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril. Outcomes measured during the 6-month study period included the proportion of days covered (PDC), treatment discontinuation, healthcare resource utilization, and changes in healthcare costs (study period minus 6-month baseline values). Risk-adjusted differences in outcomes between treatments and associated 95% confidence intervals (CIs) were estimated using multivariate regression models, controlling for demographics, region, co-morbidities, prescription drug use, and resource utilization during the baseline period. RESULTS: Adjusting for baseline characteristics, aliskiren plus ARB patients (n = 1395) demonstrated a significantly higher PDC (67.0% vs 54.3%; difference 12.7%; 95% CI 10.6, 14.7) and a significantly lower discontinuation rate (50.4% vs 68.6%; odds ratio 0.46; 95% CI 0.40, 0.54) than ACEI plus ARB patients (n = 16 507). Aliskiren plus ARB patients had significantly fewer all-cause hospitalizations (adjusted incidence rate ratio [IRR] 0.73; 95% CI 0.61, 0.86) and significantly fewer all-cause emergency room (ER) visits (adjusted IRR 0.72; 95% CI 0.61, 0.85) than ACEI plus ARB patients. Compared with ACEI plus ARB therapy, aliskiren plus ARB therapy was associated with significantly larger increases in prescription costs by $US264 post therapy initiation (95% CI 153, 375), but with non-significantly greater reductions in total healthcare costs by -$583 (95% CI -2409, 1242).[2008 values]. CONCLUSION: In adult hypertensive patients, treatment with aliskiren plus ARB was associated with significantly better compliance/persistence and fewer hospitalizations and ER visits compared with ACEI plus ARB therapy. Reductions in total healthcare costs were non-significantly different between patients treated with aliskiren plus ARB versus ACEI plus ARB, despite the increased prescription costs associated with aliskiren plus ARB therapy.

Asunto(s)

Amidas/administración & dosificación , Antagonistas de Receptores de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Fumaratos/administración & dosificación , Costos de la Atención en Salud , Recursos en Salud/estadística & datos numéricos , Hipertensión/tratamiento farmacológico , Cumplimiento de la Medicación , Adulto , Anciano , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

OBJECTIVE: To compare blood pressure (BP) goal achievement associated with the use of valsartan-based single pill combinations (SPCs) vs. angiotensin II receptor blocker (ARB)-based free combinations (FCs) among adult hypertension patients. RESEARCH DESIGN AND METHODS: Data were collected from physician-administered chart review of adult hypertension patients in the South Central region. All patients had uncontrolled BP before initiating one of the index therapies (SPCs: valsartan/amlodipine or valsartan/hydrochlorothiazide [HCTZ], FCs: ARB + calcium channel blocker [CCB] or ARB + HCTZ) between 07/2008 and 06/2009. Up to three BP measures were collected starting from 45 days after the therapy initiation. BP goal was <130/80 mmHg for patients with diabetes, chronic renal disease or coronary heart disease; or <140/90 mmHg for patients without these comorbidities. The Kaplan-Meier method with log-rank test was used to compare rates of BP goal achievement associated with valsartan-based SPCs vs. ARB-based FCs over time. Cox proportional hazard models were used to estimate the likelihood of BP goal achievement associated with SPCs vs. FCs, controlling for demographics, baseline BP, hypertension history, comorbidities, prior and concurrent use of anti-hypertensive medications, and physician specialty. RESULTS: The study included 812 patients: 414 on valsartan-based SPCs (209 on valsartan/amlodipine and 205 on valsartan/HCTZ) and 398 on ARB-based FCs (200 on ARB + CCB and 198 on ARB + HCTZ). The ARBs in the FC group included valsartan, losartan, olmesartan, telmisartan, irbesartan and candesartan. In the ARB FC group, the most commonly used ARB and CCB were valsartan (29.1%) and amlodipine (81.5%), respectively. During the observation period (81 days for valsartan SPC patients and 90 days for ARB FC patients), 65.9% of valsartan SPC patients and 55.8% of the ARB FC patients achieved BP goal. Over time, the rates of BP goal achievement were consistently higher among valsartan SPC vs. ARB FC patients (p = 0.01): 31.1% vs. 28.9% and 69.1% vs. 59.2% at month 3 and 6 after therapy initiation, respectively. Cox regression confirmed that valsartan SPC patients were more likely to achieve BP goal (HR = 1.22; p = 0.05). A similar trend was observed in the subgroup analyses comparing SPC of valsartan/amlodipine vs. FCs of ARB + CCB and SPC of valsartan/HCTZ vs. FCs of ARB + HCTZ. LIMITATIONS: Non-randomization of treatments, limited generalizability, and no records of BP measures within 45 days. CONCLUSIONS: Patients using valsartan-based SPCs were significantly more likely to achieve BP goal than those treated with ARB-based FCs in the real-world clinical practice in the South Central region. The significance was achieved at two-sided alpha = 0.05.

Asunto(s)

Antagonistas de Receptores de Angiotensina/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Tetrazoles/administración & dosificación , Valina/análogos & derivados , Adulto , Anciano , Antihipertensivos/administración & dosificación , Presión Sanguínea/fisiología , Comorbilidad , Regulación hacia Abajo/efectos de los fármacos , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Hipertensión/epidemiología , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Comprimidos , Resultado del Tratamiento , Valina/administración & dosificación , Valsartán

RESUMEN

OBJECTIVES: To compare compliance/persistence, health care resource utilization, and costs associated with single-pill combination (SPC) vs. free-combination (FC) therapies among adult hypertension patients at the national and state level. Combination therapies with angiotensin receptor blocker (ARB) + calcium channel blocker, ARB + hydrochlorothiazide, and angiotensin-converting enzyme inhibitor + hydrochlorothiazide were evaluated. METHODS: Patients initiated on SPC or FC were identified in the MarketScan Database (2006-2008). Multivariate regression models were used to compare the health care outcomes of SPC vs. FC use during the 6-month study period. National- and state-level outcomes were analyzed and reported. Compliance was measured by medication possession ratio (MPR), and persistence was assessed based on treatment discontinuation (i.e., a lapse in therapy exceeding 30 days). Utilization and cost outcomes included frequencies of inpatient and emergency room (ER) visits and changes in health care costs from baseline. RESULTS: Adjusting for baseline characteristics, SPC patients (N = 382,476) demonstrated significantly higher MPR than FC patients (N = 197,375) (difference = 11.6%; 95% confidence interval [CI]: 11.4%, 11.7%). SPC patients had fewer all-cause hospitalizations (adjusted incidence rate ratio [IRR] = 0.77; 95% CI: 0.75, 0.79) and ER visits (adjusted IRR = 0.87; 95% CI: 0.86, 0.89) than FC patients. Results for cardiovascular-related utilization were similar to all-cause results. Compared to FC, SPC patients showed significantly greater reductions post-therapy initiation in all-cause medical costs by -$208 (95% CI: -$302, -$114), but larger increases in hypertension-related prescription costs by $53 (95% CI: $51, $55). State-level results were generally consistent in magnitude and direction for comparisons of compliance and utilization, with greater regional variation in costs. Limitations include the possibility of residual confounding from factors not observable in claims. CONCLUSION: SPC use was associated with significantly better compliance/persistence and fewer hospitalizations and ER visits than FC in hypertensive patients at the national level and in almost all states. Larger reductions in medical costs with SPC use more than offset higher drug costs within most states.

Asunto(s)

Antihipertensivos/administración & dosificación , Atención a la Salud/estadística & datos numéricos , Hipertensión/tratamiento farmacológico , Cooperación del Paciente/estadística & datos numéricos , Adulto , Anciano , Antihipertensivos/economía , Combinación de Medicamentos , Quimioterapia Combinada/economía , Femenino , Costos de la Atención en Salud , Hospitalización/economía , Hospitalización/estadística & datos numéricos , Humanos , Hipertensión/economía , Hipertensión/psicología , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Aceptación de la Atención de Salud/estadística & datos numéricos , Comprimidos , Estados Unidos

RESUMEN

Declining pharmaceutical industry productivity is well recognized by drug developers, regulatory authorities and patient groups. A key part of the problem is that clinical studies are increasingly expensive, driven by the rising costs of conducting Phase II and III trials. It is therefore crucial to ensure that these phases of drug development are conducted more efficiently and cost-effectively, and that attrition rates are reduced. In this article, we argue that moving from the traditional clinical development approach based on sequential, distinct phases towards a more integrated view that uses adaptive design tools to increase flexibility and maximize the use of accumulated knowledge could have an important role in achieving these goals. Applications and examples of the use of these tools--such as Bayesian methodologies--in early- and late-stage drug development are discussed, as well as the advantages, challenges and barriers to their more widespread implementation.

Asunto(s)

Ensayos Clínicos Fase II como Asunto/métodos , Ensayos Clínicos Fase III como Asunto/métodos , Diseño de Fármacos , Teorema de Bayes , Ensayos Clínicos Fase II como Asunto/economía , Ensayos Clínicos Fase III como Asunto/economía , Análisis Costo-Beneficio , Industria Farmacéutica/economía , Industria Farmacéutica/organización & administración , Eficiencia Organizacional , Humanos

Asunto(s)

Aprobación de Drogas/legislación & jurisprudencia , Regulación Gubernamental , Guías como Asunto , United States Food and Drug Administration/legislación & jurisprudencia , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/normas , Aprobación de Drogas/métodos , Aprobación de Drogas/estadística & datos numéricos , Humanos , Comunicación Interdisciplinaria , Aplicación de Nuevas Drogas en Investigación/legislación & jurisprudencia , Aplicación de Nuevas Drogas en Investigación/métodos , Aplicación de Nuevas Drogas en Investigación/estadística & datos numéricos , Legislación de Medicamentos/normas , Estados Unidos , United States Food and Drug Administration/organización & administración , United States Food and Drug Administration/normas

RESUMEN

BACKGROUND: Mortality is increased after a hip fracture, and strategies that improve outcomes are needed. METHODS: In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. RESULTS: The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with zoledronic acid (P=0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P=0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS: An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival. (ClinicalTrials.gov number, NCT00046254 [ClinicalTrials.gov].).

Asunto(s)

Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/uso terapéutico , Fracturas Óseas/prevención & control , Fracturas de Cadera/mortalidad , Imidazoles/uso terapéutico , Anciano , Anciano de 80 o más Años , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/efectos adversos , Calcio/uso terapéutico , Difosfonatos/administración & dosificación , Difosfonatos/efectos adversos , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Fracturas Óseas/epidemiología , Fracturas de Cadera/tratamiento farmacológico , Fracturas de Cadera/cirugía , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Vitamina D/uso terapéutico , Ácido Zoledrónico

RESUMEN

Recent advances in the understanding of the epidemiology of osteoporosis suggest that certain parts of the current European guidelines for the registration of drugs in osteoporosis might be no longer substantiated. The object of this review is to provide the European regulatory authorities with an evidence-based working document providing suggestions for the revision of the "Note for guidance for the approval of drugs to be used in postmenopausal osteoporosis" (CPMP/EWP/552/95). Following an extensive review of the literature (1990-2004), the Group for the Respect of Ethics and Excellence in Science (GREES) organized a workshop including European regulators, academic scientists and representatives of the pharmaceutical industry. The outcomes of this meeting reflect the personal views of those who attended and should not, in any case, be seen as an official position paper of any regulatory agency. The group identified a certain number of points that deserve discussion. They mainly relate to the nature of the indication being granted to new chemical entities (treatment of osteoporosis in women at high risk of fracture instead of prevention and treatment of osteoporosis), the requirements of showing an anti-fracture efficacy on all or on major nonvertebral fractures (instead of the hip), the duration of pivotal trials (2 years instead of 3) and the possibility of considering bridging studies for new routes of administration, new doses or new regimens of previously approved drugs. The group also recommends that an indication could be granted for the treatment of osteoporosis in males on the basis of a placebo-controlled study, with bone mineral density changes after 1 year as the primary endpoint, for medications approved in the treatment of osteoporosis in women at high risk of fractures.

Asunto(s)

Conservadores de la Densidad Ósea/uso terapéutico , Aprobación de Drogas/legislación & jurisprudencia , Osteoporosis/tratamiento farmacológico , Densidad Ósea/efectos de los fármacos , Femenino , Fracturas Óseas/etiología , Fracturas Óseas/prevención & control , Humanos , Legislación de Medicamentos , Masculino , Osteoporosis/complicaciones , Osteoporosis Posmenopáusica/complicaciones , Osteoporosis Posmenopáusica/tratamiento farmacológico , Proyectos de Investigación/legislación & jurisprudencia

RESUMEN

BACKGROUND: The cardiovascular (CV) safety of non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors has been the subject of considerable debate. OBJECTIVE: The objective of this study was to determine the risk of CV events with lumiracoxib by meta-analysis of all completed, randomized controlled trials (RCTs) of > or =1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis. METHODS: The Novartis Lumiracoxib Clinical Trial Database, which includes all clinical studies conducted to date with lumiracoxib, was reviewed. Data were extracted from RCTs of > or =1 week and up to 1 year in duration, the maximum study duration; 34,668 patients were included in standard and cumulative meta-analyses. Twenty-two RCTs of lumiracoxib 100 to 1200 mg daily were identified; 22,781 patients were included in 1-year trials. Mean age of the patients was 61.5 years and 74% were female. More than 50% of the patients in these studies had hypertension at baseline and 6% had diabetes. Parameters analyzed were the Antiplatelet Trialists' Collaboration (APTC) composite CV end point of myocardial infarction (MI), stroke (ischemic and hemorrhagic), and CV death; MI alone; and stroke alone. Twenty-one of the 22 RCTs have been published. RESULTS: For all 3 parameters, relative risk (RR) was calculated versus non-naproxen NSAIDs, naproxen, and placebo. The results were as follows: for the APTC end point versus non-naproxen NSAIDs: RR 0.83, 95% CI, 0.46-1.51; versus naproxen: RR 1.49, 95% CI, 0.94-2.36; versus placebo: RR 1.08, 95% CI, 0.41-2.86; for MI alone versus non-naproxen NSAIDs: RR 0.80, 95% CI, 0.28-2.25; versus naproxen: RR 1.69, 95% CI, 0.82-3.48; versus placebo: RR 1.27, 95% CI, 0.25-6.56; and for stroke alone versus non-naproxen NSAIDs: RR 0.91, 95% CI, 0.35-2.35; versus naproxen: RR 1.42, 95% CI, 0.70-2.91; versus placebo: RR 0.59, 95% CI, 0.13-2.74. Cumulative meta-analyses of lumiracoxib versus all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen) did not find any significant differences in APTC, MI alone, or stroke alone. CONCLUSION: This meta-analysis of 34,668 patients receiving > or =1 week and up to 1 year of treatment found no evidence that lumiracoxib was associated with a significant increase in CV risk compared with naproxen, placebo, or all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen).

Asunto(s)

Antiinflamatorios no Esteroideos , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Cardiovasculares/inducido químicamente , Inhibidores de la Ciclooxigenasa 2 , Compuestos Orgánicos , Osteoartritis/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Bases de Datos Factuales , Diclofenaco/análogos & derivados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos Orgánicos/efectos adversos , Compuestos Orgánicos/uso terapéutico

RESUMEN

OBJECTIVES: The Group for the Respect and Excellence in Science (GREES) has reviewed and updated their recommendations for clinical trials to evaluate the efficacy and safety of new chemical entities to be used in the treatment and prevention of glucocorticoid-induced osteoporosis (GIOP). METHODS: Consensus discussion of the committee. RESULTS: With the exception of steroid use posttransplantation, there is no need to differentiate between underlying diseases. Prevention and treatment for GIOP are dependent on exposure to glucocorticoids rather than T-scores as in postmenopausal osteoporosis (PMO). If fracture data are obtained for PMO, it need not be repeated for GIOP, relying instead on bone mineral density (BMD) trials of at least 1 year. GREES recommends several changes in the previous guidance for GIOP. The committee saw no need to repeat preclinical studies if those have been previously done to assure bone quality in PMO. Similarly, phase I and phase II trials, if careful dose selection has been done for PMO, should not be repeated. The "prevention" and "treatment" claims should remain. Since the most recent evidence suggests significant increase in fracture risk for daily doses of prednisone of 5 mg/day or equivalent, clinical trials should concentrate on patients receiving at least this daily dosage. The emergence of bisphosphonates as the reference treatment, together with the rapid bone loss and high fracture incidence in glucocorticoid users, necessitates recommending a noninferiority trial design with lumbar spine BMD as the primary endpoint after 1 year. CONCLUSIONS: Registration of new chemical entities to be used in the management of GIOP should be granted, based on a 1-year noninferiority trial, using BMD as primary outcome and alendronate or risedronate as comparator. Demonstration of antifracture efficacy should have been previously demonstrated in PMO.

Asunto(s)

Ensayos Clínicos como Asunto , Glucocorticoides/efectos adversos , Directrices para la Planificación en Salud , Osteoporosis , Enfermedades Reumáticas/tratamiento farmacológico , Humanos , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control

RESUMEN

UNLABELLED: We used data from the Fracture Intervention Trial to assess the relationship change in bone turnover after 1 year of alendronate or placebo treatment and subsequent hip, non-spine, and spine fracture risk among 6186 postmenopausal women. In the alendronate group (n = 3105), greater reductions in one or more biochemical marker were associated with a lower risk of fracture. INTRODUCTION: There are few data on the relationship between short-term change in biochemical markers of bone turnover and non-spine fracture risk among bisphosphonate-treated women, and the clinical use of such measurements is unknown. MATERIALS AND METHODS: We measured biochemical markers of bone turnover (bone-specific alkaline phosphatase [bone ALP], intact N-terminal propeptide of type I collagen, and C-terminal crosslinked telopeptide of type 1 collagen) and BMD of the spine and hip at baseline and after 1 year of alendronate or placebo. During a mean follow-up of 3.6 years, 72 hip, 786 non-spine, and 336 vertebral fractures were documented. RESULTS AND CONCLUSIONS: Each 1 SD reduction in 1-year change in bone ALP was associated with fewer spine (odds ratio = 0.74; CI: 0.63, 0.87), non-spine (relative hazard [RH] = 0.89; CI: 0.78, 1.00; p < 0.050), and hip fractures (RH = 0.61; CI: 0.46, 0.78). Alendronate-treated women with at least a 30% reduction in bone ALP had a lower risk of non-spine (RH = 0.72; CI: 0.55, 0.92) and hip fractures (RH = 0.26; CI: 0.08, 0.83) relative to those with reductions <30%. We conclude that greater reductions in bone turnover with alendronate therapy are associated with fewer hip, non-spine, and vertebral fractures, and the effect is at least as strong as that observed with 1-year change in BMD.

Asunto(s)

Alendronato/uso terapéutico , Huesos/metabolismo , Fracturas Óseas/prevención & control , Anciano , Anciano de 80 o más Años , Alendronato/farmacología , Fosfatasa Alcalina/sangre , Biomarcadores/sangre , Densidad Ósea/efectos de los fármacos , Huesos/efectos de los fármacos , Huesos/enzimología , Colágeno/sangre , Colágeno Tipo I , Método Doble Ciego , Femenino , Fracturas de Cadera/epidemiología , Fracturas de Cadera/prevención & control , Humanos , Modelos Logísticos , Persona de Mediana Edad , Selección de Paciente , Huesos Pélvicos/química , Fragmentos de Péptidos/sangre , Péptidos/sangre , Procolágeno/sangre , Factores de Riesgo , Fracturas de la Columna Vertebral/prevención & control , Columna Vertebral/química , Resultado del Tratamiento

RESUMEN

Treatment of acute renal failure (ARF) would be enhanced by identification of factors that accelerate renal recovery from injury. Parathyroid hormone-related protein (PTHrP) and hepatocyte growth factor (HGF) have been shown to stimulate proliferation in proximal nephron-derived cells. For studying the pathophysiologic roles and therapeutic potential of these two factors in ARF, transgenic mice overexpressing PTHrP or HGF in the proximal tubule under the direction of the gamma-glutamyl transpeptidase-I promoter were developed. These mice display (1) abundant expression of the respective transgenes in the kidney; (2) similar PTH type I receptor and HGF receptor (c-met) expression levels in the proximal tubule compared with control littermates; and (3) normal renal morphology, function, and tubule cell proliferation under basal conditions. However, in contrast to control mice, when acute ischemic renal injury was induced, renal function rapidly and dramatically recovered in HGF-overexpressing mice. In addition, 48 h after ischemia, HGF-overexpressing transgenic mice displayed a fourfold increase in tubule cell proliferation and a threefold decrease in apoptotic tubule cell death compared with control mice. In contrast, PTHrP-overexpressing mice responded to either ischemic or folic acid-induced renal damage similarly to control mice. These studies demonstrate that overexpression of PTHrP in the proximal nephron of mice does not seem to provide protection against acute renal injury. In marked contrast, HGF overexpression results in dramatic protection from ischemia-induced ARF, without inducing any apparent alteration in the physiology of the kidney under normal conditions. These studies suggest that HGF, when targeted specifically to the proximal tubule, may have therapeutic potential in providing protection against ischemia-induced renal failure.

Asunto(s)

Lesión Renal Aguda/prevención & control , Factor de Crecimiento de Hepatocito/administración & dosificación , Riñón/irrigación sanguínea , Proteína Relacionada con la Hormona Paratiroidea/administración & dosificación , Daño por Reperfusión/prevención & control , Animales , Regulación de la Expresión Génica , Factor de Crecimiento de Hepatocito/biosíntesis , Túbulos Renales Proximales/metabolismo , Ratones , Ratones Transgénicos , Proteína Relacionada con la Hormona Paratiroidea/biosíntesis

RESUMEN

OBJECTIVE: To evaluate the efficacy and safety of alendronate 35 mg once weekly compared with alendronate 5 mg daily in the prevention of osteoporosis. METHODS: We compared the efficacy and safety of treatment with alendronate 35 mg once weekly (n = 362) and alendronate 5 mg daily (n = 361) in a 1-year, double-blind, multicenter study of postmenopausal women (6 months or greater), aged 40-70 years, with lumbar spine and femoral neck bone mineral density T-scores between -2.5 and 1. The primary efficacy end point was the comparability of lumbar spine bone mineral density increases, defined by strict prespecified criteria. RESULTS: Mean increases in lumbar spine bone mineral density at 12 months were equivalent (difference between the alendronate 35-mg once-weekly group and the alendronate 5-mg daily group [90% confidence interval] at month 12 was -0.3% [-0.6, 0.1], well within the prespecified bounds of +/-1.0%). Bone mineral density increases at other skeletal sites and effects on bone turnover were also virtually identical for the two dosing regimens. Both treatment regimens were well tolerated, and the larger weekly unit dose was not associated with an increased frequency of upper gastrointestinal events. CONCLUSION: Alendronate 35 mg once weekly is therapeutically equivalent to alendronate 5 mg daily and provides patients with greater dosing convenience, in addition to the proven efficacy of alendronate and good tolerability.

Asunto(s)

Alendronato/administración & dosificación , Difosfonatos/administración & dosificación , Osteoporosis Posmenopáusica/prevención & control , Absorciometría de Fotón , Administración Oral , Adulto , Anciano , Densidad Ósea , Método Doble Ciego , Esquema de Medicación , Inglaterra , Femenino , Fémur , Cadera , Humanos , Vértebras Lumbares , Michigan , Persona de Mediana Edad , New Jersey , Nueva Zelanda , Sudáfrica , Resultado del Tratamiento