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Now showing items 17 - 32 of 1148

  • Does mammographic density mediate risk factor associations with breast cancer? An analysis by tumor characteristics.

    Rice, Megan S   Tamimi, Rulla M   Bertrand, Kimberly A   Scott, Christopher G   Jensen, Matthew R   Norman, Aaron D   Visscher, Daniel W   Chen, Yunn-Yi   Brandt, Kathleen R   Couch, Fergus J   Shepherd, John A   Fan, Bo   Wu, Fang-Fang   Ma, Lin   Collins, Laura C   Cummings, Steven R   Kerlikowske, Karla   Vachon, Celine M  

    BACKGROUND: Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics.; METHODS: Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case-control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER-), progesterone receptor (PR+/PR-), and HER2 (HER2+/HER2-). Analyses were conducted separately in pre- and postmenopausal women.; RESULTS: Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated=3D11-27%, p=E2=89=A40.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+, PR+, and HER2- breast cancer; percent MD partially mediated these associations (percent mediated=E2=89=A531%, p=E2=89=A40.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+breast cancer (percent mediated=3D16%, p=E2=89=A40.05).; CONCLUSION: Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.=20
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  • Accelerating the Search for Interventions Aimed at Expanding the Health Span in Humans: The Role of Epidemiology

    Newman, Anne B   Kritchevsky, Stephen B   Guralnik, Jack M   Cummings, Steven R   Salive, Marcel   Kuchel, George A   Schrack, Jennifer   Morris, Martha Clare   Weir, David   Baccarelli, Andrea   Murabito, Joanne M   Ben-Shlomo, Yoav   Espeland, Mark A   Kirkland, James   Melzer, David   Ferrucci, Luigi   Le Couteur, David  

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  • Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

    Arking, Dan E   Pulit, Sara L   Crotti, Lia   van der Harst, Pim   Munroe, Patricia B   Koopmann, Tamara T   Sotoodehnia, Nona   Rossin, Elizabeth J   Morley, Michael   Wang, Xinchen   Johnson, Andrew D   Lundby, Alicia   Gudbjartsson, Daniel F   Noseworthy, Peter A   Eijgelsheim, Mark   Bradford, Yuki   Tarasov, Kirill V   Dorr, Marcus   Muller-Nurasyid, Martina   Lahtinen, Annukka M   Nolte, Ilja M   Smith, Albert Vernon   Bis, Joshua C   Isaacs, Aaron   Newhouse, Stephen J   Evans, Daniel S   Post, Wendy S   Waggott, Daryl   Lyytikainen, Leo-Pekka   Hicks, Andrew A   Eisele, Lewin   Ellinghaus, David   Hayward, Caroline   Navarro, Pau   Ulivi, Sheila   Tanaka, Toshiko   Tester, David J   Chatel, Stephanie   Gustafsson, Stefan   Kumari, Meena   Morris, Richard W   Naluai, Asa T   Padmanabhan, Sandosh   Kluttig, Alexander   Strohmer, Bernhard   Panayiotou, Andrie G   Torres, Maria   Knoflach, Michael   Hubacek, Jaroslav A   Slowikowski, Kamil   Raychaudhuri, Soumya   Kumar, Runjun D   Harris, Tamara B   Launer, Lenore J   Shuldiner, Alan R   Alonso, Alvaro   Bader, Joel S   Ehret, Georg   Huang, Hailiang   Kao, W H Linda   Strait, James B   Macfarlane, Peter W   Brown, Morris   Caulfield, Mark J   Samani, Nilesh J   Kronenberg, Florian   Willeit, Johann   Smith, J Gustav   Greiser, Karin H   Meyer Zu Schwabedissen, Henriette   Werdan, Karl   Carella, Massimo   Zelante, Leopoldo   Heckbert, Susan R   Psaty, Bruce M   Rotter, Jerome I   Kolcic, Ivana   Polasek, Ozren   Wright, Alan F   Griffin, Maura   Daly, Mark J   Arnar, David O   Holm, Hilma   Thorsteinsdottir, Unnur   Denny, Joshua C   Roden, Dan M   Zuvich, Rebecca L   Emilsson, Valur   Plump, Andrew S   Larson, Martin G   O'Donnell, Christopher J   Yin, Xiaoyan   Bobbo, Marco   D'Adamo, Adamo P   Iorio, Annamaria   Sinagra, Gianfranco   Carracedo, Angel   Cummings, Steven R   Nalls, Michael A   Jula, Antti   Kontula, Kimmo K   Marjamaa, Annukka   Oikarinen, Lasse   Perola, Markus   Porthan, Kimmo   Erbel, Raimund   Hoffmann, Per   Jockel, Karl-Heinz   Kalsch, Hagen   Nothen, Markus M   den Hoed, Marcel   Loos, Ruth J F   Thelle, Dag S   Gieger, Christian   Meitinger, Thomas   Perz, Siegfried   Peters, Annette   Prucha, Hanna   Sinner, Moritz F   Waldenberger, Melanie   de Boer, Rudolf A   Franke, Lude   van der Vleuten, Pieter A   Beckmann, Britt Maria   Martens, Eimo   Bardai, Abdennasser   Hofman, Nynke   Wilde, Arthur A M   Behr, Elijah R   Dalageorgou, Chrysoula   Giudicessi, John R   Medeiros-Domingo, Argelia   Barc, Julien   Kyndt, Florence   Probst, Vincent   Ghidoni, Alice   Insolia, Roberto   Hamilton, Robert M   Scherer, Stephen W   Brandimarto, Jeffrey   Margulies, Kenneth   Moravec, Christine E   del Greco M, Fabiola   Fuchsberger, Christian   O'Connell, Jeffrey R   Lee, Wai K   Watt, Graham C M   Campbell, Harry   Wild, Sarah H   El Mokhtari, Nour E   Frey, Norbert   Asselbergs, Folkert W   Mateo Leach, Irene   Navis, Gerjan   van den Berg, Maarten P   van Veldhuisen, Dirk J   Kellis, Manolis   Krijthe, Bouwe P   Franco, Oscar H   Hofman, Albert   Kors, Jan A   Uitterlinden, Andre G   Witteman, Jacqueline C M   Kedenko, Lyudmyla   Lamina, Claudia   Oostra, Ben A   Abecasis, Goncalo R   Lakatta, Edward G   Mulas, Antonella   Orru, Marco   Schlessinger, David   Uda, Manuela   Markus, Marcello R P   Volker, Uwe   Snieder, Harold   Spector, Timothy D   Arnlov, Johan   Lind, Lars   Sundstrom, Johan   Syvanen, Ann-Christine   Kivimaki, Mika   Kahonen, Mika   Mononen, Nina   Raitakari, Olli T   Viikari, Jorma S   Adamkova, Vera   Kiechl, Stefan   Brion, Maria   Nicolaides, Andrew N   Paulweber, Bernhard   Haerting, Johannes   Dominiczak, Anna F   Nyberg, Fredrik   Whincup, Peter H   Hingorani, Aroon D   Schott, Jean-Jacques   Bezzina, Connie R   Ingelsson, Erik   Ferrucci, Luigi   Gasparini, Paolo   Wilson, James F   Rudan, Igor   Franke, Andre   Muhleisen, Thomas W   Pramstaller, Peter P   Lehtimaki, Terho J   Paterson, Andrew D   Parsa, Afshin   Liu, Yongmei   van Duijn, Cornelia M   Siscovick, David S   Gudnason, Vilmundur   Jamshidi, Yalda   Salomaa, Veikko   Felix, Stephan B   Sanna, Serena   Ritchie, Marylyn D   Stricker, Bruno H   Stefansson, Kari   Boyer, Laurie A   Cappola, Thomas P   Olsen, Jesper V   Lage, Kasper   Schwartz, Peter J   Kaab, Stefan   Chakravarti, Aravinda   Ackerman, Michael J   Pfeufer, Arne   de Bakker, Paul I W   Newton-Cheh, Christopher  

    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. =20
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  • Proximal femoral structure and the prediction of hip fracture in men: a large prospective study using QCT.

    Black, Dennis M   Bouxsein, Mary L   Marshall, Lynn M   Cummings, Steven R   Lang, Thomas F   Cauley, Jane A   Ensrud, Kristine E   Nielson, Carrie M   Orwoll, Eric S  

    The structure of the femoral neck contributes to hip strength, but the relationship of specific structural features of the hip to hip fracture risk is unclear. The objective of this study is to determine the contribution of structural features and volumetric density of both trabecular and cortical bone in the proximal femur to the prediction of hip fracture in older men. Baseline QCT scans of the hip were obtained in 3347 men >or=65 yr of age enrolled in the Osteoporotic Fractures in Men Study (MrOS). All men were followed prospectively for an average of 5.5 yr. Areal BMD (aBMD) by DXA was also assessed. We determined the associations between QCT-derived measures of femoral neck structure, volumetric bone density, and hip fracture risk. Forty-two men sustained incident hip fractures during follow-up: an overall rate of 2.3/1000 person-years. Multivariable analyses showed that, among the QCT-derived measures, lower percent cortical volume (hazard ratio [HR] per SD decrease: 3.2; 95% CI: 2.2-4.6), smaller minimal cross-sectional area (HR: 1.6; 95% CI: 1.2-2.1), and lower trabecular BMD (HR: 1.7; 95% CI: 1.2-2.4) were independently related to increased hip fracture risk. Femoral neck areal BMD was also strongly related to hip fracture risk (HR: 4.1; 95% CI: 2.7-6.4). In multivariable models, percent cortical volume and minimum cross-sectional area remained significant predictors of hip fracture risk after adjustment for areal BMD, but overall prediction was not improved by adding QCT parameters to DXA. Specific structural features of the proximal femur were related to an increased risk of hip fracture. Whereas overall hip fracture prediction was not improved relative to aBMD, by adding QCT parameters, these results yield useful information concerning the causation of hip fracture, the evaluation of hip fracture risk, and potential targets for therapeutic intervention.
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  • Methods and reliability of radiographic vertebral fracture detection in older men: the osteoporotic fractures in men study.

    Cawthon, Peggy M   Haslam, Jane   Fullman, Robin   Peters, Katherine W   Black, Dennis   Ensrud, Kristine E   Cummings, Steven R   Orwoll, Eric S   Barrett-Connor, Elizabeth   Marshall, Lynn   Steiger, Peter   Schousboe, John T  

    We describe the methods and reliability of radiographic vertebral fracture assessment in MrOS, a cohort of community dwelling men aged =E2=89=A565yrs. Lateral spine radiographs were obtained at Visit 1 (2000-2) and 4.6years later (Visit 2). Using a workflow tool (SpineAnalyzer, Optasia Medical), a physician reader completed semi-quantitative (SQ) scoring. Prior to SQ scoring, technicians performed "triage" to reduce physician reader workload, whereby clearly normal spine images were eliminated from SQ scoring with all levels assumed to be SQ=3D0 (no fracture, "triage negative"); spine images with any possible fracture or abnormality were passed to the physician reader as "triage positive" images. Using a quality assurance sample of images (n=3D20 participants; 8 with baseline only and 12 with baseline and follow-up images) read multiple times, we calculated intra-reader kappa statistics and percent agreement for SQ scores. A subset of 494 participants' images was read regardless of triage classification to calculate the specificity and sensitivity of triage. Technically adequate images were available for 5958 of 5994 participants at Visit 1, and 4399 of 4423 participants at Visit 2. Triage identified 3215 (53.9%) participants with radiographs that required further evaluation by the physician reader. For prevalent fractures at Visit 1 (SQ=E2=89=A51), intra-reader kappa statistics ranged from 0.79 to 0.92; percent agreement ranged from 96.9% to 98.9%; sensitivity of the triage was 96.8% and specificity of triage was 46.3%. In conclusion, SQ scoring had excellent intra-rater reliability in our study. The triage process reduces expert reader workload without hindering the ability to identify vertebral fractures. Copyright =C2=A9 2014. Published by Elsevier Inc.
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  • Inflammatory markers and incident fracture risk in older men and women: the Health Aging and Body Composition Study.

    Cauley, Jane A   Danielson, Michelle E   Boudreau, Robert M   Forrest, Kimberly Yz   Zmuda, Joseph M   Pahor, Marco   Tylavsky, Frances A   Cummings, Steven R   Harris, Tamara B   Newman, Anne B  

    UNLABELLED: The inflammation of aging hypothesis purports that aging is the accumulation of damage, which results, in part, from chronic activation of inflammation process. We tested this hypothesis in relationship to fractures in 2985 men and women enrolled in the Health ABC study. Results showed that subjects with the greatest number of inflammatory markers have the highest risk of fracture.INTRODUCTION: Cytokines play major roles in regulating bone remodeling in the bone microenvironment, but their relationship to fractures is uncertain.MATERIALS AND METHODS: The study population includes 2985 well-functioning white and black women and men (42%, black; 51%, women) 70-79 yr of age enrolled in the Health Aging and Body Composition Study. Inflammatory markers were measured in frozen serum using standardized assays. We measured interleukin (IL-6), TNFalpha, C-reactive protein (CRP), and soluble receptors (IL-2 sR, IL-6 sR, TNF sR1and TNF sR2).Cytokine-soluble receptors were measured in a subset (n = 1430). Total hip BMD was measured by DXA. During 5.8 +/- 1.6 yr of 95% complete follow-up, incident fractures were confirmed in 268 subjects. The risk of fracture was compared among subjects with the highest inflammatory markers (quartile 4) versus lower levels (quartiles 1, 2, and 3) using proportional hazard models.RESULTS AND CONCLUSIONS: Subjects who fractured were more likely to be white and female. Baseline markers of inflammation were higher among subjects who subsequently experienced an incident fracture. In multivariate models, the relative risk of fracture (95% CIs) for subjects with the highest inflammatory markers (quartile 4) compared with those with lower inflammatory markers (quartiles 1, 2, and 3) was 1.34 (0.99, 1.82) for CRP; 1.28 (0.95-1.74) for IL-6; 1.28 (0.97-1.70) for TNFalpha; 1.52 (1.04-2.21) for IL-2 sR; 1.33 (0.90-1.96) for IL-6 sR; 1.73 (1.18-2.55) for TNF sR1 and 1.48 (1.01-2.20) for TNF sR2. In subjects with three or more (out of seven) high inflammatory markers, the relative risk of fracture was 2.65 (1.44-4.89) in comparison with subjects with no elevated markers. (p trend = 0.001). We conclude that elevated inflammatory markers are prognostic for fractures, extending the inflammation hypothesis of aging to osteoporotic fractures.
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  • BMD and risk of hip and nonvertebral fractures in older men: a prospective study and comparison with older women.

    Cummings, Steven R   Cawthon, Peggy M   Ensrud, Kristine E   Cauley, Jane A   Fink, Howard A   Orwoll, Eric S  

    UNLABELLED: In a prospective study of 5384 older men, hip BMD was a very strong predictor of hip fracture, much stronger than spine BMD. The relationship between hip BMD and hip fracture risk seemed to be stronger than observed in a large prospective study of women. Hip BMD is an excellent test for predicting fracture risk in men.INTRODUCTION: There have been few studies of the relationship between BMD and risk of fractures in men and none for the association between lumbar spine BMD and risk of hip and nonvertebral fractures. There is also controversy about whether the associations between BMD and risk of fracture are the same in men and women.MATERIALS AND METHODS: We measured proximal femur and lumbar spine BMD in 5384 men, 5384 men, >or= 65 years of age. We compared the results to the very similar cohort of 7871 women >or=65 of age. During 4.4 years of 99% complete follow-up, we validated 317 nonvertebral (59 hip) fractures in men and 1169 nonvertebral (208 hip) fractures in women.RESULTS: Total hip BMD was very strongly associated with risk hip fracture in men (3.2-fold increased risk per sex-specific SD decrease in BMD; 95% CI, 2.4-4.1). The association was stronger than observed in SOF (2.1; 95% CI, 1.8, 2.4; p < 0.001 for interaction). Among the men, lumbar spine BMD was weakly associated with risk of hip fracture (relative risk [RR] per sex-specific SD decrease in BMD: 1.5; 95% CI, 1.2, 2.0). The association between total hip BMD and risk of nonvertebral fractures was somewhat stronger for men (RR = 1.6; 95% CI, 1.5, 1.8) than found for women (p = 0.01 for interaction). The risk of nonvertebral fracture was substantially higher in women than in men for all T scores of hip BMD, regardless of whether sex-specific or female reference values were used.CONCLUSIONS: Hip BMD is strongly associated with risk of nonvertebral, and especially hip fracture, in older men. These associations are at least as strong as in women. As in women, lumbar spine BMD in men is only weakly associated with risk of hip fracture. Regardless of whether sex-specific or female reference values were used, T scores indicated different risks of fractures in men than in women.
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  • Relationship between pretreatment rate of bone loss and bone density response to once-yearly ZOL: HORIZON-PFT extension study.

    Eastell, Richard   Boonen, Steven   Cosman, Felicia   Reid, Ian R   Palermo, Lisa   Cummings, Steven R   Black, Dennis M  

    Several studies have shown that high bone turnover is associated with greater rates of bone loss and greater bone mineral density (BMD) response to antiresorptive therapy in postmenopausal osteoporosis. However, it is not known whether greater rates of bone loss before therapy are associated with greater BMD response to antiresorptive therapy. In the HORIZON-PFT study and its extension, one group of women who were randomized to receive placebo for 3 years (years 1, 2, and 3) were then switched to zoledronic acid (ZOL) 5mg annually for up to three injections (years 4, 5, and 6, P3Z3 arm) (n=3D1223). We measured total hip BMD at baseline, 1, 2, and 3 years on placebo and at 4.5 and 6 years on ZOL. The procollagen type I N-terminal propeptide (PINP) was measured at 3, 4.5, and 6 years. By design, not all subjects were followed for as long as 6 years, so this analysis focused on the results at 4.5 years. Those with the largest loss in total hip BMD on placebo in years 0 to 3 had the largest gain during ZOL (years 3 to 4.5): (r=3D-0.39, p<0.0001). The change in total hip BMD in years 0 to 3 on placebo was related to the serum PINP at the end of the 3-year period (r=3D-0.24, p<0.0001). The change in total hip BMD on ZOL from year 3 to 4.5 was related to the serum PINP at the end of the 3-year period (r=3D0.26, p<0.0001). We conclude that BMD response to ZOL is greater in postmenopausal women who had larger loss before treatment. This association may result from higher bone turnover being associated with both greater bone loss on placebo and greater BMD response to ZOL. =C2=A9 2014 American Society for Bone and Mineral Research.
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  • Joint relative risks for estrogen receptor-positive breast cancer from a clinical model, polygenic risk score, and sex hormones.

    Shieh, Yiwey   Hu, Donglei   Ma, Lin   Huntsman, Scott   Gard, Charlotte C   Leung, Jessica W T   Tice, Jeffrey A   Ziv, Elad   Kerlikowske, Karla   Cummings, Steven R  

    BACKGROUND: Models that predict the risk of estrogen receptor (ER)-positive breast cancers may improve our ability to target chemoprevention. We investigated the contributions of sex hormones to the discrimination of the Breast Cancer Surveillance Consortium (BCSC) risk model and a polygenic risk score comprised of 83 single nucleotide polymorphisms.; METHODS: We conducted a nested case-control study of 110 women with ER-positive breast cancers and 214 matched controls within a mammography screening cohort. Participants were postmenopausal and not on hormonal therapy. The associations of estradiol, estrone, testosterone, and sex hormone binding globulin with ER-positive breast cancer were evaluated using conditional logistic regression. We assessed the individual and combined discrimination of estradiol, the BCSC risk score, and polygenic risk score using the area under the receiver operating characteristic curve (AUROC).; RESULTS: Of the sex hormones assessed, estradiol (OR 3.64, 95% CI 1.64-8.06 for top vs bottom quartile), and to a lesser degree estrone, was most strongly associated with ER-positive breast cancer in unadjusted analysis. The BCSC risk score (OR 1.32, 95% CI 1.00-1.75 per 1% increase) and polygenic risk score (OR 1.58, 95% CI 1.06-2.36 per standard deviation) were also associated with ER-positive cancers. A model containing the BCSC risk score, polygenic risk score, and estradiol levels showed good discrimination for ER-positive cancers (AUROC 0.72, 95% CI 0.65-0.79), representing a significant improvement over the BCSC risk score (AUROC 0.58, 95% CI 0.50-0.65).; CONCLUSION: Adding estradiol and a polygenic risk score to a clinical risk model improves discrimination for postmenopausal ER-positive breast cancers.=20
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  • Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs.

    Cummings, Steven R   Karpf, David B   Harris, Fran   Genant, Harry K   Ensrud, Kristine   LaCroix, Andrea Z   Black, Dennis M  

    PURPOSE: To estimate how much the improvement in bone mass accounts for the reduction in risk of vertebral fracture that has been observed in randomized trials of antiresorptive treatments for osteoporosis.METHODS: After a systematic search, we conducted a meta-analysis of 12 trials to describe the relation between improvement in spine bone mineral density and reduction in risk of vertebral fracture in postmenopausal women. We also used logistic models to estimate the proportion of the reduction in risk of vertebral fracture observed with alendronate in the Fracture Intervention Trial that was due to improvement in bone mineral density.RESULTS: Across the 12 trials, a 1% improvement in spine bone mineral density was associated with a 0.03 decrease (95% confidence interval [CI]: 0.02 to 0.05) in the relative risk (RR) of vertebral fracture. The reductions in risk were greater than predicted from improvement in bone mineral density; for example, the model estimated that treatments predicted to reduce fracture risk by 20% (RR = 0.80), based on improvement in bone mineral density, actually reduce the risk of fracture by about 45% (RR = 0.55). In the Fracture Intervention Trial, improvement in spine bone mineral density explained 16% (95% CI: 11% to 27%) of the reduction in the risk of vertebral fracture with alendronate.CONCLUSION: Improvement in spine bone mineral density during treatment with antiresorptive drugs accounts for a predictable but small part of the observed reduction in the risk of vertebral fracture.
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  • Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial.

    Jamal, Sophie A   Bauer, Douglas C   Ensrud, Kristine E   Cauley, Jane A   Hochberg, Marc   Ishani, Areef   Cummings, Steven R  

    UNLABELLED: To determine if alendronate had differential effects on BMD and fracture by renal function, we performed a secondary data analysis of women participating in the FIT. Alendronate increased BMD and decreased fractures to a similar degree among women with and without reduced renal function. There was no increase in adverse events among women with impaired renal function treated with alendronate. Alendronate is safe and effective among this group of women with reduced renal function.INTRODUCTION: Alendronate is cleared by the kidney and may have sustained effects on bone in subjects with impaired renal function. We hypothesized that, with decreasing renal function, alendronate treatment would result in greater increases in BMD and greater decreases in fractures and that the frequency of adverse events would be increased.MATERIALS AND METHODS: We studied women participating in the Fracture Intervention Trial (FIT), a randomized controlled trial of alendronate or placebo (n = 6458). We estimated baseline creatinine clearance (eGFR) using the Cockcroft Gault Formula.RESULTS: Five hundred eighty-one (9.9%) participants had a severely reduced eGFR (<45 ml/minute). Alendronate increased BMD regardless of eGFR, but women with reduced eGFR had a 5.6% (95% CI: 4.8-6.5) increase in total hip BMD compared with 4.8% (95% CI: 4.6-5.0) among women with normal to moderate renal dysfunction (interaction: p = 0.04). Compared with placebo, alendronate increased spine BMD by 6.6 +/- 5.8%, but there was no significant interaction for the increase in spine BMD (interaction: p = 0.75). Treatment with alendronate reduced the risk of clinical fractures to a similar degree in those with (OR: 0.78; 95% CI: 0.51-1.21) and without reduced renal function (OR: 0.80; 95% CI; 0.70-0.93; p for interaction = 0.89). Treatment with alendronate reduced the risk of spine fractures to a similar degree in those with (OR: 0.72; 95% CI: 0.31-1.7) and without reduced renal function (OR: 0.50; 95% CI: 0.32-0.76; p for interaction = 0.44). There were no differences in adverse events by renal function.CONCLUSIONS: Alendronate is safe and effective at increasing BMD and decreasing fractures among this group of women with reduced renal function.
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  • Effect of alendronate for reducing fracture by FRAX score and femoral neck bone mineral density: the Fracture Intervention Trial.

    Donaldson, Meghan G   Palermo, Lisa   Ensrud, Kristine E   Hochberg, Marc C   Schousboe, John T   Cummings, Steven R  

    The WHO Fracture Risk Assessment Tool (FRAX; http://www.shef.ac.uk/FRAX) estimates the 10-year probability of major osteoporotic fracture. Clodronate and bazedoxifene reduced nonvertebral and clinical fracture more effectively on a relative scale in women with higher FRAX scores. We used data from the Fracture Intervention Trial (FIT) to evaluate the interaction between FRAX score and treatment with alendronate. We combined the Clinical Fracture (CF) arm and Vertebral Fracture (VF) arm of FIT. The CF and VF arm of FIT randomized 4432 and 2027 women, respectively, to placebo or alendronate for 4 and 3 years, respectively. FRAX risk factors were assessed at baseline. FRAX scores were calculated by WHO. We used Poisson regression models to assess the interaction between alendronate and FRAX score on the risk of nonvertebral, clinical, major osteoporotic, and radiographic vertebral fractures. Overall, alendronate significantly reduced the risk of nonvertebral fracture (incidence rate ratio [IRR] 0.86; 95% confidence interval [CI], 0.75-0.99), but the effect was greater for femoral neck (FN) bone mineral density (BMD) T-score =E2=89=A4 -2.5 (IRR 0.76; 95% CI, 0.62-0.93) than for FN T-score>-2.5 (IRR 0.96; 95% CI, 0.80-1.16) (p=3D0.02, interaction between alendronate and FN BMD). However, there was no evidence of an interaction between alendronate and FRAX score with FN BMD for risk of nonvertebral fracture (interaction p=3D0.61). The absolute benefit of alendronate was greatest among women with highest FRAX scores. Results were similar for clinical fractures, major osteoporotic fractures, and radiographic vertebral fractures and whether or not FRAX scores included FN BMD. Among this cohort of women with low bone mass there was no significant interaction between FRAX score and alendronate for nonvertebral, clinical or major osteoporotic fractures, or radiographic vertebral fractures. These results suggest that the effect of alendronate on a relative scale does not vary by FRAX score. A randomized controlled trial testing the effect of antifracture agents among women with high FRAX score but without osteoporosis is warranted. Copyright =C2=A9 2012 American Society for Bone and Mineral Research.
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  • Web-based trial to evaluate the efficacy and safety of tolterodine ER 4 mg in participants with overactive bladder: REMOTE trial.

    Orri, Miguel   Lipset, Craig H   Jacobs, Bradly P   Costello, Anthony J   Cummings, Steven R  

    INTRODUCTION: Participatory patient-centered, web-based methods could streamline and improve the convenience of clinical trial participation. We used an entirely web-based approach to conduct a randomized, placebo-controlled, Phase 4 (REMOTE) trial under an Investigational New Drug (IND) application to evaluate tolterodine extended release (ER) 4 mg for overactive bladder.; METHODS: The trial was designed to replicate previous clinic-based trials of tolterodine ER but was conducted via the web from one clinical site overseen by physicians. Participants were recruited via the web, screened for eligibility using web-based questionnaires, had laboratory testing in their community, and entered a run-in phase requiring bladder e-diaries. Informed consent was obtained using an interactive web-based method with physician countersignature. Study medication was shipped directly to participants.; RESULTS: With a goal of 283 randomized participants, 5157 registered on the trial website. Of 456 who passed initial screening, identification verification, and signed consent, 237 passed additional medical screening and were countersigned by the investigator. After laboratory testing, 118 entered the placebo run-in; only 18 passed e-diary assessments and were randomized to treatment. At week 12, the mean change from the baseline in micturitions/24 hours (primary endpoint) was -2.4 for tolterodine ER versus -0.8 for placebo [treatment difference (95% CI): -1.6 (-3.9, 0.6)].; CONCLUSION: The REMOTE trial is the first entirely web-based trial conducted under an IND application. The efficacy observed was consistent with results from conventional trials. With simplification of multi-step screening and testing, web-based trials or their component parts should provide a participant-friendly approach to many clinical trials. Copyright =C2=A9 2014 Elsevier Inc. All rights reserved.
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  • Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid: when is it reasonable to discontinue treatment?

    Cosman, Felicia   Cauley, Jane A   Eastell, Richard   Boonen, Steven   Palermo, Lisa   Reid, Ian R   Cummings, Steven R   Black, Dennis M  

    CONTEXT: Data are needed to guide therapeutic decisions about stopping bisphosphonates after an initial treatment period.; OBJECTIVE: To define significant predictors of fracture and quantify fracture incidence in risk factor-defined subgroups of women who discontinue zoledronic acid (ZOL) after 3 years of treatment. To determine if continuing ZOL reduces fracture risk in subgroups.; DESIGN: This study is based on data from the 3 year extension of HORIZON.; SETTING: Subjects were in the ZOL arm of the Multicenter HORIZON trial.; PARTICIPANTS: One thousand two hundred thirty three women who previously received 3 ZOL treatments during the Core trial.; INTERVENTION: Randomization to three additional annual ZOL (Z6, n =3D 616) or placebo infusions (Z3P3, n =3D 617).; MAIN OUTCOMES: The risk of morphometric vertebral fractures (MorphVertFx) and clinical nonvertebral fractures (NVF).; RESULTS: The incidence of MorphVertFx in Z3P3 was predicted by femoral neck (FN) t-score =E2=89=A4-2.5 [OR 3.3 (1.4, 8.0), p =3D .008], total hip (TH) t-score =E2=89=A4-2.5 [OR 4.0 (1.8, 9.0), p =3D .0007], and incident MorphVertFx during Core [OR 4.75 (1.4, 16.8), p < .015]. Incidence of NVF was predicted by TH t-score [for 1 decline, HR 1.7 (1.2, 2.6), p =3D .008], incident NVF during Core [HR 2.5 (1.2, 5.3), p =3D .014], and prevalent vertebral fracture [HR 3.0 (1.4, 6.3), p =3D .005]. For MorphVertFx, there were no significant treatment subgroup interactions; absolute fracture reductions with continued ZOL were greatest in high-risk subgroups. For NVF, there were no significant treatment reductions overall or in subgroups and no significant interactions.; CONCLUSIONS: After 3 years of ZOL, in women who have a TH t-score above -2.5, no recent incident fracture and no more than one risk factor (almost 55% of the population), risk for subsequent fracture (over three additional years) is low if treatment is discontinued (for MorphVertFx, average risk 3.2% and for NVF, average risk 5.8%). In these patients, discontinuation for up to 3 years is reasonable.=20
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  • Effect of Combination Folic Acid, Vitamin B6 , and Vitamin B12 Supplementation on Fracture Risk in Women: A Randomized, Controlled Trial.

    Stone, Katie L   Lui, Li-Yung   Christen, William G   Troen, Aron M   Bauer, Douglas C   Kado, Deborah   Schambach, Christopher   Cummings, Steven R   Manson, JoAnn E  

    Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B12 , B6 , and folic acid are cofactors in homocysteine metabolism, and supplementation with B vitamins is effective in lowering homocysteine levels in humans. However, randomized trials of supplemental B vitamins for reduction of fracture risk have been limited. Therefore, we performed an ancillary study to the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a large randomized trial of women with preexisting cardiovascular disease or three or more coronary risk factors, to test whether a daily B vitamin intervention including folic acid (2.5mg/day), vitamin B6 (50mg/day), and vitamin B12 (1mg/day) reduces nonspine fracture risk over 7.3 years of treatment and follow-up. Among 4810 women, we confirmed 349 nonspine fracture cases by centralized review of medical records. In a substudy of 300 women (150 in treatment group and 150 controls) with paired plasma samples at randomization and follow-up (7.3 years later), we measured two bone turnover markers, including C-terminal cross-linking telopeptide of type I collagen (CTX) and intact type I procollagen N-propeptide (P1NP). In Cox proportional hazards models based on intention-to-treat, we found no significant effects of B vitamin supplementation on nonspine fracture risk (relative hazard=3D1.08; 95% confidence interval, 0.88 to 1.34). In a nested case-cohort analysis, there were no significant effects of B vitamins on fracture risk among women with elevated plasma homocysteine levels, or low levels of vitamins B12 or B6 , or folate at baseline. Furthermore, treatment with B vitamins had no effect on change in markers of bone turnover. We found no evidence that daily supplementation with B vitamins reduces fracture risk or rates of bone metabolism in middle-aged and older women at high risk of cardiovascular disease. =C2=A9 2017 American Society for Bone and Mineral Research. =C2=A9 2017 American Society for Bone and Mineral Research.
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  • Steven R. Garfin

    Goel, Vijay; Bono, Chris; Herkowitz, Harry; Boden, Scott  

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