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Osteoporosis: HELP
Articles by Steven R. Cummings
Based on 64 articles published since 2010
(Why 64 articles?)
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Between 2010 and 2020, S. Cummings wrote the following 64 articles about Osteoporosis.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
26 Article Sex hormones, sex hormone binding globulin, and vertebral fractures in older men. 2016

Cawthon, Peggy M / Schousboe, John T / Harrison, Stephanie L / Ensrud, Kristine E / Black, Dennis / Cauley, Jane A / Cummings, Steven R / LeBlanc, Erin S / Laughlin, Gail A / Nielson, Carrie M / Broughton, Augusta / Kado, Deborah M / Hoffman, Andrew R / Jamal, Sophie A / Barrett-Connor, Elizabeth / Orwoll, Eric S / Anonymous1530855. ·Research Institute, California Pacific Medical Center, San Francisco, CA, USA. Electronic address: pcawthon@sfcc-cpmc.net. · Park Nicollet Institute for Research and Education, University of Minnesota, Minneapolis, MN, USA. · Research Institute, California Pacific Medical Center, San Francisco, CA, USA. · Minneapolis Veterans Affairs Health Care System, and University of Minnesota, Minneapolis, MN, USA. · University of California, San Francisco, CA, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Kaiser Permanente Center for Health Research NW, Portland, OR, USA. · Universtity of California, San Diego, CA, USA. · Oregon Health and Science University, Portland, OR, USA. · Stanford University, Stanford, CA, USA. · University of Toronto, Toronto, ON, Canada. ·Bone · Pubmed #26778261.

ABSTRACT: The association between sex hormones and sex hormone binding globin (SHBG) with vertebral fractures in men is not well studied. In these analyses, we determined whether sex hormones and SHBG were associated with greater likelihood of vertebral fractures in a prospective cohort study of community dwelling older men. We included data from participants in MrOS who had been randomly selected for hormone measurement (N=1463, including 1054 with follow-up data 4.6years later). Major outcomes included prevalent vertebral fracture (semi-quantitative grade≥2, N=140, 9.6%) and new or worsening vertebral fracture (change in SQ grade≥1, N=55, 5.2%). Odds ratios per SD decrease in sex hormones and per SD increase in SHBG were estimated with logistic regression adjusted for potentially confounding factors, including age, bone mineral density, and other sex hormones. Higher SHBG was associated with a greater likelihood of prevalent vertebral fractures (OR: 1.38 per SD increase, 95% CI: 1.11, 1.72). Total estradiol analyzed as a continuous variable was not associated with prevalent vertebral fractures (OR per SD decrease: 0.86, 95% CI: 0.68 to 1.10). Men with total estradiol values ≤17pg/ml had a borderline higher likelihood of prevalent fracture than men with higher values (OR: 1.46, 95% CI: 0.99, 2.16). There was no association between total testosterone and prevalent fracture. In longitudinal analyses, SHBG (OR: 1.42 per SD increase, 95% CI: 1.03, 1.95) was associated with new or worsening vertebral fracture, but there was no association with total estradiol or total testosterone. In conclusion, higher SHBG (but not testosterone or estradiol) is an independent risk factor for vertebral fractures in older men.

27 Article Abdominal aortic calcification and risk of fracture among older women - The SOF study. 2015

Szulc, Pawel / Blackwell, Terri / Kiel, Douglas P / Schousboe, John T / Cauley, Jane / Hillier, Teresa / Hochberg, Marc / Rodondi, Nicolas / Taylor, Brent C / Black, Dennis / Cummings, Steven / Ensrud, Kristine E / Anonymous4580834. ·INSERM UMR 1033, University of Lyon, Lyon, France. Electronic address: pawel.szulc@inserm.fr. · California Pacific Medical Center Research Institute, San Francisco, CA, USA. · Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. · Park Nicollet Institute, Minneapolis, MN, USA; Division of Health Policy and Management, University of Minnesota, Minneapolis, MN, USA. · Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. · Center for Health Research, Kaiser Permanente Hawaii, Honolulu, HI, USA; Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA. · Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Department Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA. · Department of General Internal Medicine, University Hospital of Bern, Bern, Switzerland. · Department of Medicine and Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA; Center for Chronic Disease Outcomes Research, VA Health Care System, Minneapolis, MN, USA. · Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA. ·Bone · Pubmed #26115911.

ABSTRACT: Data concerning the link between severity of abdominal aortic calcification (AAC) and fracture risk in postmenopausal women are discordant. This association may vary by skeletal site and duration of follow-up. Our aim was to assess the association between the AAC severity and fracture risk in older women over the short- and long term. This is a case-cohort study nested in a large multicenter prospective cohort study. The association between AAC and fracture was assessed using Odds Ratios (OR) and 95% confidence intervals (95%CI) for vertebral fractures and using Hazard Risks (HR) and 95%CI for non-vertebral and hip fractures. AAC severity was evaluated from lateral spine radiographs using Kauppila's semiquantitative score. Severe AAC (AAC score 5+) was associated with higher risk of vertebral fracture during 4 years of follow-up, after adjustment for confounders (age, BMI, walking, smoking, hip bone mineral density, prevalent vertebral fracture, systolic blood pressure, hormone replacement therapy) (OR=2.31, 95%CI: 1.24-4.30, p<0.01). In a similar model, severe AAC was associated with an increase in the hip fracture risk (HR=2.88, 95%CI: 1.00-8.36, p=0.05). AAC was not associated with the risk of any non-vertebral fracture. AAC was not associated with the fracture risk after 15 years of follow-up. In elderly women, severe AAC is associated with higher short-term risk of vertebral and hip fractures, but not with the long-term risk of these fractures. There is no association between AAC and risk of non-vertebral-non-hip fracture in older women. Our findings lend further support to the hypothesis that AAC and skeletal fragility are related.

28 Article Hip Fractures Risk in Older Men and Women Associated With DXA-Derived Measures of Thigh Subcutaneous Fat Thickness, Cross-Sectional Muscle Area, and Muscle Density. 2015

Malkov, Serghei / Cawthon, Peggy M / Peters, Kathy Wilt / Cauley, Jane A / Murphy, Rachel A / Visser, Marjolein / Wilson, Joseph P / Harris, Tamara / Satterfield, Suzanne / Cummings, Steve / Shepherd, John A / Anonymous5110819. ·Bone and Breast Density Research Group, Department of Radiology, University of California, San Francisco, San Francisco, CA, USA. · California Pacific Medical Center Research Institute, San Francisco, CA, USA. · Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. · Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA. · Department of Health Sciences, VU University Amsterdam, Amsterdam, The Netherlands. · Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. · Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA. ·J Bone Miner Res · Pubmed #25644748.

ABSTRACT: Mid-thigh cross-sectional muscle area (CSA), muscle attenuation, and greater trochanter soft tissue thickness have been shown to be independent risk factors of hip fracture. Our aim was to determine whether muscle and adipose tissue measures derived from dual-energy X-ray absorptiometry (DXA) scans would have a similar risk association as those measured using other imaging methods. Using a case-cohort study design, we identified 169 incident hip fracture cases over an average of 13.5 years among participants from the Health ABC Study, a prospective study of 3075 individuals initially aged 70 to 79 years. We modeled the thigh 3D geometry and compared DXA and computed tomography (CT) measures. DXA-derived thigh CSA, muscle attenuation, and subcutaneous fat thickness were found to be highly correlated to their CT counterparts (Pearson's r = 0.82, 0.45, and 0.91, respectively; p < 0.05). The fracture risk of men and women were calculated separately. We found that decreased subcutaneous fat, CT thigh muscle attenuation, and appendicular lean mass by height squared (ALM/Ht(2)) were associated with fracture risk in men; hazard ratios (HR) = 1.44 (1.02, 2.02), 1.40 (1.05, 1.85), and 0.58 (0.36, 0.91), respectively, after adjusting for age, race, clinical site, body mass index (BMI), chronic disease, hip bone mineral density (BMD), self-reported health, alcohol use, smoking status, education, physical activity, and cognitive function. In a similar model for women, only decreases in subcutaneous fat and DXA CSA were associated with hip fracture risk; HR = 1.39 (1.07, 1.82) and 0.78 (0.62, 0.97), respectively. Men with a high ALM/Ht(2) and low subcutaneous fat thickness had greater than 8 times higher risk for hip fracture compared with those with low ALM/Ht(2) and high subcutaneous fat. In women, ALM/Ht(2) did not improve the model when subcutaneous fat was included. We conclude that the DXA-derived subcutaneous fat thickness is a strong marker for hip fracture risk in both men and women, especially in men with high ALM/Ht(2).

29 Article Arterialized venous bicarbonate is associated with lower bone mineral density and an increased rate of bone loss in older men and women. 2015

Tabatabai, L S / Cummings, S R / Tylavsky, F A / Bauer, D C / Cauley, J A / Kritchevsky, S B / Newman, A / Simonsick, E M / Harris, T B / Sebastian, A / Sellmeyer, D E / Anonymous3591108. ·Division of Endocrinology (L.S.T., D.E.S.), Johns Hopkins Hospital, Johns Hopkins School of Medicine, Baltimore, Maryland 21224 · California Pacific Medical Center Research Institute (S.R.C.), San Francisco, California 94118 · Department of Preventive Medicine (F.A.T.), University of Tennessee Health Science Center, Memphis, Tennessee 38163 · Department of Medicine (D.C.B., A.S.), School of Medicine, University of California, San Francisco, San Francisco, California 94143 · Department of Epidemiology (J.A.C., A.N.), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 · Department of Internal Medicine (S.B.K.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157 · Translational Gerontology Branch (E.M.S.), National Institute on Aging, Baltimore, Maryland 21224 · and Laboratory of Epidemiology and Population Science (T.B.H.), National Institute on Aging, Bethesda, Maryland 20892. ·J Clin Endocrinol Metab · Pubmed #25642590.

ABSTRACT: CONTEXT: Higher dietary net acid loads have been associated with increased bone resorption, reduced bone mineral density (BMD), and increased fracture risk. OBJECTIVE: The objective was to compare bicarbonate (HCO3) measured in arterialized venous blood samples to skeletal outcomes. DESIGN: Arterialized venous samples collected from participants in the Health, Aging and Body Composition (Health ABC) Study were compared to BMD and rate of bone loss. SETTING: The setting was a community-based observational cohort. PARTICIPANTS: A total of 2287 men and women age 74 ± 3 years participated. INTERVENTION: Arterialized venous blood was obtained at the year 3 study visit and analyzed for pH and pCO2. HCO3 was determined using the Henderson-Hasselbalch equation. MAIN OUTCOME MEASURE: BMD was measured at the hip by dual-energy x-ray absorptiometry at the year 1 (baseline) and year 3 study visits. RESULTS: Plasma HCO3 was positively associated with BMD at both year 1 (P = .001) and year 3 (P = .001) in models adjusted for age, race, sex, clinic site, smoking, weight, and estimated glomerular filtration rate. Plasma HCO3 was inversely associated with rate of bone loss at the total hip over the 2.1 ± 0.3 (mean ± SD) years between the two bone density measurements (P < .001). Across quartiles of plasma HCO3, the rate of change in BMD over the 2.1 years ranged from a loss of 0.72%/y in the lowest quartile to a gain of 0.15%/y in the highest quartile of HCO3. CONCLUSIONS: Arterialized plasma HCO3 was associated positively with cross-sectional BMD and inversely with the rate of bone loss, implying that systemic acid-base status is an important determinant of skeletal health during aging. Ongoing bone loss was linearly related to arterialized HCO3, even after adjustment for age and renal function. Further research in this area may have major public health implications because reducing dietary net acid load is possible through dietary intervention or through supplementation with alkaline potassium compounds.

30 Article The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). 2015

Black, Dennis M / Reid, Ian R / Cauley, Jane A / Cosman, Felicia / Leung, Ping Chung / Lakatos, Peter / Lippuner, Kurt / Cummings, Steven R / Hue, Trisha F / Mukhopadhyay, Amitava / Tan, Monique / Aftring, R Paul / Eastell, Richard. ·University of California, San Francisco, CA, USA. ·J Bone Miner Res · Pubmed #25545380.

ABSTRACT: While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p = 0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits.

31 Article Relationship between pretreatment rate of bone loss and bone density response to once-yearly ZOL: HORIZON-PFT extension study. 2015

Eastell, Richard / Boonen, Steven / Cosman, Felicia / Reid, Ian R / Palermo, Lisa / Cummings, Steven R / Black, Dennis M. ·Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK. ·J Bone Miner Res · Pubmed #25214069.

ABSTRACT: 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) 5 mg annually for up to three injections (years 4, 5, and 6, P3Z3 arm) (n = 1223). 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 = -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 = -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 = 0.26, 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.

32 Article Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid: when is it reasonable to discontinue treatment? 2014

Cosman, Felicia / Cauley, Jane A / Eastell, Richard / Boonen, Steven / Palermo, Lisa / Reid, Ian R / Cummings, Steven R / Black, Dennis M. ·Helen Hayes Hospital (F.C.), West Haverstraw, New York 10993 · Department of Medicine (F.C.), Columbia University College of Physicians and Surgeons, New York, New York 10032 · Department of Epidemiology (J.A.C.), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 · Academic Unit of Bone Metabolism (R.E.), University of Sheffield, Sheffield, United Kingdon, S5 7AU · Department of Experimental Medicine (S.B.) · Leuven University Hospital, Leuven, B-3000 Belgium · Department of Epidemiology and Department of Biostatistics (L.P., S.R.C., D.M.B.), University of California San Francisco, San Francisco, California 94107 · and Faculty of Medical and Health Sciences (I.R.R.), University of Auckland, Auckland, New Zealand, 1023. ·J Clin Endocrinol Metab · Pubmed #25215556.

ABSTRACT: 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 = 616) or placebo infusions (Z3P3, n = 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 ≤-2.5 [OR 3.3 (1.4, 8.0), p = .008], total hip (TH) t-score ≤-2.5 [OR 4.0 (1.8, 9.0), p = .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 = .008], incident NVF during Core [HR 2.5 (1.2, 5.3), p = .014], and prevalent vertebral fracture [HR 3.0 (1.4, 6.3), p = .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.

33 Article Prediction models of prevalent radiographic vertebral fractures among older women. 2014

Schousboe, John T / Rosen, Harold R / Vokes, Tamara J / Cauley, Jane A / Cummings, Steven R / Nevitt, Michael / Black, Dennis M / Orwoll, Eric S / Kado, Deborah M / Ensrud, Kristine E / Anonymous4270786. ·Park Nicollet Osteoporosis Center and Institute for Research and Education, Minneapolis, MN, USA and Division of Health Policy and Management, University of Minnesota, Minneapolis, MN, USA. Electronic address: john.schousboe@parknicollet.com. · Beth Israel Deaconess Medical Center, Boston, MA, USA. · Department of Medicine, University of Chicago, Chicago, IL, USA. · Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. · San Francisco Coordinating Center, California Pacific Medical Center, San Francisco, CA, USA. · Division of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA. · Bone and Mineral Unit, Oregon Health and Science University, Portland, OR, USA. · Departments of Family and Preventive Medicine and Internal Medicine, University of California at San Diego, San Diego, CA, USA. · Division of Epidemiology, University of Minnesota, Minneapolis, MN, USA and Minneapolis Veterans Administration Medical Center, Minneapolis, MN, USA. ·J Clin Densitom · Pubmed #24582085.

ABSTRACT: It is unknown how well prediction models incorporating multiple risk factors identify women with radiographic prevalent vertebral fracture (PVFx) compared with simpler models and what their value might be in clinical practice to select older women for lateral spine imaging. We compared 4 regression models for predicting PVFx in women aged 68 y and older enrolled in the Study of Osteoporotic Fractures with a femoral neck T-score ≤ -1.0, using area under receiving operator characteristic curves (AUROC) and a net reclassification index. The AUROC for a model with age, femoral neck bone mineral density, historical height loss (HHL), prior nonspine fracture, body mass index, back pain, and grip strength was only minimally better than that of a more parsimonious model with age, femoral neck bone mineral density, and historical height loss (AUROC 0.689 vs 0.679, p values for difference in 5 bootstrapped samples <0.001-0.35). The prevalence of PVFx among this older population of Caucasian women remained more than 20% even when women with low probability of PVFx, as estimated by the prediction models, were included in the screened population. These results suggest that lateral spine imaging is appropriate to consider for all Caucasian women aged 70 y and older with low bone mass to identify those with PVFx.

34 Article Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. 2014

Moayyeri, Alireza / Hsu, Yi-Hsiang / Karasik, David / Estrada, Karol / Xiao, Su-Mei / Nielson, Carrie / Srikanth, Priya / Giroux, Sylvie / Wilson, Scott G / Zheng, Hou-Feng / Smith, Albert V / Pye, Stephen R / Leo, Paul J / Teumer, Alexander / Hwang, Joo-Yeon / Ohlsson, Claes / McGuigan, Fiona / Minster, Ryan L / Hayward, Caroline / Olmos, José M / Lyytikäinen, Leo-Pekka / Lewis, Joshua R / Swart, Karin M A / Masi, Laura / Oldmeadow, Chris / Holliday, Elizabeth G / Cheng, Sulin / van Schoor, Natasja M / Harvey, Nicholas C / Kruk, Marcin / del Greco M, Fabiola / Igl, Wilmar / Trummer, Olivia / Grigoriou, Efi / Luben, Robert / Liu, Ching-Ti / Zhou, Yanhua / Oei, Ling / Medina-Gomez, Carolina / Zmuda, Joseph / Tranah, Greg / Brown, Suzanne J / Williams, Frances M / Soranzo, Nicole / Jakobsdottir, Johanna / Siggeirsdottir, Kristin / Holliday, Kate L / Hannemann, Anke / Go, Min Jin / Garcia, Melissa / Polasek, Ozren / Laaksonen, Marika / Zhu, Kun / Enneman, Anke W / McEvoy, Mark / Peel, Roseanne / Sham, Pak Chung / Jaworski, Maciej / Johansson, Åsa / Hicks, Andrew A / Pludowski, Pawel / Scott, Rodney / Dhonukshe-Rutten, Rosalie A M / van der Velde, Nathalie / Kähönen, Mika / Viikari, Jorma S / Sievänen, Harri / Raitakari, Olli T / González-Macías, Jesús / Hernández, Jose L / Mellström, Dan / Ljunggren, Osten / Cho, Yoon Shin / Völker, Uwe / Nauck, Matthias / Homuth, Georg / Völzke, Henry / Haring, Robin / Brown, Matthew A / McCloskey, Eugene / Nicholson, Geoffrey C / Eastell, Richard / Eisman, John A / Jones, Graeme / Reid, Ian R / Dennison, Elaine M / Wark, John / Boonen, Steven / Vanderschueren, Dirk / Wu, Frederick C W / Aspelund, Thor / Richards, J Brent / Bauer, Doug / Hofman, Albert / Khaw, Kay-Tee / Dedoussis, George / Obermayer-Pietsch, Barbara / Gyllensten, Ulf / Pramstaller, Peter P / Lorenc, Roman S / Cooper, Cyrus / Kung, Annie Wai Chee / Lips, Paul / Alen, Markku / Attia, John / Brandi, Maria Luisa / de Groot, Lisette C P G M / Lehtimäki, Terho / Riancho, José A / Campbell, Harry / Liu, Yongmei / Harris, Tamara B / Akesson, Kristina / Karlsson, Magnus / Lee, Jong-Young / Wallaschofski, Henri / Duncan, Emma L / O'Neill, Terence W / Gudnason, Vilmundur / Spector, Timothy D / Rousseau, François / Orwoll, Eric / Cummings, Steven R / Wareham, Nick J / Rivadeneira, Fernando / Uitterlinden, Andre G / Prince, Richard L / Kiel, Douglas P / Reeve, Jonathan / Kaptoge, Stephen K. ·Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ·Hum Mol Genet · Pubmed #24430505.

ABSTRACT: Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

35 Article Standardising the descriptive epidemiology of osteoporosis: recommendations from the Epidemiology and Quality of Life Working Group of IOF. 2013

Kanis, J A / Adachi, J D / Cooper, C / Clark, P / Cummings, S R / Diaz-Curiel, M / Harvey, N / Hiligsmann, M / Papaioannou, A / Pierroz, D D / Silverman, S L / Szulc, P / Anonymous5990764. ·WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, UK, w.j.pontefract@sheffield.ac.uk. ·Osteoporos Int · Pubmed #23884436.

ABSTRACT: INTRODUCTION: The prevalence of osteoporosis as defined by the T-score is inconsistently reported in the literature which makes comparisons between studies problematic. METHODS: The Epidemiology and Quality of Life Working Group of IOF convened to make its recommendations and endorsement sought thereafter from the Committee of Scientific Advisors of IOF. RESULTS: The Committee of Scientific Advisors of IOF recommends that papers describing the descriptive epidemiology of osteoporosis using BMD at the femoral neck include T-scores derived from the National Health and Nutrition Examination Survey III reference database for femoral neck measurements in Caucasian women aged 20-29 years. CONCLUSIONS: It is expected that the use of the reference standard will help resolve difficulties in the comparison of results between studies and the comparative assessment of new technologies.

36 Article Sclerostin and bone strength in women in their 10th decade of life. 2013

Thorson, Sara / Prasad, Tanushree / Sheu, Yahtyng / Danielson, Michelle E / Arasu, Aarthi / Cummings, Steven R / Cauley, Jane A. ·School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. ·J Bone Miner Res · Pubmed #23505206.

ABSTRACT: Sclerostin is a potent inhibitor of bone formation but has been shown to correlate positively with areal bone mineral density (aBMD). Little is known about its relationship to parameters of bone strength and volumetric BMD (vBMD) as measured by peripheral quantitative computed tomography (pQCT). We measured both serum sclerostin and parameters of tibial bone size and strength by pQCT to characterize this relationship. Our study population consisted of 223 white and 35 African American women (mean age 87 years) from the Study of Osteoporotic Fractures (SOF) cohort, who had usable pQCT scans of the tibia at sites 4% (T4%), 33% (T33%), and 66% (T66%) from the ankle. Analysis of covariance was used to test for differences in age-adjusted means of aBMD, pQCT variables, and serum biomarkers across sclerostin quartiles. African American women had significantly lower median sclerostin (34.3 pmol/L) than white women (48.5 pmol/L) (p = 0.05). Women in the highest sclerostin quartile had 7% to 14.5% higher hip aBMD and pQCT parameters of vBMD and bone size than those in the lowest quartile in multivariate models adjusting for age, race, weight, height, and diabetes status. The association of sclerostin with parameters of bone strength differed dramatically between T33% and T66% sites. At T66%, women in the highest sclerostin quartile had pQCT strength parameters 9.4% to 15.3% greater than the lowest quartile, whereas no trend was found for the T33% site. Our results suggest paradoxical associations between circulating sclerostin and bone size, density, and strength.

37 Article Effects of antiresorptive therapies on glucose metabolism: results from the FIT, HORIZON-PFT, and FREEDOM trials. 2013

Schwartz, Ann V / Schafer, Anne L / Grey, Andrew / Vittinghoff, Eric / Palermo, Lisa / Lui, Li-Yung L / Wallace, Robert B / Cummings, Steven R / Black, Dennis M / Bauer, Douglas C / Reid, Ian R. ·University of California San Francisco, San Francisco, CA, USA. aschwartz@psg.ucsf.edu ·J Bone Miner Res · Pubmed #23322676.

ABSTRACT: In rodent models, undercarboxylated osteocalcin (ucOC) acts as a hormone that promotes insulin sensitivity and secretion. If ucOC plays a similar role in humans, then antiresorptive therapies, which reduce ucOC levels, may increase the risk of insulin resistance and diabetes. We tested whether antiresorptive therapies result in higher fasting glucose, increased weight, or greater diabetes incidence in post hoc analyses of three randomized, placebo-controlled trials in postmenopausal women: Fracture Intervention Trial (FIT) (N = 6151) of alendronate (4 years), Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) (N = 7113) of zoledronic acid (3 years), and Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (N = 7076) of denosumab (3 years). Fasting glucose was measured annually in FIT and HORIZON in a subset of women, and every 6 months in FREEDOM in all participants. Weight was measured annually in all trials. Incident diabetes was identified from adverse event reports, initiation of diabetes medication, or elevated fasting glucose. Differences in fasting glucose changes from randomization to trial conclusion between treatment and placebo groups were not statistically significant: -0.47 mg/dL in FIT, 0.20 mg/dL in HORIZON-PFT, and 0.09 mg/dL in FREEDOM, all p > 0.6. Weight change differed between treatment and placebo groups in FIT (0.32 kg, p = 0.003) and FREEDOM (0.31 kg, p = 0.023) but not in HORIZON-PFT (0.15 kg, p = 0.132). In the three trials combined, diabetes occurred in 203 and 225 women assigned to treatment or placebo, respectively. Diabetes incidence was not increased in any of the treatment groups or in the pooled estimate (pooled relative risk [RR] = 0.90; 95% confidence interval [CI] 0.74-1.10). Antiresorptive therapy does not have a clinically important effect on fasting glucose, weight, or diabetes risk in postmenopausal women. Contrary to predictions from mouse models, reduced bone turnover does not appear to play a significant role in glucose metabolism in humans.

38 Article Cystatin C and risk of hip fractures in older women. 2013

Ensrud, Kristine E / Parimi, Neeta / Cauley, Jane A / Ishani, Areef / Slinin, Yelena / Hillier, Teresa A / Taylor, Brent C / Steffes, Michael / Cummings, Steven R / Anonymous4700746. ·Department of Medicine, University of Minnesota, Minneapolis, MN, USA. ensru001@umn.edu ·J Bone Miner Res · Pubmed #23300153.

ABSTRACT: To test the hypothesis that older women with higher cystatin C are at increased risk of hip fracture independent of traditional risk factors including hip bone mineral density (BMD), we performed a case-cohort analysis nested in a cohort of 4709 white women attending a Year 10 (1997-1998) examination of the Study of Osteoporotic Fractures that included a random sample of 1170 women and the first 300 women with incident hip fracture occurring after Year 10 examination. Serum cystatin C and creatinine were measured in Year 10 sera. In a model adjusted for age, clinical site, body mass index, and total hip BMD, higher cystatin C was associated with an increased risk of hip fracture (p for linear trend 0.008) with women in quartile 4 having a 1.9-fold higher risk (hazard ratio [HR] 1.91; 95% confidence interval [CI], 1.24-2.95) compared with those in quartile 1 (referent group). Further adjustment for additional risk factors only slightly attenuated the association; the risk for hip fracture was 1.7-fold higher (HR 1.74; 95% CI, 1.11-2.72) in women in quartile 4 compared with those in quartile 1. In contrast, neither serum creatinine nor creatinine-based estimated glomerular filtration rate (eGFRCr ) were associated with risk of hip fracture. Older women with higher cystatin C, but not higher serum creatinine or lower eGFRCr , have an increased risk of hip fracture independent of traditional risk factors. These findings suggest that cystatin C may be a promising biomarker for identification of older adults at high risk of hip fracture.

39 Article Goal-directed treatment of osteoporosis. 2013

Cummings, Steven R / Cosman, Felicia / Eastell, Richard / Reid, Ian R / Mehta, Mona / Lewiecki, E Michael. ·San Francisco Coordinating Center, California Pacific Medical Center Research Institute and the Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. scummings@sfcc-cpmc.net ·J Bone Miner Res · Pubmed #23300146.

ABSTRACT: Drug treatment for osteoporosis typically begins with an oral bisphosphonate, regardless of initial bone mineral density (BMD) or fracture risk, and decisions to continue or change treatment are often based on evidence of response to treatment based on changes in BMD, bone turnover markers, and occurrence of fractures. This pattern differs from preventive therapy for other conditions, such as hypertension, where treatment is based on achieving a goal. We propose that a goal be established to guide treatments to reduce fracture risk. The goal could be a certain risk of fracture or level of BMD. Goal-directed treatment would individualize the initial choice of treatment based on the probability that alternatives would achieve the patient's goal. In contrast to changing treatments based on years of use or failure to respond, the patient's BMD and risk would be reassessed periodically and decisions to stop or change treatment would be based on achieving or maximizing the chance of reaching an acceptable level of fracture risk or BMD. The acceptance of goal-directed treatment and application to practice will require a consensus on a number of issues about goals along with models of fracture risk while on treatment and probabilities of achieving goals. The result could be more rational and effective use of the expanding array of treatments for osteoporosis.

40 Article Cost-effectiveness of bone densitometry among Caucasian women and men without a prior fracture according to age and body weight. 2013

Schousboe, J T / Gourlay, M / Fink, H A / Taylor, B C / Orwoll, E S / Barrett-Connor, E / Melton, L J / Cummings, S R / Ensrud, K E / Anonymous731034. ·Park Nicollet Institute, Minneapolis, MN, USA. john.schousboe@parknicollet.com ·Osteoporos Int · Pubmed #22349916.

ABSTRACT: INTRODUCTION: Bone densitometry may be more cost-effective for those with lower body weight since the prevalence of osteoporosis is higher for those with low body weight. Our purpose was to estimate weight thresholds below which bone densitometry is cost-effective for women and men without a prior clinical fracture at ages 55, 60, 65, 75, and 80 years. METHODS: We used a microsimulation model to estimate the costs and health benefits of bone densitometry and 5 years of fracture prevention therapy for those without prior fracture but with femoral neck osteoporosis (T-score ≤ -2.5) and a 10-year hip fracture risk of ≥3%. Threshold pre-test probabilities of low BMD warranting drug therapy at which bone densitometry is cost-effective were calculated. Corresponding body weight thresholds were estimated using data from the Study of Osteoporotic Fractures (SOF), the Osteoporotic Fractures in Men (MrOS) study, and the National Health and Nutrition Examination Survey (NHANES) for 2005-2006. RESULTS: Assuming a willingness to pay of $75,000 per quality adjusted life year (QALY) and drug cost of $500/year, body weight thresholds below which bone densitometry is cost-effective for those without a prior fracture were 74, 90, and 100 kg, respectively, for women aged 55, 65, and 80 years; and were 67, 101, and 108 kg, respectively, for men aged 55, 75, and 80 years. CONCLUSIONS: For women aged 55-65 years and men aged 55-75 years without a prior fracture, body weight can be used to select those for whom bone densitometry is cost-effective.

41 Article Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial. 2012

Adami, Silvano / Libanati, Cesar / Boonen, Steven / Cummings, Steven R / Ho, Pei-Ran / Wang, Andrea / Siris, Ethel / Lane, Joseph / Anonymous3570740 / Adachi, Jonathan D / Bhandari, Mohit / de Gregorio, Luiz / Gilchrist, Nigel / Lyritis, George / Möller, Gerd / Palacios, Santiago / Pavelka, Karel / Heinrich, Resch / Roux, Christian / Uebelhart, Daniel. ·Faculty of Medicine & Surgery, University of Verona, P. le Scuro 10, 37134, Verona, Italy. ·J Bone Joint Surg Am · Pubmed #23097066.

ABSTRACT: BACKGROUND: Fracture is the major complication of osteoporosis, and it allows the identification of individuals needing medical intervention for osteoporosis. After nonvertebral fracture, patients often do not receive osteoporosis medical treatment despite evidence that this treatment reduces the risk of subsequent fracture. In this pre planned analysis of the results of the three-year, placebo-controlled FREEDOM trial, we evaluated the effect of denosumab administration on fracture-healing to address theoretical concerns related to initiating or continuing denosumab therapy in patients presenting with a nonvertebral fracture. METHODS: Postmenopausal women aged sixty to ninety years with osteoporosis were randomized to receive 60 mg of denosumab (n = 3902) or a placebo (n = 3906) subcutaneously every six months for three years. Investigators reported complications associated with a fracture or its management and with fracture-healing for all nonvertebral fractures that occurred during the study. Delayed healing was defined as incomplete fracture-healing six months after the fracture. RESULTS: Six hundred and sixty-seven subjects (303 treated with denosumab and 364 who received a placebo) had a total of 851 nonvertebral fractures (386 in the denosumab group and 465 in the placebo group), including 199 fractures (seventy-nine in the denosumab group and 120 in the placebo group) that were treated surgically. Delayed healing was reported in seven subjects (two in the denosumab group and five in the placebo group), including one with subsequent nonunion (in the placebo group). Neither delayed healing nor nonunion was observed in any subject who had received denosumab within six weeks preceding or following the fracture. A complication associated with the fracture or intervention occurred in five subjects (2%) and twenty subjects (5%) in the denosumab and placebo groups,respectively (p = 0.009). CONCLUSIONS: Denosumab in a dose of 60 mg every six months does not seem to delay fracture-healing or contribute to other complications, even when it is administered at or near the time of the fracture.

42 Article Continuing bisphosphonate treatment for osteoporosis--for whom and for how long? 2012

Black, Dennis M / Bauer, Douglas C / Schwartz, Ann V / Cummings, Steven R / Rosen, Clifford J. ·Department of Epidemiology and Biostatistics, University of California, San Francisco, USA. ·N Engl J Med · Pubmed #22571169.

ABSTRACT: -- No abstract --

43 Article Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. 2012

Estrada, Karol / Styrkarsdottir, Unnur / Evangelou, Evangelos / Hsu, Yi-Hsiang / Duncan, Emma L / Ntzani, Evangelia E / Oei, Ling / Albagha, Omar M E / Amin, Najaf / Kemp, John P / Koller, Daniel L / Li, Guo / Liu, Ching-Ti / Minster, Ryan L / Moayyeri, Alireza / Vandenput, Liesbeth / Willner, Dana / Xiao, Su-Mei / Yerges-Armstrong, Laura M / Zheng, Hou-Feng / Alonso, Nerea / Eriksson, Joel / Kammerer, Candace M / Kaptoge, Stephen K / Leo, Paul J / Thorleifsson, Gudmar / Wilson, Scott G / Wilson, James F / Aalto, Ville / Alen, Markku / Aragaki, Aaron K / Aspelund, Thor / Center, Jacqueline R / Dailiana, Zoe / Duggan, David J / Garcia, Melissa / Garcia-Giralt, Natàlia / Giroux, Sylvie / Hallmans, Göran / Hocking, Lynne J / Husted, Lise Bjerre / Jameson, Karen A / Khusainova, Rita / Kim, Ghi Su / Kooperberg, Charles / Koromila, Theodora / Kruk, Marcin / Laaksonen, Marika / Lacroix, Andrea Z / Lee, Seung Hun / Leung, Ping C / Lewis, Joshua R / Masi, Laura / Mencej-Bedrac, Simona / Nguyen, Tuan V / Nogues, Xavier / Patel, Millan S / Prezelj, Janez / Rose, Lynda M / Scollen, Serena / Siggeirsdottir, Kristin / Smith, Albert V / Svensson, Olle / Trompet, Stella / Trummer, Olivia / van Schoor, Natasja M / Woo, Jean / Zhu, Kun / Balcells, Susana / Brandi, Maria Luisa / Buckley, Brendan M / Cheng, Sulin / Christiansen, Claus / Cooper, Cyrus / Dedoussis, George / Ford, Ian / Frost, Morten / Goltzman, David / González-Macías, Jesús / Kähönen, Mika / Karlsson, Magnus / Khusnutdinova, Elza / Koh, Jung-Min / Kollia, Panagoula / Langdahl, Bente Lomholt / Leslie, William D / Lips, Paul / Ljunggren, Östen / Lorenc, Roman S / Marc, Janja / Mellström, Dan / Obermayer-Pietsch, Barbara / Olmos, José M / Pettersson-Kymmer, Ulrika / Reid, David M / Riancho, José A / Ridker, Paul M / Rousseau, François / Slagboom, P Eline / Tang, Nelson L S / Urreizti, Roser / Van Hul, Wim / Viikari, Jorma / Zarrabeitia, María T / Aulchenko, Yurii S / Castano-Betancourt, Martha / Grundberg, Elin / Herrera, Lizbeth / Ingvarsson, Thorvaldur / Johannsdottir, Hrefna / Kwan, Tony / Li, Rui / Luben, Robert / Medina-Gómez, Carolina / Palsson, Stefan Th / Reppe, Sjur / Rotter, Jerome I / Sigurdsson, Gunnar / van Meurs, Joyce B J / Verlaan, Dominique / Williams, Frances M K / Wood, Andrew R / Zhou, Yanhua / Gautvik, Kaare M / Pastinen, Tomi / Raychaudhuri, Soumya / Cauley, Jane A / Chasman, Daniel I / Clark, Graeme R / Cummings, Steven R / Danoy, Patrick / Dennison, Elaine M / Eastell, Richard / Eisman, John A / Gudnason, Vilmundur / Hofman, Albert / Jackson, Rebecca D / Jones, Graeme / Jukema, J Wouter / Khaw, Kay-Tee / Lehtimäki, Terho / Liu, Yongmei / Lorentzon, Mattias / McCloskey, Eugene / Mitchell, Braxton D / Nandakumar, Kannabiran / Nicholson, Geoffrey C / Oostra, Ben A / Peacock, Munro / Pols, Huibert A P / Prince, Richard L / Raitakari, Olli / Reid, Ian R / Robbins, John / Sambrook, Philip N / Sham, Pak Chung / Shuldiner, Alan R / Tylavsky, Frances A / van Duijn, Cornelia M / Wareham, Nick J / Cupples, L Adrienne / Econs, Michael J / Evans, David M / Harris, Tamara B / Kung, Annie Wai Chee / Psaty, Bruce M / Reeve, Jonathan / Spector, Timothy D / Streeten, Elizabeth A / Zillikens, M Carola / Thorsteinsdottir, Unnur / Ohlsson, Claes / Karasik, David / Richards, J Brent / Brown, Matthew A / Stefansson, Kari / Uitterlinden, André G / Ralston, Stuart H / Ioannidis, John P A / Kiel, Douglas P / Rivadeneira, Fernando. ·Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ·Nat Genet · Pubmed #22504420.

ABSTRACT: Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

44 Article Breast cancer incidence in postmenopausal women with osteoporosis or low bone mass using arzoxifene. 2012

Powles, Trevor J / Diem, Susan J / Fabian, Carol J / Neven, Patrick / Wickerham, D Lawrence / Cox, David A / Muram, David / Agnusdei, Donato / Dowsett, Sherie A / Amewou-Atisso, Messan / Cummings, Steven R. ·Breast Unit, The Cancer Centre London at Parkside, Wimbledon, London, UK. trevorpowles@aol.com ·Breast Cancer Res Treat · Pubmed #22484799.

ABSTRACT: The Generations trial, a multicenter, placebo-controlled, double-blind trial, compared arzoxifene 20 mg/day and placebo in 9,354 postmenopausal women with osteoporosis (N=5,252) or low bone mass (N=4,102). Primary outcomes were vertebral fracture in the osteoporotic population and invasive breast cancer in all study participants. Here, we report the detailed breast cancer findings from the trial. Breast cancers were detected by annual mammograms and clinical examination. After 48 months follow-up, breast cancer incidence was compared between treatment groups by estrogen receptor (ER) and progesterone receptor (PR) status and baseline risk factors. Baseline breast cancer risk factors, including age, estimated Gail risk, and bone mineral density, were well balanced between treatment groups. A total of 75 breast cancers occurred 53 in the placebo group and 22 in the arzoxifene group (HR 0.41, 95% CI 0.25-0.68, P<0.001). There were 62 invasive breast cancers, 39 identified as invasive ER-positive (placebo 30, arzoxifene 9; HR 0.30, 95% CI 0.14-0.63, P=0.001) and 30 identified as invasive PR-positive (placebo 23, arzoxifene 7; HR 0.30, 95% CI 0.13-0.71, P=0.003). Breast cancer risk reduction with arzoxifene was similar between Gail risk groups (P interaction=0.31) and between low bone mass and osteoporosis groups (P interaction=0.35). Although generally well tolerated, there was a significant increase in venous thromboembolism, vasomotor symptoms, muscle cramps, and some gynecological events with arzoxifene. These findings demonstrate that in this study arzoxifene reduced the risk of ER-positive breast cancer in this population of postmenopausal women with low bone mass or osteoporosis, an effect similar to that seen with other SERMs.

45 Article Effects of 3 years of lasofoxifene treatment on bone turnover markers in women with postmenopausal osteoporosis. 2012

Eastell, Richard / Reid, David M / Vukicevic, Slobodan / Ensrud, Kristine E / LaCroix, Andrea Z / Thompson, John R / Thompson, David D / Cummings, Steven R. ·Centre for Biomedical Research, Northern General Hospital, Herries Road, Sheffield, South Yorkshire, S5 7AU, UK. r.eastell@sheffield.ac.uk ·Bone · Pubmed #22348983.

ABSTRACT: The aims of this study were to describe the changes in bone turnover markers (BTMs) in response to lasofoxifene therapy; to describe the changes in BTMs in the individual; and to examine the relationships between BTM levels on treatment and treatment outcomes. Women (n=1126) aged 59-80years with femoral neck or spine bone mineral density T-scores ≤-2.5 were randomized to lasofoxifene 0.25mg/d, 0.5mg/d, or placebo for 5years. We measured serum C-telopeptide of type I collagen (CTX) and serum procollagen I N-propeptide (PINP), osteocalcin, and bone alkaline phosphatase (ALP) at baseline and at 1, 3, 6, 12, 24, and 36months. Lasofoxifene therapy resulted in a decrease in the concentrations of bone resorption and bone formation markers compared with placebo; the decrease was maximal between 6 and 24months. The effect of lasofoxifene 0.5mg/d was similar to that of lasofoxifene 0.25mg/d. The decrease in bone ALP was less than the decreases in CTX, osteocalcin, and PINP. Lasofoxifene therapy 0.5mg/d resulted in BTM-defined response rates for CTX (decrease in concentration from baseline >60%), PINP (>50%), and bone ALP (>30%) of 35%, 45%, and 43% of women at month 12, respectively, compared with placebo responses of 4%, 4%, and 7%. In contrast, the increase in BMD took longer (50% responded after 36months of lasofoxifene 0.5mg/d) and was not as specific (15% of placebo group responded). Bone density change was weakly inversely correlated with change in the concentrations of BTMs. BTMs may prove useful in the monitoring of the response to lasofoxifene treatment for women with postmenopausal osteoporosis early in the course of treatment.

46 Article The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). 2012

Black, Dennis M / Reid, Ian R / Boonen, Steven / Bucci-Rechtweg, Christina / Cauley, Jane A / Cosman, Felicia / Cummings, Steven R / Hue, Trisha F / Lippuner, Kurt / Lakatos, Peter / Leung, Ping Chung / Man, Zulema / Martinez, Ruvie Lou Maria / Tan, Monique / Ruzycky, Mary Ellen / Su, Guoqin / Eastell, Richard. ·Department of Epidemiology and Biostastistics, University of California, San Francisco, CA 94107, USA. dblack@psg.ucsf.edu ·J Bone Miner Res · Pubmed #22161728.

ABSTRACT: Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment.

47 Article Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. 2012

McClung, Michael R / Boonen, Steven / Törring, Ove / Roux, Christian / Rizzoli, René / Bone, Henry G / Benhamou, Claude-Laurent / Lems, Willem F / Minisola, Salvatore / Halse, Johan / Hoeck, Hans C / Eastell, Richard / Wang, Andrea / Siddhanti, Suresh / Cummings, Steven R. ·Oregon Osteoporosis Center, Portland, OR 97213, USA. mmcclung@orost.com ·J Bone Miner Res · Pubmed #21976367.

ABSTRACT: Denosumab reduces the risk of new vertebral and nonvertebral fractures. Previous trials suggest that the efficacy of antiresorptives on fractures might differ by patients' characteristics, such as age, bone mineral density (BMD), and fracture history. In the FREEDOM study, 7808 women aged 60 to 90 years with osteoporosis were randomly assigned to receive subcutaneous injections of denosumab (60 mg) or placebo every 6 months for 3 years. New vertebral and nonvertebral fractures were radiologically confirmed. Subgroup analyses described in this article were prospectively planned before study unblinding to evaluate the effect of denosumab on new vertebral and nonvertebral fractures across various subgroups. Compared with placebo, denosumab decreased the risk of new vertebral fractures in the overall study population over 3 years. This effect did not significantly differ for any of the nine subgroups analyzed (p > 0.09 for all potential interactions). Denosumab also reduced all nonvertebral fractures by 20% in the full study cohort over 3 years. This risk reduction was statistically significant in women with a baseline femoral neck BMD T-score ≤ -2.5 but not in those with a T-score > -2.5; in those with a body mass index (BMI) < 25 kg/m(2) but not ≥ 25 kg/m(2); and in those without but not with a prevalent vertebral fracture. These differential treatment effects were not explained by differences in BMD responses to denosumab. Denosumab 60 mg administered every 6 months for 3 years in women with osteoporosis reduced the risk of new vertebral fractures to a similar degree in all subgroups. The effect of denosumab on nonvertebral fracture risk differed by femoral neck BMD, BMI, and prevalent vertebral fracture at baseline.

48 Article Risk factors for nonvertebral fracture in obese older women. 2011

Premaor, M O / Ensrud, K / Lui, L / Parker, R A / Cauley, J / Hillier, T A / Cummings, S / Compston, J E / Anonymous17990697. ·Department of Clinical Medicine, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul 97105-900, Brazil. mopremaor@bol.com.br ·J Clin Endocrinol Metab · Pubmed #21677038.

ABSTRACT: CONTEXT: A high prevalence of obesity has recently been reported in postmenopausal women with low trauma fracture, suggesting that higher bone mineral density (BMD) in obese individuals may not be protective against fracture. OBJECTIVE: The aim of this study was to compare BMD and other risk factors for nonvertebral fracture in 1377 obese postmenopausal women. DESIGN: Characteristics of obese women with and without incident nonvertebral fracture were investigated among the prospective cohort in the Study of Osteoporotic Fractures. SETTING: The Study of Osteoporotic Fractures is a multicenter study of 9704 women (>99% Caucasian) aged 65 yr and over who were recruited between September 1986 and October 1988 from population-based listings at four U.S. clinical centers. MAIN OUTCOME MEASURE: The main outcome measure was nonvertebral fracture. RESULTS: BMD T-scores in the spine, femoral neck, and total hip were significantly lower in obese women who experienced fractures than in obese women without fracture: mean differences, -0.56 [95% confidence interval (CI) = -0.73 to -0.39], -0.46 (95% CI = -0.57 to -0.36), and -0.51 (95% CI = -0.62 to -0.39), respectively (P < 0.0001 for all). A previous history of fracture [odds ratio = 1.69 (95% CI = 1.33-2.14); P < 0.0001] and femoral neck BMD [1.62 (95% CI = 1.42-1.85) per sd decrease in BMD; P < 0.0001] were independently associated with incident nonvertebral fracture. CONCLUSIONS: Obese postmenopausal women who sustain nonvertebral fractures have significantly lower BMD on average than obese women without fracture and are more likely to have a past history of fracture. Fractures in obese postmenopausal women thus exhibit some characteristics of fragility fractures.

49 Article WHO absolute fracture risk models (FRAX): do clinical risk factors improve fracture prediction in older women without osteoporosis? 2011

Hillier, Teresa A / Cauley, Jane A / Rizzo, Joanne H / Pedula, Kathryn L / Ensrud, Kristine E / Bauer, Douglas C / Lui, Li-Yung / Vesco, Kimberly K / Black, Dennis M / Donaldson, Meghan G / Leblanc, Erin S / Cummings, Steven R. ·Center for Health Research, Kaiser Permanente Northwest/Hawaii, Portland, OR 97227, USA. teresa.hillier@kpchr.org ·J Bone Miner Res · Pubmed #21351144.

ABSTRACT: Bone mineral density (BMD) is a strong predictor of fracture, yet most fractures occur in women without osteoporosis by BMD criteria. To improve fracture risk prediction, the World Health Organization recently developed a country-specific fracture risk index of clinical risk factors (FRAX) that estimates 10-year probabilities of hip and major osteoporotic fracture. Within differing baseline BMD categories, we evaluated 6252 women aged 65 or older in the Study of Osteoporotic Fractures using FRAX 10-year probabilities of hip and major osteoporotic fracture (ie, hip, clinical spine, wrist, and humerus) compared with incidence of fractures over 10 years of follow-up. Overall ability of FRAX to predict fracture risk based on initial BMD T-score categories (normal, low bone mass, and osteoporosis) was evaluated with receiver-operating-characteristic (ROC) analyses using area under the curve (AUC). Over 10 years of follow-up, 368 women incurred a hip fracture, and 1011 a major osteoporotic fracture. Women with low bone mass represented the majority (n = 3791, 61%); they developed many hip (n = 176, 48%) and major osteoporotic fractures (n = 569, 56%). Among women with normal and low bone mass, FRAX (including BMD) was an overall better predictor of hip fracture risk (AUC = 0.78 and 0.70, respectively) than major osteoporotic fractures (AUC = 0.64 and 0.62). Simpler models (eg, age + prior fracture) had similar AUCs to FRAX, including among women for whom primary prevention is sought (no prior fracture or osteoporosis by BMD). The FRAX and simpler models predict 10-year risk of incident hip and major osteoporotic fractures in older US women with normal or low bone mass.

50 Article Raloxifene, a selective estrogen receptor modulator, is renoprotective: a post-hoc analysis. 2011

Melamed, Michal L / Blackwell, Terri / Neugarten, Joel / Arnsten, Julia H / Ensrud, Kristine E / Ishani, Areef / Cummings, Steven R / Silbiger, Sharon R. ·Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA. mmelamed@aecom.yu.edu ·Kidney Int · Pubmed #20927038.

ABSTRACT: Estrogens have a protective effect on kidney fibrosis in several animal models. Here, we tested the effect of raloxifene, an estrogen receptor modulator, on the change in serum creatinine or estimated glomerular filtration rate (eGFR) and incident kidney-related adverse events. We performed a post-hoc analysis of the multiple outcomes of raloxifene evaluation trial, a double-masked, placebo-controlled randomized clinical trial encompassing 7705 post-menopausal women (aged 31-80 years) with osteoporosis. Participants were randomized to either of two doses of raloxifene, 60 or 120 mg/day, or placebo. Serum creatinine was measured at a central laboratory at baseline and annually. Adverse events were assessed every 6 months and uniformly categorized. Compared with those in the placebo group, participants on raloxifene had a slower yearly rate of increase in creatinine (significant at the low dose) and a significantly slower yearly rate of decrease in eGFR for both doses over 3 years of follow-up. Raloxifene was associated with significantly fewer kidney-related adverse events compared with placebo. Thus, treatment with raloxifene was safe and renoprotective. Clinical trials of raloxifene in post-menopausal women with kidney disease designed to look at kidney outcomes are needed to confirm these findings.

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