03363nas a2200241 4500008004100000022001400041245014100055210006900196260001600265300001200281490000800293520258100301100003002882700002102912700001802933700001902951700002002970700002102990700002103011700001503032710003803047856003603085 2018 eng d a1873-276300aAssociation of bone mineral density with hemoglobin and change in hemoglobin among older men and women: The Cardiovascular Health Study.0 aAssociation of bone mineral density with hemoglobin and change i c2018 Nov 15 a321-3260 v1203 a

PURPOSE: Osteoblasts and their precursors support hematopoiesis in the bone marrow. We hypothesized that declines in Hgb levels are associated with bone mineral density (BMD).

METHODS: The Cardiovascular Health Study is a prospective longitudinal study that enrolled 5888 community-dwelling adults aged >65 years and measured hemoglobin twice, in 1989-90 and 1992-93, as well as BMD by dual-energy X-ray absorptiometry (DXA) in 1994-95. In a subset of 1513 men and women with a Hgb in 1992-93 and BMD, we used linear regression to estimate associations of Hgb (per standard deviation (SD)) with total hip (TH), lumbar spine (LS) and total body (TB) BMD, and used Poisson regression to estimate associations of anemia (in 1992-93; Hgb <13 g/dL in men; <12 g/dL in women) with "low BMD" defined as T-score less than -1 at the TH. In 1277 participants with Hgb measured on average 2.9 years apart and BMD, we used linear regression to estimate the associations of annualized change in Hgb with TH, LS and TB BMD. All models included age, sex, study-site, race, smoking, alcohol use, weight, height, steroid use, physical activity score, self-reported health, previous cardiovascular disease and prior anti-fracture medication use.

RESULTS: No significant association was observed between Hgb, measured a mean 2.2 years prior to BMD, and BMD at the TH and LS in men (TH beta = -0.60 [x 10 g/cmper 1.1 g/dL Hgb], 95% CI: -1.88 to 0.68; LS beta = -1.69, 95% CI: -3.83 to 0.45) or women (TH beta = -0.49 [x 10 g/cmper 1.3 g/dL Hgb], 95% CI: -1.57 to 0.59; LS beta = -0.40, 95% CI: -2.57 to 1.76). Anemia was not observed to be significantly associated with low BMD in men (RR = 0.99, 95% CI: 0.72-1.40) nor women (RR = 0.98, 95% CI: 0.82-1.17). The mean change in Hgb was a loss of 0.06 g/dL/year (SD = 0.32). Change in Hgb was not observed to be significantly associated with BMD in men (TH beta = -0.55[x 10 g/cmper 1 g/dL annualized Hgb change], 95% CI: -4.28 to 3.19; LS beta = 0.63, 95% CI: -5.38 to 6.65) or women (TH beta = 0.92, 95% CI: -1.96 to 3.79; LS beta = -1.77, 95% CI: -7.52 to 3.98). No significant association was observed between anemia and low bone density by T-score in men and women.

CONCLUSIONS: These findings support neither the hypothesis that low Hgb prior to bone density or decreases in Hgb are associated with bone density in older community-dwelling adults nor the use of Hgb level as a case-finding tool to prompt BMD measurement.

1 aValderrábano, Rodrigo, J1 aBůzková, Petra1 aChang, Po-Yin1 aZakai, Neil, A1 aFink, Howard, A1 aRobbins, John, A1 aLee, Jennifer, S1 aWu, Joy, Y1 aCardiovascular Health Study group uhttps://chs-nhlbi.org/node/793002724nas a2200265 4500008004100000022001400041245012000055210006900175260001200244300001400256490000700270520190700277100002102184700001902205700002402224700002402248700001902272700001802291700003002309700002402339700002202363700001702385700002002402856003602422 2018 eng d a1935-554800aBiochemical Markers of Bone Turnover and Risk of Incident Diabetes in Older Women: The Cardiovascular Health Study.0 aBiochemical Markers of Bone Turnover and Risk of Incident Diabet c2018 09 a1901-19080 v413 a

OBJECTIVE: To investigate the relationship of osteocalcin (OC), a marker of bone formation, and C-terminal cross-linked telopeptide of type I collagen (CTX), a marker of bone resorption, with incident diabetes in older women.

RESEARCH DESIGN AND METHODS: The analysis included 1,455 female participants from the population-based Cardiovascular Health Study (CHS) (mean [SD] age 74.6 [5.0] years). The cross-sectional association of serum total OC and CTX levels with insulin resistance (HOMA-IR) was examined using multiple linear regression. The longitudinal association of both markers with incident diabetes, defined by follow-up glucose measurements, medications, and ICD-9 codes, was examined using multivariable Cox proportional hazards models.

RESULTS: OC and CTX were strongly correlated ( = 0.80). In cross-sectional analyses, significant or near-significant inverse associations with HOMA-IR were observed for continuous levels of OC (β = -0.12 per SD increment; = 0.004) and CTX (β = -0.08 per SD; = 0.051) after full adjustment for demographic, lifestyle, and clinical covariates. During a median follow-up of 11.5 years, 196 cases of incident diabetes occurred. After full adjustment, both biomarkers exhibited inverse associations with incident diabetes (OC: hazard ratio 0.85 per SD [95% CI 0.71-1.02; = 0.075]; CTX: 0.82 per SD [0.69-0.98; = 0.031]), associations that were comparable in magnitude and approached or achieved statistical significance.

CONCLUSIONS: In late postmenopausal women, lower OC and CTX levels were associated with similarly increased risks of insulin resistance at baseline and incident diabetes over long-term follow-up. Further research to delineate the mechanisms linking abnormal bone homeostasis and energy metabolism could uncover new approaches for the prevention of these age-related disorders.

1 aMassera, Daniele1 aBiggs, Mary, L1 aWalker, Marcella, D1 aMukamal, Kenneth, J1 aIx, Joachim, H1 aDjoussé, Luc1 aValderrábano, Rodrigo, J1 aSiscovick, David, S1 aTracy, Russell, P1 aXue, XiaoNan1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/780402027nas a2200217 4500008004100000022001400041245012700055210006900182260001500251300001600266490000700282520132500289100002301614700002101637700002401658700003001682700002101712700002001733700002001753856003601773 2020 eng d a1945-458900aAssociation of skeletal muscle mass, kidney disease and mortality in older men and women: the cardiovascular health study.0 aAssociation of skeletal muscle mass kidney disease and mortality c2020 11 02 a21023-210360 v123 a

Low muscle mass (sarcopenia) is a prevalent and major concern in the aging population as well as in patients with chronic kidney disease (CKD). We hypothesized that sarcopenia is an independent predictor of incident and progressive CKD and increased mortality in older men and women (≥65 years) from the Cardiovascular Health Study. Sarcopenia was defined by bioimpedance-estimated skeletal muscle mass index (SMI) as a continuous variable and categorically (normal, class I, and class II). Cox regression hazard ratios (HRs) estimated the risk of incident and prevalent CKD and mortality in individuals with and without CKD. Low SMI was associated with increased prevalence of CKD in men (p<0.001), but lower prevalence of CKD in women (p=0.03). Low muscle mass was not associated with incident CKD or rapid CKD progression (>3 ml/minute/1.73m/year decline in eGFR) in men, but was associated with lower risk of incident CKD in women ([adjusted RR=0.69, 95% (0.51,0.94)]. Low muscle mass (class II) was independently associated with higher mortality only in men [(adjusted HR=1.26, 95% (1.05,1.50)]. Neither definition of sarcopenia was associated with mortality in men or women with CKD. Further studies are needed to understand the mechanisms by which sarcopenia contributes to higher mortality in aging men.

1 aKruse, Nicholas, T1 aBůzková, Petra1 aBarzilay, Joshua, I1 aValderrábano, Rodrigo, J1 aRobbins, John, A1 aFink, Howard, A1 aJalal, Diana, I uhttps://chs-nhlbi.org/node/862702665nas a2200313 4500008004100000022001400041245010000055210006900155260001600224520170900240100002001949700002101969700002501990700002002015700002402035700002202059700001502081700002102096700002402117700003002141700002002171700002202191700001902213700002002232700002302252700002002275700002002295856003602315 2023 eng d a1432-082700aAssociation of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study.0 aAssociation of Immune Cell Subsets with Incident Hip Fracture Th c2023 Aug 313 a

In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4CD28 T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

1 aElam, Rachel, E1 aBůzková, Petra1 aDelaney, Joseph, A C1 aFink, Howard, A1 aBarzilay, Joshua, I1 aCarbone, Laura, D1 aSaha, Rick1 aRobbins, John, A1 aMukamal, Kenneth, J1 aValderrábano, Rodrigo, J1 aPsaty, Bruce, M1 aTracy, Russell, P1 aOlson, Nels, C1 aHuber, Sally, A1 aDoyle, Margaret, F1 aLanday, Alan, L1 aCauley, Jane, A uhttps://chs-nhlbi.org/node/947803396nas a2200433 4500008004100000022001400041245015600055210006900211260001600280520204800296100002202344700002002366700002002386700002402406700002102430700002402451700001702475700001902492700002602511700002102537700002002558700002402578700002002602700002302622700002402645700002402669700002102693700002002714700002102734700001602755700002602771700002602797700003002823700001502853700002002868700001902888700001902907856003602926 2024 eng d a1523-468100aLarge-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.0 aLargescale circulating proteome association study CPAS metaanaly c2024 Jan 043 a

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5 K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 × 10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.

1 aAustin, Thomas, R1 aFink, Howard, A1 aJalal, Diana, I1 aTörnqvist, Anna, E1 aBůzková, Petra1 aBarzilay, Joshua, I1 aLu, Tianyuan1 aCarbone, Laura1 aGabrielsen, Maiken, E1 aGrahnemo, Louise1 aHveem, Kristian1 aJonasson, Christian1 aKizer, Jorge, R1 aLanghammer, Arnulf1 aMukamal, Kenneth, J1 aGerszten, Robert, E1 aNethander, Maria1 aPsaty, Bruce, M1 aRobbins, John, A1 aSun, Yan, V1 aSkogholt, Anne, Heidi1 aÅsvold, Bjørn, Olav1 aValderrábano, Rodrigo, J1 aZheng, Jie1 aRichards, Brent1 aCoward, Eivind1 aOhlsson, Claes uhttps://chs-nhlbi.org/node/963502684nas a2200457 4500008004100000022001400041245006400055210006000119260001600179520137200195100002201567700002101589700002001610700002401630700002001654700002101674700002401695700001901719700002601738700002101764700001701785700002001802700002401822700002001846700002301866700002401889700002401913700002001937700002101957700001601978700002601994700001902020700002202039700002602061700003002087700001502117700002002132700001902152700001902171856003602190 2024 eng d a2662-846500aA plasma protein-based risk score to predict hip fractures.0 aplasma proteinbased risk score to predict hip fractures c2024 May 273 a

As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Trøndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53-1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined.

1 aAustin, Thomas, R1 aNethander, Maria1 aFink, Howard, A1 aTörnqvist, Anna, E1 aJalal, Diana, I1 aBůzková, Petra1 aBarzilay, Joshua, I1 aCarbone, Laura1 aGabrielsen, Maiken, E1 aGrahnemo, Louise1 aLu, Tianyuan1 aHveem, Kristian1 aJonasson, Christian1 aKizer, Jorge, R1 aLanghammer, Arnulf1 aMukamal, Kenneth, J1 aGerszten, Robert, E1 aPsaty, Bruce, M1 aRobbins, John, A1 aSun, Yan, V1 aSkogholt, Anne, Heidi1 aKanis, John, A1 aJohansson, Helena1 aÅsvold, Bjørn, Olav1 aValderrábano, Rodrigo, J1 aZheng, Jie1 aRichards, Brent1 aCoward, Eivind1 aOhlsson, Claes uhttps://chs-nhlbi.org/node/9700