@article {721, title = {Hormone replacement therapy and sleep-disordered breathing.}, journal = {Am J Respir Crit Care Med}, volume = {167}, year = {2003}, month = {2003 May 01}, pages = {1186-92}, abstract = {

Disordered breathing during sleep is more common among postmenopausal women than among their premenopausal counterparts, possibly because of declining levels of estrogen and progesterone. We examined the relationship between the use of replacement hormones and sleep-disordered breathing in a sample of 2,852 noninstitutionalized women, 50 years of age or older, who participated in the Sleep Heart Health Study. The frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index) was determined by unattended, single-night polysomnography at the participant{\textquoteright}s home. The prevalence of sleep-disordered breathing (apnea-hypopnea index of 15 or more) among hormone users (61 of 907) was approximately half the prevalence among nonusers (286 of 1,945). Multivariable adjustment for known determinants of the disorder, including age, body mass index, and neck circumference, has attenuated the association, but only moderately (adjusted odds ratio, 0.55; 95\% confidence interval, 0.41 to 0.75). The inverse association between hormone use and sleep-disordered breathing was evident in various subgroups and was particularly strong among women 50 to 59 years old (adjusted odds ratio, 0.36; 95\% confidence interval, 0.21 to 0.60). If the observed associations are causal, hormone replacement therapy could have a role in preventing or alleviating sleep-disordered breathing.

}, keywords = {Age Distribution, Aged, Body Mass Index, Causality, Cohort Studies, Confidence Intervals, Estrogen Replacement Therapy, Female, Humans, Logistic Models, Middle Aged, Multivariate Analysis, Odds Ratio, Polysomnography, Postmenopause, Prevalence, Sensitivity and Specificity, Severity of Illness Index, Sleep Apnea Syndromes, Sleep Stages, United States}, issn = {1073-449X}, doi = {10.1164/rccm.200210-1238OC}, author = {Shahar, Eyal and Redline, Susan and Young, Terry and Boland, Lori L and Baldwin, Carol M and Nieto, F Javier and O{\textquoteright}Connor, George T and Rapoport, David M and Robbins, John A} } @article {805, title = {Barriers to health care access among the elderly and who perceives them.}, journal = {Am J Public Health}, volume = {94}, year = {2004}, month = {2004 Oct}, pages = {1788-94}, abstract = {

OBJECTIVES: We evaluated self-perceived access to health care in a cohort of Medicare beneficiaries.

METHODS: We identified patterns of use and barriers to health care from self-administered questionnaires collected during the 1993-1994 annual examination of the Cardiovascular Health Study.

RESULTS: The questionnaires were completed by 4889 (91.1\%) participants, with a mean age of 76.0 years. The most common barriers to seeing a physician were the doctor{\textquoteright}s lack of responsiveness to patient concerns, medical bills, transportation, and street safety. Low income, no supplemental insurance, older age, and female gender were independently related to perceptions of barriers. Race was not significant after adjustment for other factors.

CONCLUSIONS: Psychological and physical barriers affect access to care among the elderly; these may be influenced by poverty more than by race.

}, keywords = {Aged, Aged, 80 and over, Chi-Square Distribution, Female, Health Behavior, Health Services Accessibility, Humans, Logistic Models, Male, Medicare, Patients, Surveys and Questionnaires, United States}, issn = {0090-0036}, doi = {10.2105/ajph.94.10.1788}, author = {Fitzpatrick, Annette L and Powe, Neil R and Cooper, Lawton S and Ives, Diane G and Robbins, John A} } @article {752, title = {Sleep apnea and markers of vascular endothelial function in a large community sample of older adults.}, journal = {Am J Respir Crit Care Med}, volume = {169}, year = {2004}, month = {2004 Feb 01}, pages = {354-60}, abstract = {

Clinical studies have suggested that sleep apnea is associated with impaired brachial artery flow-mediated dilation, a surrogate of endothelial dysfunction. We examined this question among older participants in the baseline examination of the Sleep Heart Health/Cardiovascular Health Study cohort (n = 1,037, age 68 years or older, 56\% female). Indices of sleep apnea, derived from 12-channel home polysomnography, were the apnea-hypopnea index (average number of apneas/hypopneas per hour) and the hypoxemia index (percentage of time below 90\% O2 saturation). Baseline arterial diameter and percentage of flow-mediated dilation were measured by ultrasound. Sleep apnea measures were associated with baseline diameter and the percentage of flow-mediated dilation, although these associations were weakened after adjustment for other cardiovascular risk factors, particularly body mass index. However, a statistically significant linear association between the hypoxemia index and baseline diameter was observed even after adjustment for body mass index and other confounders (p < 0.01). The associations were stronger among participants who were younger than 80 years and among those who with hypertension. This study adds to the growing body of evidence linking sleep apnea with vascular dysfunction in older subjects. Whether these relationships are entirely independent of obesity is unclear. This association might be one of the mechanisms explaining the relationship between sleep apnea, hypertension, and cardiovascular disease.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, Body Mass Index, Brachial Artery, Cardiovascular Diseases, Cohort Studies, Comorbidity, Endothelium, Vascular, Female, Humans, Hypertension, Linear Models, Male, Polysomnography, Prevalence, Probability, Residence Characteristics, Risk Assessment, Sampling Studies, Severity of Illness Index, Sleep Apnea Syndromes, Ultrasonography, Doppler}, issn = {1073-449X}, doi = {10.1164/rccm.200306-756OC}, author = {Nieto, F Javier and Herrington, David M and Redline, Susan and Benjamin, Emelia J and Robbins, John A} } @article {783, title = {Sleep-disordered breathing and white matter disease in the brainstem in older adults.}, journal = {Sleep}, volume = {27}, year = {2004}, month = {2004 May 01}, pages = {474-9}, abstract = {

STUDY OBJECTIVES: To examine whether sleep-disordered breathing is associated with white matter disease in the brainstem.

DESIGN: A population-based longitudinal study.

SETTING: Allegheny County, PA; Sacramento County, CA; and Washington County, MD.

PATIENTS OR PARTICIPANTS: A total of 789 individuals, aged 68 years or older, drawn from the Sleep Heart Health Study.

INTERVENTIONS: N/A.

MEASUREMENTS AND RESULTS: The participants underwent home polysomnography in 1995-1998 and cerebral magnetic resonance imaging in both 1992-1993 and 1997-1998. The apnea-hypopnea index was not associated with white matter disease in the brainstem, with or without adjusting for age, sex, race, community, body mass index, smoking status, alcohol use, systolic blood pressure, and the use of antihypertensive medication. In contrast, the arousal index (number of arousals per hour of sleep) was inversely associated with brainstem white matter disease (odds ratio = 0.75 for a SD increase in the arousal index, 95\% confidence interval: 0.62, 0.92).

CONCLUSIONS: The frequency of apneas and hypopneas was not associated with brainstem white matter disease in these older adults. A unique relationship with arousal frequency suggests that ischemic changes in the brainstem may be associated with arousals during sleep.

}, keywords = {Aged, Arousal, Brain, Brain Stem, Cerebrovascular Disorders, Electrooculography, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Polysomnography, Population Surveillance, Severity of Illness Index, Sleep Apnea Syndromes, Sleep Stages}, issn = {0161-8105}, doi = {10.1093/sleep/27.3.474}, author = {Ding, Jingzhong and Nieto, F Javier and Beauchamp, Norman J and Harris, Tamara B and Robbins, John A and Hetmanski, Jacqueline B and Fried, Linda P and Redline, Susan} } @article {782, title = {Sleep-disordered breathing is not associated with the presence of retinal microvascular abnormalities: the Sleep Heart Health Study.}, journal = {Sleep}, volume = {27}, year = {2004}, month = {2004 May 01}, pages = {467-73}, abstract = {

STUDY OBJECTIVE: Sleep apnea and milder forms of sleep-disordered breathing (SDB) have been associated with overt clinical cardiovascular disease, but it is unknown whether SDB is associated with arterial microvascular pathology. We examined the relation between SDB and retinal microvascular abnormalities.

DESIGN: Cross-sectional study.

PARTICIPANTS: Subjects were 2,927 men and women, aged 51 to 97 years, who participated in the Sleep Heart Health Study and had retinal photographs taken within approximately 3 years of overnight, unattended, at-home polysomnography.

MEASUREMENTS AND RESULTS: A respiratory disturbance index (RDI), calculated as the average number of apneas and hypopneas per hour of sleep, was used as an indicator of SDB in analysis. The overall prevalence of retinopathy was slightly higher in people with higher RDI values (5.4\%, 4.9\%, 8.6\%, and 7.6\%, respectively, in increasing quartiles of RDI), but after adjustment for age, body-mass index, hypertension, diabetes, and other factors, the presence of retinopathy was not associated with SDB. With the possible exceptions of microaneurysms and generalized arteriolar narrowing, as measured by lower arteriole-to-venule ratio, specific retinal abnormalities were not associated consistently with the RDI. Relative to the first quartile of RDI, the adjusted odds ratios (95\% confidence interval) for the presence of microaneurysm in the second, third, and fourth quartiles of RDI were 1.05 (0.44-2.55), 1.97 (0.89-4.37), and 1.79 (0.78-4.10), respectively. An increase of RDI from 0 to 10 was associated with a predicted decrease in arteriole-to-venule ratio of 0.01. Results were similar when analyses were conducted in normotensive and nondiabetic persons separately.

CONCLUSIONS: These data do not demonstrate a notable relation between SDB and retinal abnormalities. However, since this is the first investigation of a link between retinopathy and SDB, similar studies should be conducted in other population samples to demonstrate either consistency or inconsistency of our findings across studies.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Coronary Disease, Cross-Sectional Studies, Female, Humans, Hypoxia, Middle Aged, Polysomnography, Positive-Pressure Respiration, Retina, Retinal Vessels, Sleep Apnea Syndromes}, issn = {0161-8105}, doi = {10.1093/sleep/27.3.467}, author = {Boland, Lori L and Shahar, Eyal and Wong, Tien Y and Klein, Ronald and Punjabi, Naresh and Robbins, John A and Newman, Anne B} } @article {822, title = {Age-dependent associations between sleep-disordered breathing and hypertension: importance of discriminating between systolic/diastolic hypertension and isolated systolic hypertension in the Sleep Heart Health Study.}, journal = {Circulation}, volume = {111}, year = {2005}, month = {2005 Feb 08}, pages = {614-21}, abstract = {

BACKGROUND: Sleep-disordered breathing (SDB) is associated with hypertension in the middle-aged. The association is less clear in older persons. Most middle-aged hypertensives have systolic/diastolic hypertension, whereas isolated systolic hypertension (ISH) is common among persons over 60 years. Mechanistically, only systolic/diastolic hypertension is expected to be associated with SDB, but few studies of SDB and hypertension distinguish systolic/diastolic hypertension from ISH. Prior investigations may have underestimated an association between SDB and systolic/diastolic hypertension in the elderly by categorizing individuals with ISH as simply hypertensive.

METHODS AND RESULTS: We conducted cross-sectional analyses of 6120 participants in the Sleep Heart Health Study, stratified by age: 40 to 59 (n=2477) and > or =60 years. Outcome measures included apnea-hypopnea index (AHI; average number of apneas plus hypopneas per hour of sleep), systolic/diastolic hypertension (> or =140 and > or =90 mm Hg), and ISH (> or =140 and <90 mm Hg). With adjustment for covariates, ISH was not associated with SDB in either age category. In those aged<60 years, AHI was significantly associated with higher odds of systolic/diastolic hypertension (AHI 15 to 29.9, OR=2.38 [95\% CI 1.30 to 4.38]; AHI > or =30, OR=2.24 [95\% CI 1.10 to 4.54]). Among those aged > or =60 years, no adjusted association between AHI and systolic/diastolic hypertension was found.

CONCLUSIONS: SDB is associated with systolic/diastolic hypertension in those aged <60 years. No association was found between SDB and systolic/diastolic hypertension in those aged > or =60 years or between SDB and ISH in either age category. These findings have implications for SDB screening and treatment. Distinguishing between hypertensive subtypes reveals a stronger association between SDB and hypertension for those aged <60 years than previously reported.

}, keywords = {Adult, Age Factors, Aged, Antihypertensive Agents, Cross-Sectional Studies, Diastole, Female, Humans, Hypertension, Male, Middle Aged, Risk Factors, Sleep Apnea Syndromes, Sleep Apnea, Central, Systole}, issn = {1524-4539}, doi = {10.1161/01.CIR.0000154540.62381.CF}, author = {Haas, Donald C and Foster, Gregory L and Nieto, F Javier and Redline, Susan and Resnick, Helaine E and Robbins, John A and Young, Terry and Pickering, Thomas G} } @article {820, title = {Incidence of cardiovascular disease in older Americans: the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {53}, year = {2005}, month = {2005 Feb}, pages = {211-8}, abstract = {

OBJECTIVES: To estimate incidence rates of major cardiovascular disease (CVD) in older Americans.

DESIGN: Longitudinal cohort study using prospectively collected data on cardiovascular events.

SETTING: Four U.S. communities in the Cardiovascular Health Study (CHS).

PARTICIPANTS: Five thousand eight hundred eighty-eight participants in CHS, aged 65 or older at enrollment, including 3,393 women (581 African American) and 2,495 men (343 African American).

MEASUREMENTS: At semiannual contacts, participants reported any occurrence of clinical CVD. Medical records were obtained and adjudicated to confirm diagnosis of CVD.

RESULTS: During 10 years of follow-up, incidence of coronary heart disease (CHD) per 1,000 person-years was 39.6 (95\% confidence interval (CI)=36.4-43.1) in men and 22.3 (95\% CI=20.4-24.2) in women. Cumulative event rates for CHD and myocardial infarction for women aged 75 and older at baseline were similar to those for men aged 65 to 74. The overall incidence of stroke was similar for men and women (14.7 (95\% CI=13.0-16.6) and 13.7 (95\% CI=12.4-15.1) per 1,000 person-years, respectively), but the risk of stroke increased with age more rapidly in women, resulting in a greater cumulative event rate for stroke in women than in men aged 75 and older. The incidence of congestive heart failure increased 9\% with each year of age over 65 and was greater than 6\% per year in Caucasian men and women aged 85 and older at baseline. Rates were similar in African Americans and Caucasians.

CONCLUSION: The occurrence of new CVD in older Americans is high, indicating that preventive efforts need to be maintained into older ages.

}, keywords = {African Americans, Age Distribution, Aged, Aged, 80 and over, Cardiovascular Diseases, European Continental Ancestry Group, Female, Geriatric Assessment, Humans, Incidence, Longitudinal Studies, Male, Sex Distribution, Survival Rate, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.53105.x}, author = {Arnold, Alice M and Psaty, Bruce M and Kuller, Lewis H and Burke, Gregory L and Manolio, Teri A and Fried, Linda P and Robbins, John A and Kronmal, Richard A} } @article {878, title = {10-year follow-up of subclinical cardiovascular disease and risk of coronary heart disease in the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {166}, year = {2006}, month = {2006 Jan 09}, pages = {71-8}, abstract = {

BACKGROUND: The incidence of coronary heart disease (CHD) is very high among individuals 65 years or older.

METHODS: We evaluated the relationships between measurements of subclinical disease at baseline (1989-1990) and at the third-year follow-up examination (1992-1993) and subsequent incidence of cardiovascular disease and total mortality as of June 2001. Approximately 61\% of the participants without clinical cardiovascular disease at baseline had subclinical disease based on our previously described criteria from the Cardiovascular Health Study.

RESULTS: The incidence of CHD was substantially increased for participants with subclinical disease compared with those who had no subclinical disease: 30.5 per 1000 person-years with and 16.3 per 1000 person-years without for white individuals, and 31.2 per 1000 person-years with and 12.5 per 1000 person-years without for black individuals. The risk persisted over the entire follow-up period. Incidence rates were higher for men than for women with or without subclinical disease, but there was little difference in rates for black individuals and white individuals.

CONCLUSIONS: In multivariable models, subclinical disease at baseline remained a significant predictor of CHD in both men and women; the hazard ratios (95\% confidence intervals) of their relative risks were 1.64 (1.30-2.06) and 1.49 (1.21-1.84), respectively. The presence of subclinical disease substantially increased the risk of subsequent CHD for participants with hypertension, diabetes mellitus, or elevated C-reactive protein. In summary, subclinical disease is very prevalent among older individuals, is independently associated with risk of CHD even over a 10-year follow-up period, and substantially increases the risk of CHD among participants with hypertension or diabetes mellitus.

}, keywords = {African Continental Ancestry Group, Aged, Blood Chemical Analysis, Cardiovascular Diseases, Comorbidity, Coronary Disease, Echocardiography, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Incidence, Male, Multivariate Analysis, Prevalence, Proportional Hazards Models, Regression Analysis, Risk Factors, Sex Distribution, United States}, issn = {0003-9926}, doi = {10.1001/archinte.166.1.71}, author = {Kuller, Lewis H and Arnold, Alice M and Psaty, Bruce M and Robbins, John A and O{\textquoteright}Leary, Daniel H and Tracy, Russell P and Burke, Gregory L and Manolio, Teri A and Chaves, Paolo H M} } @article {934, title = {Adjusted mortality after hip fracture: From the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {54}, year = {2006}, month = {2006 Dec}, pages = {1885-91}, abstract = {

OBJECTIVES: To estimate the risk of death associated with hip fracture (HFx), stratifying by sex and time since fracture.

DESIGN: Prospective cohort study compared participants with and without hip fracture, matched on sex, age, race, recruitment period, and time since enrollment.

SETTING: The Cardiovascular Health Study, a more-than-15-year longitudinal study of 5,888 older individuals from four U.S. sites.

PARTICIPANTS: Three hundred seventy-nine individuals with HFx were compared with 1,134 without HFx.

MEASUREMENTS: Extended Cox models were used to estimate mortality hazard ratios (HRs) for different periods after fracture, adjusting for prefracture health.

RESULTS: Age- and race-adjusted excess mortality was 9\% in women and 24\% in men 1 year after fracture, and 24\% in women and 26\% men 5 years postfracture. Multivariable-adjusted HRs of mortality associated with HFx in women were 7.1 (95\% confidence interval (CI) = 2.3-21.5), 2.1 (95\% CI = 1.0-4.1), 1.4 (95\% CI = 1.1-2.0), and 1.0 (95\% CI = 0.6-1.5) for 0 to 1 months, 2 to 6 months, 7 months to 4 years, and 5 to 8 years, respectively, after index date. In men, respective HRs for the same time periods were 39.9 (95\% CI = 5.2-308.7), 3.8 (95\% CI = 1.4-10.3), 1.1 (95\% CI = 0.7-1.8), and 1.0 (95\% CI = 0.3-2.7). HRs adjusted for age and race were 20\% to 40\% higher.

CONCLUSION: The risk of mortality was highest in the first 6 months after HFx. In men, the risk of death approximated that of men without HFx after 6 months; in women, a moderately greater risk persisted through the fourth year. Although the mortality pattern was different in women and men, excess mortality 5 years postfracture was similar for both sexes.

}, keywords = {Aged, Cohort Studies, Female, Health Status, Health Surveys, Hip Fractures, Humans, Male, Mortality, Multicenter Studies as Topic, Proportional Hazards Models, Sex Distribution, Time Factors, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2006.00985.x}, author = {Robbins, John A and Biggs, Mary L and Cauley, Jane} } @article {1122, title = {Sleep-disordered breathing and mortality: a prospective cohort study.}, journal = {PLoS Med}, volume = {6}, year = {2009}, month = {2009 Aug}, pages = {e1000132}, abstract = {

BACKGROUND: Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.

METHODS AND FINDINGS: We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea-hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0-14.9 events/h), moderate (AHI: 15.0-29.9 events/h), and severe (AHI: >or=30.0 events/h) sleep-disordered breathing were 0.93 (95\% CI: 0.80-1.08), 1.17 (95\% CI: 0.97-1.42), and 1.46 (95\% CI: 1.14-1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40-70 y (hazard ratio: 2.09; 95\% CI: 1.31-3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease-related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.

CONCLUSIONS: Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40-70 y with severe sleep-disordered breathing. Please see later in the article for the Editors{\textquoteright} Summary.

}, keywords = {Aged, Coronary Artery Disease, Female, Humans, Hypoxia, Male, Middle Aged, Odds Ratio, Proportional Hazards Models, Prospective Studies, Risk Factors, Sex Factors, Sleep Apnea Syndromes, Survival Analysis}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1000132}, author = {Punjabi, Naresh M and Caffo, Brian S and Goodwin, James L and Gottlieb, Daniel J and Newman, Anne B and O{\textquoteright}Connor, George T and Rapoport, David M and Redline, Susan and Resnick, Helaine E and Robbins, John A and Shahar, Eyal and Unruh, Mark L and Samet, Jonathan M} } @article {1124, title = {Total and cause-specific mortality in the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {64}, year = {2009}, month = {2009 Dec}, pages = {1251-61}, abstract = {

BACKGROUND: Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity.

METHODS: A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models.

RESULTS: Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E epsilon4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death.

CONCLUSIONS: In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Cardiovascular Diseases, Cause of Death, Chronic Disease, Cohort Studies, Female, Geriatric Assessment, Health Surveys, Humans, Kaplan-Meier Estimate, Male, Probability, Proportional Hazards Models, Retrospective Studies, Risk Assessment, Severity of Illness Index, Sex Factors, Survival Analysis, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glp127}, author = {Newman, Anne B and Sachs, Michael C and Arnold, Alice M and Fried, Linda P and Kronmal, Richard and Cushman, Mary and Psaty, Bruce M and Harris, Tamara B and Robbins, John A and Burke, Gregory L and Kuller, Lewis H and Lumley, Thomas} } @article {1185, title = {Long-term retention of older adults in the Cardiovascular Health Study: implications for studies of the oldest old.}, journal = {J Am Geriatr Soc}, volume = {58}, year = {2010}, month = {2010 Apr}, pages = {696-701}, abstract = {

OBJECTIVES: To describe retention according to age and visit type (clinic, home, telephone) and to determine characteristics associated with visit types for a longitudinal epidemiological study in older adults.

DESIGN: Longitudinal cohort study.

SETTING: Four U.S. clinical sites.

PARTICIPANTS: Five thousand eight hundred eighty-eight Cardiovascular Health Study (CHS) participants aged 65 to 100 at 1989/90 or 1992/93 enrollment (58.6\% female; 15.7\% black). CHS participants were contacted every 6 months, with annual assessments through 1999 and in 2005/06 for the All Stars Study visit of the CHS cohort (aged 77-102; 66.5\% female; 16.6\% black).

MEASUREMENTS: All annual contacts through 1999 (n=43,772) and for the 2005/06 visit (n=1,942).

RESULTS: CHS had 43,772 total participant contacts from 1989 to 1999: 34,582 clinic visits (79.0\%), 2,238 refusals (5.1\%), 4,401 telephone visits (10.1\%), 1,811 home visits (4.1\%), and 740 other types (1.7\%). In 2005/06, the All Stars participants of the CHS cohort had 36.6\% clinic, 22.3\% home, and 41.1\% telephone visits. Compared with participants aged 65 to 69, odds ratios of not attending a CHS clinic visit were 1.82 (95\% confidence interval (CI)=1.54-2.13), 2.94 (95\% CI=2.45-3.57), 4.55 (95\% CI=3.70-5.56), and 9.09 (95\% CI=7.69-11.11) for those aged 70 to 74, 75 to 79, 80 to 84, and 85 and older, respectively, in sex-adjusted regression. In multivariable regression, participants with a 2005/06 clinic visit were younger, more likely to be male and in good health, and had had better cognitive and physical function 7 years earlier than participants with other visit types. Participants with home, telephone, and missing visits were similar on characteristics measured 7 years earlier.

CONCLUSION: Offering home, telephone, and proxy visits are essential to optimizing follow-up of aging cohorts. Home visits increased in-person retention from 36.5\% to 58.8\% and diversified the cohort with respect to age, health, and physical functioning.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Ambulatory Care Facilities, Analysis of Variance, Cardiovascular Diseases, Chi-Square Distribution, Epidemiologic Studies, Female, Geriatric Assessment, House Calls, Humans, Logistic Models, Longitudinal Studies, Male, Multivariate Analysis, Patient Dropouts, Patient Selection, Research Subjects, Telephone, United States}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2010.02770.x}, author = {Strotmeyer, Elsa S and Arnold, Alice M and Boudreau, Robert M and Ives, Diane G and Cushman, Mary and Robbins, John A and Harris, Tamara B and Newman, Anne B} } @article {1566, title = {The Impact of Sleep-Disordered Breathing on Body Mass Index (BMI): The Sleep Heart Health Study (SHHS).}, journal = {Southwest J Pulm Crit Care}, volume = {3}, year = {2011}, month = {2011 Dec 08}, pages = {159-168}, abstract = {

INTRODUCTION: It is well known that obesity is a risk factor for sleep-disordered breathing (SDB). However, whether SDB predicts increase in BMI is not well defined. Data from the Sleep Heart Health Study (SHHS) were analyzed to determine whether SDB predicts longitudinal increase in BMI, adjusted for confounding factors. METHODS: A full-montage unattended home polysomnogram (PSG) and body anthropometric measurements were obtained approximately five years apart in 3001 participants. Apnea-hypopnea index (AHI) was categorized using clinical thresholds: < 5 (normal), >= 5 to <15 (mild sleep apnea), and >= 15 (moderate to severe sleep apnea). Linear regression was used to examine the association between the three AHI groups and increased BMI. The model included age, gender, race, baseline BMI, and change in AHI as covariates. RESULTS: Mean (SD) age was 62.2 years (10.14), 55.2\% were female and 76.1\% were Caucasian. Five-year increase in BMI was modest with a mean (SD) change of 0.53 (2.62) kg/m(2) (p=0.071). A multivariate regression model showed that subjects with a baseline AHI between 5-15 had a mean increase in BMI of 0.22 kg/m(2) (p=0.055) and those with baseline AHI >= 15 had a BMI increase of 0.51 kg/m(2) (p<0.001) compared to those with baseline AHI of <5. CONCLUSION: Our findings suggest that there is a positive association between severity of SDB and subsequent increased BMI over approximately 5 years. This observation may help explain why persons with SDB have difficulty losing weight.

}, issn = {2160-6773}, author = {Brown, Mark A and Goodwin, James L and Silva, Graciela E and Behari, Ajay and Newman, Anne B and Punjabi, Naresh M and Resnick, Helaine E and Robbins, John A and Quan, Stuart F} } @article {1285, title = {Mineral metabolism markers and the long-term risk of hip fracture: the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {96}, year = {2011}, month = {2011 Jul}, pages = {2186-93}, abstract = {

CONTEXT: Disturbances in mineral metabolism are associated with lower bone mineral density and fracture; however, previous human studies have assessed individual mineral metabolism markers in isolation.

OBJECTIVE: We assessed serum concentrations of 25-hydroxyvitamin D (25-OHD), PTH, and bone-specific alkaline phosphatase (BAP) concentrations individually, and in combination, in association with the long-term risk of hip fracture among a general population of older adults.

DESIGN AND SETTING: We studied 2294 participants from the Cardiovascular Health Study (mean age 74 yr) who were ambulatory and free of hip fracture and known cardiovascular disease at baseline. We used proportional hazards models to evaluate associations of baseline serum 25-OHD, PTH, and BAP concentrations with the time to first hospitalized hip fracture.

RESULTS: During a median of 13 yr of follow-up, 242 participants (10.6\%) developed an incident hip fracture. Serum 25-OHD concentrations less than 15 ng/ml were associated with a 61\% greater adjusted risk of fracture (95\% confidence interval 12-132\% greater). In contrast, neither serum PTH nor BAP concentrations were significantly associated with fracture risk. The association of 25-OHD deficiency with hip fracture was not significantly altered by either PTH or BAP concentrations.

CONCLUSIONS: Serum concentrations of 25-OHD, but not PTH or BAP, are associated with long-term hip fracture risk among ambulatory older adults. These data suggest that 25-OHD is the most relevant mineral metabolism marker of fracture risk among older people.

}, keywords = {Aged, Aged, 80 and over, Alkaline Phosphatase, Biomarkers, Bone Density, Female, Hip Fractures, Humans, Male, Parathyroid Hormone, Risk, Vitamin D}, issn = {1945-7197}, doi = {10.1210/jc.2010-2878}, author = {Robinson-Cohen, Cassianne and Katz, Ronit and Hoofnagle, Andrew N and Cauley, Jane A and Furberg, Curt D and Robbins, John A and Chen, Zhao and Siscovick, David S and de Boer, Ian H and Kestenbaum, Bryan} } @article {1314, title = {Potential explanatory factors for higher incident hip fracture risk in older diabetic adults.}, journal = {Curr Gerontol Geriatr Res}, volume = {2011}, year = {2011}, month = {2011}, pages = {979270}, abstract = {

Type 2 diabetes is associated with higher fracture risk. Diabetes-related conditions may account for this risk. Cardiovascular Health Study participants (N = 5641; 42.0\% men; 15.5\% black; 72.8{\textpm}5.6 years) were followed 10.9 {\textpm} 4.6 years. Diabetes was defined as hypoglycemic medication use or fasting glucose (FG) >=126 mg/dL. Peripheral artery disease (PAD) was defined as ankle-arm index <0.9. Incident hip fractures were from medical records. Crude hip fracture rates (/1000 person-years) were higher for diabetic vs. non-diabetic participants with BMI <25 (13.6, 95\% CI: 8.9-20.2 versus 11.4, 95\% CI: 10.1-12.9) and BMI >=25 to <30 (8.3, 95\% CI: 5.7-11.9 versus 6.6, 95\% CI: 5.6-7.7), but similar for BMI >=30. Adjusting for BMI, sex, race, and age, diabetes was related to fractures (HR = 1.34; 95\% CI: 1.01-1.78). PAD (HR = 1.25 (95\% CI: 0.92-1.57)) and longer walk time (HR = 1.07 (95\% CI: 1.04-1.10)) modified the fracture risk in diabetes (HR = 1.17 (95\% CI: 0.87-1.57)). Diabetes was associated with higher hip fracture risk after adjusting for BMI though this association was modified by diabetes-related conditions.

}, issn = {1687-7071}, doi = {10.1155/2011/979270}, author = {Strotmeyer, Elsa S and Kamineni, Aruna and Cauley, Jane A and Robbins, John A and Fried, Linda F and Siscovick, David S and Harris, Tamara B and Newman, Anne B} } @article {1352, title = {Serum 25-hydroxyvitamin D and physical function in older adults: the Cardiovascular Health Study All Stars.}, journal = {J Am Geriatr Soc}, volume = {59}, year = {2011}, month = {2011 Oct}, pages = {1793-801}, abstract = {

OBJECTIVES: To examine the association between 25-hydroxyvitamin D (25(OH)D) and physical function in adults of advanced age.

DESIGN: Cross-sectional and longitudinal analysis of physical function over 3~years of follow-up in the Cardiovascular Health Study All Stars.

SETTING: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania.

PARTICIPANTS: Community-dwelling adults aged 77 to 100 (N~=~988).

MEASUREMENTS: Serum 25-hydroxyvitamin D 25(OH)D), Short Physical Performance Battery (SPPB), and grip and knee extensor strength assessed at baseline. Mobility disability (difficulty walking half a mile or up 10 steps) and activities of daily living (ADLs) disability were assessed at baseline and every 6~months over 3~years of follow-up.

RESULTS: Almost one-third (30.8\%) of participants were deficient in 25(OH)D (<20~ng/mL). SPPB scores were lower in those with deficient 25(OH)D (mean (standard error) 6.53~(0.24)) than in those with sufficient 25(OH)D (>=30~ng/mL) (7.15~(0.25)) after adjusting for sociodemographic characteristics, season, health behaviors, and chronic conditions (P~=~.006). Grip strength adjusted for body size was also lower in those with deficient 25(OH)D than in those with sufficient 25(OH)D (24.7~(0.6)~kg vs 26.0~(0.6)~kg, P~=~.02). Participants with deficient 25(OH)D were more likely to have prevalent mobility (OR~=~1.44, 95\% confidence interval (CI))~=~0.96-2.14) and ADL disability (OR~=~1.51, 95\% CI~=~1.01-2.25) at baseline than those with sufficient 25(OH)D. Furthermore, participants with deficient 25(OH)D were at greater risk of incident mobility disability over 3~years of follow-up (hazard ratio~=~1.56, 95\% CI~=~1.06-2.30).

CONCLUSION: Vitamin D deficiency was common and was associated with poorer physical performance, lower muscle strength, and prevalent mobility and ADL disability in community-dwelling older adults. Moreover, vitamin D deficiency predicted incident mobility disability.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Female, Follow-Up Studies, Geriatric Assessment, Health Surveys, Humans, Male, Mobility Limitation, Muscle Strength, Physical Fitness, Proportional Hazards Models, Reference Values, United States, Vitamin D, Vitamin D Deficiency}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2011.03601.x}, author = {Houston, Denise K and Tooze, Janet A and Davis, Cralen C and Chaves, Paulo H M and Hirsch, Calvin H and Robbins, John A and Arnold, Alice M and Newman, Anne B and Kritchevsky, Stephen B} } @article {1556, title = {Assessment of gene-by-sex interaction effect on bone mineral density.}, journal = {J Bone Miner Res}, volume = {27}, year = {2012}, month = {2012 Oct}, pages = {2051-64}, abstract = {

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 {\texttimes} 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 {\texttimes} 10(-5) ; female effect = -0.007 and p = 3.3 {\texttimes} 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 {\texttimes} 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08\% of the variation in these traits per implicated SNP. {\textcopyright} 2012 American Society for Bone and Mineral Research.

}, keywords = {Bone Density, Cohort Studies, Female, Genes, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reproducibility of Results, Sex Characteristics}, issn = {1523-4681}, doi = {10.1002/jbmr.1679}, author = {Liu, Ching-Ti and Estrada, Karol and Yerges-Armstrong, Laura M and Amin, Najaf and Evangelou, Evangelos and Li, Guo and Minster, Ryan L and Carless, Melanie A and Kammerer, Candace M and Oei, Ling and Zhou, Yanhua and Alonso, Nerea and Dailiana, Zoe and Eriksson, Joel and Garc{\'\i}a-Giralt, Natalia and Giroux, Sylvie and Husted, Lise Bjerre and Khusainova, Rita I and Koromila, Theodora and Kung, Annie Waichee and Lewis, Joshua R and Masi, Laura and Mencej-Bedrac, Simona and Nogues, Xavier and Patel, Millan S and Prezelj, Janez and Richards, J Brent and Sham, Pak Chung and Spector, Timothy and Vandenput, Liesbeth and Xiao, Su-Mei and Zheng, Hou-Feng and Zhu, Kun and Balcells, Susana and Brandi, Maria Luisa and Frost, Morten and Goltzman, David and Gonz{\'a}lez-Mac{\'\i}as, Jes{\'u}s and Karlsson, Magnus and Khusnutdinova, Elza K and Kollia, Panagoula and Langdahl, Bente Lomholt and Ljunggren, Osten and Lorentzon, Mattias and Marc, Janja and Mellstr{\"o}m, Dan and Ohlsson, Claes and Olmos, Jos{\'e} M and Ralston, Stuart H and Riancho, Jos{\'e} A and Rousseau, Fran{\c c}ois and Urreizti, Roser and Van Hul, Wim and Zarrabeitia, Mar{\'\i}a T and Castano-Betancourt, Martha and Demissie, Serkalem and Grundberg, Elin and Herrera, Lizbeth and Kwan, Tony and Medina-G{\'o}mez, Carolina and Pastinen, Tomi and Sigurdsson, Gunnar and Thorleifsson, Gudmar and Vanmeurs, Joyce Bj and Blangero, John and Hofman, Albert and Liu, Yongmei and Mitchell, Braxton D and O{\textquoteright}Connell, Jeffrey R and Oostra, Ben A and Rotter, Jerome I and Stefansson, Kari and Streeten, Elizabeth A and Styrkarsdottir, Unnur and Thorsteinsdottir, Unnur and Tylavsky, Frances A and Uitterlinden, Andre and Cauley, Jane A and Harris, Tamara B and Ioannidis, John Pa and Psaty, Bruce M and Robbins, John A and Zillikens, M Carola and Vanduijn, Cornelia M and Prince, Richard L and Karasik, David and Rivadeneira, Fernando and Kiel, Douglas P and Cupples, L Adrienne and Hsu, Yi-Hsiang} } @article {1357, title = {Predicting late-life disability and death by the rate of decline in physical performance measures.}, journal = {Age Ageing}, volume = {41}, year = {2012}, month = {2012 Mar}, pages = {155-61}, abstract = {

BACKGROUND: the rate of performance decline may influence the risk of disability or death.

METHODS: for 4,182 Cardiovascular Health Study participants, we used multinomial Poisson log-linear models to assess the contribution of physical performance in 1998-99, and the rate of performance change between 1992-93 and 1998-99, to the risk of death or disability in 2005-06 in three domains: mobility, upper-extremity function (UEF) and activities of daily living (ADL). We evaluated performance in finger-tapping, grip strength, stride length, gait speed and chair stands separately and together for each outcome, adjusting for age, gender, race and years of disability in that outcome between 1992-93 and 1998-99.

RESULTS: participants{\textquoteright} age averaged 79.4 in 1998-99; 1,901 died over 7 years. Compared with the lowest change quintile in stride length, the highest quintile had a 1.32 relative risk (RR) of ADL disability (95\% CI: 1.16 -1.96) and a 1.27 RR of death (95\% CI: 1.07 -1.51). The highest change quintile for grip strength increased the risk of ADL disability by 35\% (95\% CI: 1.13 -1.61) and death by 31\% (95\% CI: 1.16 -1.49), compared with the lowest quintile. The annual change in stride length and grip strength also predicted disability in mobility and UEF.

CONCLUSION: performance trajectories independently predict death and disability.

}, keywords = {Activities of Daily Living, Age Factors, Aged, Aged, 80 and over, Aging, Disability Evaluation, Disabled Persons, Female, Geriatric Assessment, Hand Strength, Health Surveys, Humans, Linear Models, Male, Mobility Limitation, Mortality, Motor Skills, Predictive Value of Tests, Risk Assessment, Risk Factors, Survival Analysis, Time Factors, United States, Upper Extremity, Walking}, issn = {1468-2834}, doi = {10.1093/ageing/afr151}, author = {Hirsch, Calvin Hayes and B{\r u}zkov{\'a}, Petra and Robbins, John A and Patel, Kushang V and Newman, Anne B} } @article {6625, title = {Ratio of urine albumin to creatinine attenuates the association of dementia with hip fracture risk.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Nov}, pages = {4116-23}, abstract = {

CONTEXT: Microvascular disease is a leading cause of cognitive impairment. Approximately 50\% of people with a hip fracture have cognitive impairment.

OBJECTIVE: We tested the hypothesis that microvascular diseases of the brain (lacunar infarcts and white matter disease [WMD]), kidney (albuminuria [>= 30 mg/g creatinine] and albumin creatinine ratio [ACR]), and eye (retinal vascular disorders) attenuate the association of cognitive impairment with hip fracture risk.

SETTING: The Cardiovascular Health Cognition Study.

PATIENTS: Three thousand, one-hundred six participants (mean age, \~{} 79 y; 8.84 y median follow-up) with cognitive testing. Subsets received ACR testing (n=2389), brain magnetic resonance imaging scans (n = 2094), and retinal photography (n = 1098).

MAIN OUTCOME MEASURE: Incident hip fracture.

RESULTS: There were 488 participants (16\%) with mild cognitive impairment (MCI) and 564 (18\%) with dementia. There were 337 incident hip fractures, of which 19\% occurred in participants with MCI and 26\% in participants with dementia. Adjusted hazard ratios (HR) and 95\% confidence interval for hip fracture in participants with MCI were 2.45 (1.67-3.61) and for dementia 2.35 (1.57-3.52). With doubling of ACR, the HR for fracture was attenuated in participants with dementia compared with participants with normal cognition [interaction HR 0.70 (0.55-0.91)]. No such effect was found in participants with MCI. Albuminuria, lacunar infarcts, WMD, and retinal vascular disease (RVD) did not modify the association of dementia or MCI with hip fracture risk.

CONCLUSIONS: ACR attenuates part of the risk of hip fracture in people with dementia, suggesting that these disorders share a common pathogenesis.

}, keywords = {Aged, Aged, 80 and over, Albuminuria, Creatinine, Dementia, Female, Hip Fractures, Humans, Incidence, Magnetic Resonance Imaging, Male, Mild Cognitive Impairment, Neuropsychological Tests, Prospective Studies, Risk}, issn = {1945-7197}, doi = {10.1210/jc.2014-2409}, author = {B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I and Fink, Howard A and Robbins, John A and Cauley, Jane A and Fitzpatrick, Annette L} } @article {6854, title = {Sleep Disturbances and Glucose Metabolism in Older Adults: The Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {38}, year = {2015}, month = {2015 Nov}, pages = {2050-8}, abstract = {

OBJECTIVE: We examined the associations of symptoms of sleep-disordered breathing (SDB), which was defined as loud snoring, stopping breathing for a while during sleep, and daytime sleepiness, and insomnia with glucose metabolism and incident type 2 diabetes in older adults.

RESEARCH DESIGN AND METHODS: Between 1989 and 1993, the Cardiovascular Health Study recruited 5,888 participants >=65 years of age from four U.S. communities. Participants reported SDB and insomnia symptoms yearly through 1989-1994. In 1989-1990, participants underwent an oral glucose tolerance test, from which insulin secretion and insulin sensitivity were estimated. Fasting glucose levels were measured in 1989-1990 and again in 1992-1993, 1994-1995, 1996-1997, and 1998-1999, and medication use was ascertained yearly. We determined the cross-sectional associations of sleep symptoms with fasting glucose levels, 2-h glucose levels, insulin sensitivity, and insulin secretion using generalized estimated equations and linear regression models. We determined the associations of updated and averaged sleep symptoms with incident diabetes in Cox proportional hazards models. We adjusted for sociodemographics, lifestyle factors, and medical history.

RESULTS: Observed apnea, snoring, and daytime sleepiness were associated with higher fasting glucose levels, higher 2-h glucose levels, lower insulin sensitivity, and higher insulin secretion. The risk of the development of type 2 diabetes was positively associated with observed apnea (hazard ratio [HR] 1.84 [95\% CI 1.19-2.86]), snoring (HR 1.27 [95\% CI 0.95-1.71]), and daytime sleepiness (HR 1.54 [95\% CI 1.13-2.12]). In contrast, we did not find consistent associations between insomnia symptoms and glucose metabolism or incident type 2 diabetes.

CONCLUSIONS: Easily collected symptoms of SDB are strongly associated with insulin resistance and the incidence of type 2 diabetes in older adults. Monitoring glucose metabolism in such patients may prove useful in identifying candidates for lifestyle or pharmacological therapy. Further studies are needed to determine whether insomnia symptoms affect the risk of diabetes in younger adults.

}, keywords = {Adult, Aged, Blood Glucose, Cardiovascular System, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Fasting, Female, Glucose Tolerance Test, Humans, Incidence, Insulin, Insulin Resistance, Male, Middle Aged, Sleep Apnea Syndromes, Sleep Initiation and Maintenance Disorders, Snoring, United States}, issn = {1935-5548}, doi = {10.2337/dc15-0137}, author = {Strand, Linn Beate and Carnethon, Mercedes and Biggs, Mary Lou and Djouss{\'e}, Luc and Kaplan, Robert C and Siscovick, David S and Robbins, John A and Redline, Susan and Patel, Sanjay R and Janszky, Imre and Mukamal, Kenneth J} } @article {7593, title = {A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women.}, journal = {Bone Rep}, volume = {5}, year = {2016}, month = {2016 Dec}, pages = {233-242}, abstract = {

BACKGROUND: Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50-70\% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis.

METHODS: Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women{\textquoteright}s Health Initiative (WHI) (N~=~8155), Cardiovascular Health Study (CHS) (N~=~504), BioVU (N~=~704), Health ABC (N~=~651), and the Johnston County Osteoarthritis Project (JoCoOA) (N~=~291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~~2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P~<~5~{\texttimes}~10-~8.

RESULTS: One SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P~=~4.0~{\texttimes}~10-~8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2~=~0). This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed.

CONCLUSION: This GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans.

}, issn = {2352-1872}, doi = {10.1016/j.bonr.2016.08.005}, author = {Taylor, Kira C and Evans, Daniel S and Edwards, Digna R Velez and Edwards, Todd L and Sofer, Tamar and Li, Guo and Liu, Youfang and Franceschini, Nora and Jackson, Rebecca D and Giri, Ayush and Donneyong, Macarius and Psaty, Bruce and Rotter, Jerome I and LaCroix, Andrea Z and Jordan, Joanne M and Robbins, John A and Lewis, Beth and Stefanick, Marcia L and Liu, Yongmei and Garcia, Melissa and Harris, Tamara and Cauley, Jane A and North, Kari E} } @article {7246, title = {Targeted Sequencing of Genome Wide Significant Loci Associated with Bone Mineral Density (BMD) Reveals Significant Novel and Rare Variants: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.}, journal = {Hum Mol Genet}, year = {2016}, month = {2016 Sep 11}, abstract = {

BACKGROUND: Bone mineral density (BMD) is a heritable phenotype that predicts fracture risk. We performed fine-mapping by targeted sequencing at WLS, MEF2C, ARHGAP1/F2 and JAG1 loci prioritized by eQTL and bioinformatic approaches among 56 BMD loci from our previous GWAS meta-analysis.

METHODS AND RESULTS: Targeted sequencing was conducted in 1,291 Caucasians from the Framingham Heart Study (n=925) and Cardiovascular Health Study (n=366), including 206 women and men with extreme low femoral neck (FN) BMD. A total of 4,964 sequence variants (SNVs) were observed and 80\% were rare with MAF <1\%. The associations between previously identified SNPs in these loci and BMD, while nominally significant in sequenced participants, were no longer significant after multiple testing corrections. Conditional analyses did not find protein-coding variants that may be responsible for GWAS signals. On the other hand, in the sequenced subjects, we identified novel associations in WLS, ARHGAP1, and 5{\textquoteright} of MEF2C (p-values < 8x10(-5); false discovery rate (FDR) q-values < 0.01) that were much more strongly associated with BMD compared to the GWAS SNPs. These associated SNVs are less-common; independent from previous GWAS signals in the same loci; and located in gene regulatory elements.

CONCLUSIONS: Our findings suggest that protein-coding variants in selected GWAS loci did not contribute to GWAS signals. By performing targeted sequencing in GWAS loci, we identified less-common and rare non-coding SNVs associated with BMD independently from GWAS common SNPs, suggesting both common and less-common variants may associate with disease risks and phenotypes in the same loci.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddw289}, author = {Hsu, Yi-Hsiang and Li, Guo and Liu, Ching-Ti and Brody, Jennifer A and Karasik, David and Chou, Wen-Chi and Demissie, Serkalem and Nandakumar, Kannabiran and Zhou, Yanhua and Cheng, Chia-Ho and Gill, Richard and Gibbs, Richard A and Muzny, Donna and Santibanez, Jireh and Estrada, Karol and Rivadeneira, Fernando and Harris, Tamara and Gudnason, Vilmundur and Uitterlinden, Andre and Psaty, Bruce M and Robbins, John A and Adrienne Cupples, L and Kiel, Douglas P} } @article {7341, title = {Association of Plasma SDF-1 with Bone Mineral Density, Body Composition, and Hip Fractures in Older Adults: The Cardiovascular Health Study.}, journal = {Calcif Tissue Int}, volume = {100}, year = {2017}, month = {2017 Jun}, pages = {599-608}, abstract = {

Aging is associated with an increase in circulating inflammatory factors. One, the cytokine stromal cell-derived factor 1 (SDF-1 or CXCL12), is critical to stem cell mobilization, migration, and homing as well as to bone marrow stem cell (BMSC), osteoblast, and osteoclast function. SDF-1 has pleiotropic roles in bone formation and BMSC differentiation into osteoblasts/osteocytes, and in osteoprogenitor cell survival. The objective of this study was to examine the association of plasma SDF-1 in participants in the cardiovascular health study (CHS) with bone mineral density (BMD), body composition, and incident hip fractures. In 1536 CHS participants, SDF-1 plasma levels were significantly associated with increasing age (p < 0.01) and male gender (p = 0.04), but not with race (p = 0.63). In multivariable-adjusted models, higher SDF-1 levels were associated with lower total hip BMD (p = 0.02). However, there was no significant association of SDF-1 with hip fractures (p = 0.53). In summary, circulating plasma levels of SDF-1 are associated with increasing age and independently associated with lower total hip BMD in both men and women. These findings suggest that SDF-1 levels are linked to bone homeostasis.

}, issn = {1432-0827}, doi = {10.1007/s00223-017-0245-8}, author = {Carbone, Laura D and B{\r u}zkov{\'a}, Petra and Fink, Howard A and Robbins, John A and Bethel, Monique and Hamrick, Mark W and Hill, William D} } @article {7600, title = {Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 Jul 19}, pages = {80}, abstract = {

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 {\texttimes} 10-8) or suggestively genome wide (p < 2.3 {\texttimes} 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

}, issn = {2041-1723}, doi = {10.1038/s41467-017-00031-7}, author = {Zillikens, M Carola and Demissie, Serkalem and Hsu, Yi-Hsiang and Yerges-Armstrong, Laura M and Chou, Wen-Chi and Stolk, Lisette and Livshits, Gregory and Broer, Linda and Johnson, Toby and Koller, Daniel L and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Malkin, Ida and Ried, Janina S and Smith, Albert V and Thorleifsson, Gudmar and Vandenput, Liesbeth and Hua Zhao, Jing and Zhang, Weihua and Aghdassi, Ali and {\r A}kesson, Kristina and Amin, Najaf and Baier, Leslie J and Barroso, In{\^e}s and Bennett, David A and Bertram, Lars and Biffar, Rainer and Bochud, Murielle and Boehnke, Michael and Borecki, Ingrid B and Buchman, Aron S and Byberg, Liisa and Campbell, Harry and Campos Obanda, Natalia and Cauley, Jane A and Cawthon, Peggy M and Cederberg, Henna and Chen, Zhao and Cho, Nam H and Jin Choi, Hyung and Claussnitzer, Melina and Collins, Francis and Cummings, Steven R and De Jager, Philip L and Demuth, Ilja and Dhonukshe-Rutten, Rosalie A M and Diatchenko, Luda and Eiriksdottir, Gudny and Enneman, Anke W and Erdos, Mike and Eriksson, Johan G and Eriksson, Joel and Estrada, Karol and Evans, Daniel S and Feitosa, Mary F and Fu, Mao and Garcia, Melissa and Gieger, Christian and Girke, Thomas and Glazer, Nicole L and Grallert, Harald and Grewal, Jagvir and Han, Bok-Ghee and Hanson, Robert L and Hayward, Caroline and Hofman, Albert and Hoffman, Eric P and Homuth, Georg and Hsueh, Wen-Chi and Hubal, Monica J and Hubbard, Alan and Huffman, Kim M and Husted, Lise B and Illig, Thomas and Ingelsson, Erik and Ittermann, Till and Jansson, John-Olov and Jordan, Joanne M and Jula, Antti and Karlsson, Magnus and Khaw, Kay-Tee and Kilpel{\"a}inen, Tuomas O and Klopp, Norman and Kloth, Jacqueline S L and Koistinen, Heikki A and Kraus, William E and Kritchevsky, Stephen and Kuulasmaa, Teemu and Kuusisto, Johanna and Laakso, Markku and Lahti, Jari and Lang, Thomas and Langdahl, Bente L and Launer, Lenore J and Lee, Jong-Young and Lerch, Markus M and Lewis, Joshua R and Lind, Lars and Lindgren, Cecilia and Liu, Yongmei and Liu, Tian and Liu, Youfang and Ljunggren, Osten and Lorentzon, Mattias and Luben, Robert N and Maixner, William and McGuigan, Fiona E and Medina-G{\'o}mez, Carolina and Meitinger, Thomas and Melhus, H{\r a}kan and Mellstr{\"o}m, Dan and Melov, Simon and Micha{\"e}lsson, Karl and Mitchell, Braxton D and Morris, Andrew P and Mosekilde, Leif and Newman, Anne and Nielson, Carrie M and O{\textquoteright}Connell, Jeffrey R and Oostra, Ben A and Orwoll, Eric S and Palotie, Aarno and Parker, Stephen C J and Peacock, Munro and Perola, Markus and Peters, Annette and Polasek, Ozren and Prince, Richard L and R{\"a}ikk{\"o}nen, Katri and Ralston, Stuart H and Ripatti, Samuli and Robbins, John A and Rotter, Jerome I and Rudan, Igor and Salomaa, Veikko and Satterfield, Suzanne and Schadt, Eric E and Schipf, Sabine and Scott, Laura and Sehmi, Joban and Shen, Jian and Soo Shin, Chan and Sigurdsson, Gunnar and Smith, Shad and Soranzo, Nicole and Stan{\v c}{\'a}kov{\'a}, Alena and Steinhagen-Thiessen, Elisabeth and Streeten, Elizabeth A and Styrkarsdottir, Unnur and Swart, Karin M A and Tan, Sian-Tsung and Tarnopolsky, Mark A and Thompson, Patricia and Thomson, Cynthia A and Thorsteinsdottir, Unnur and Tikkanen, Emmi and Tranah, Gregory J and Tuomilehto, Jaakko and van Schoor, Natasja M and Verma, Arjun and Vollenweider, Peter and V{\"o}lzke, Henry and Wactawski-Wende, Jean and Walker, Mark and Weedon, Michael N and Welch, Ryan and Wichmann, H-Erich and Widen, Elisabeth and Williams, Frances M K and Wilson, James F and Wright, Nicole C and Xie, Weijia and Yu, Lei and Zhou, Yanhua and Chambers, John C and D{\"o}ring, Angela and van Duijn, Cornelia M and Econs, Michael J and Gudnason, Vilmundur and Kooner, Jaspal S and Psaty, Bruce M and Spector, Timothy D and Stefansson, Kari and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Ossowski, Vicky and Waterworth, Dawn and Loos, Ruth J F and Karasik, David and Harris, Tamara B and Ohlsson, Claes and Kiel, Douglas P} } @article {7930, title = {Association of bone mineral density with hemoglobin and change in hemoglobin among older men and women: The Cardiovascular Health Study.}, journal = {Bone}, volume = {120}, year = {2018}, month = {2018 Nov 15}, pages = {321-326}, abstract = {

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.

}, issn = {1873-2763}, doi = {10.1016/j.bone.2018.11.010}, author = {Valderr{\'a}bano, Rodrigo J and B{\r u}zkov{\'a}, Petra and Chang, Po-Yin and Zakai, Neil A and Fink, Howard A and Robbins, John A and Lee, Jennifer S and Wu, Joy Y} } @article {7787, title = {Sleep characteristics that predict atrial fibrillation.}, journal = {Heart Rhythm}, volume = {15}, year = {2018}, month = {2018 Sep}, pages = {1289-1295}, abstract = {

BACKGROUND: The relationship between sleep disruption, independent of obstructive sleep apnea (OSA), and atrial fibrillation (AF) is unknown.

OBJECTIVE: The purpose of this study was to determine whether poor sleep itself is a risk factor for AF.

METHODS: We first performed an analysis of participants in the Health eHeart Study and validated those findings in the longitudinal Cardiovascular Health Study, including a subset of patients undergoing polysomnography. To determine whether the observed relationships readily translated to medical practice, we examined 2005-2009 data from the California Healthcare Cost and Utilization Project.

RESULTS: Among 4553 Health eHeart participants, the 526 with AF exhibited more frequent nighttime awakening (odd ratio [OR] 1.47; 95\% confidence interval [CI] 1.14-1.89; P = .003). In 5703 Cardiovascular Health Study participants followed for a median 11.6 years, frequent nighttime awakening predicted a 33\% greater risk of AF (hazard ratio [HR] 1.33; 95\% CI 1.17-1.51; P <.001). In patients with polysomnography (N = 1127), every standard deviation percentage decrease in rapid eye movement (REM) sleep was associated with a 18\% higher risk of developing AF (HR 1.18; 95\% CI 1.00-1.38; P = .047). Among 14,330,651 California residents followed for a median 3.9 years, an insomnia diagnosis predicted a 36\% increased risk of new AF (HR 1.36; 95\% CI 1.30-1.42; P <.001).

CONCLUSION: Sleep disruption consistently predicted AF before and after adjustment for OSA and other potential confounders across several different populations. Sleep quality itself may be important in the pathogenesis of AF, potentially representing a novel target for prevention.

}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2018.05.008}, author = {Christensen, Matthew A and Dixit, Shalini and Dewland, Thomas A and Whitman, Isaac R and Nah, Gregory and Vittinghoff, Eric and Mukamal, Kenneth J and Redline, Susan and Robbins, John A and Newman, Anne B and Patel, Sanjay R and Magnani, Jared W and Psaty, Bruce M and Olgin, Jeffrey E and Pletcher, Mark J and Heckbert, Susan R and Marcus, Gregory M} } @article {8104, title = {The Association of Aromatic Amino Acids with Incident Hip Fracture, aBMD, and Body Composition from the Cardiovascular Health Study.}, journal = {Calcif Tissue Int}, volume = {105}, year = {2019}, month = {2019 Aug}, pages = {161-172}, abstract = {

In 5187 persons~from the Cardiovascular Health Study,~there was no significant association of dietary intakes of aromatic amino acids (AAA) with areal BMD of the hip~or body composition. However, those who had the lowest dietary intakes of AAA were at increased risk for incident hip fractures. Prior studies of the association of protein intake with osteoporosis are conflicting and have not directly examined the relationship of aromatic amino acids (AAA) with fractures, areal bone mineral density (aBMD), and body composition. We sought to determine the relationship of dietary intakes of AAA with osteoporosis parameters in elderly men and women. 5187 men and women aged >= 65~years from the Cardiovascular Health Study (CHS) with dietary intakes of AAA (tryptophan, phenylalanine, tyrosine) estimated by food frequency questionnaire (FFQ) were included. We examined the relationship between a one-time estimate of daily dietary AAA intake with risk of incident hip fractures over a median of 13.2~years of fracture follow-up. A subset (n = 1336) who had dual energy X-ray absorptiometry (DXA) performed were included in a cross-sectional analysis of the association of dietary AAA intake with aBMD of the total hip and measurements of body composition. In multivariable models adjusted for demographic and clinical variables, medication use, and diet, higher dietary AAA intake was not significantly associated with incident hip fractures. All hazard ratios (HR) were less than one (tryptophan, HR 0.14, 95\% CI 0.01 to 1.89; phenylalanine, HR 0.60, 95\% CI 0.23 to 1.55; tyrosine, HR 0.59, 95\% CI 0.27 to 1.32), but confidence intervals were wide and included no difference. However, in post hoc analyses, the lowest quartile of intake for each AAA was associated with an increased risk for hip fracture compared to higher quartiles (p <= 0.047 for all). Dietary AAA intakes were not significantly associated with total hip aBMD or any measurements of body composition. Overall, there was no significant association of dietary AAA intake with hip fractures, aBMD of the hip, or body composition. However, there may be a subset of elderly individuals with low dietary intakes of AAA who are at increased for hip fractures.

}, issn = {1432-0827}, doi = {10.1007/s00223-019-00562-9}, author = {Le, Brian and B{\r u}zkov{\'a}, Petra and Robbins, John A and Fink, Howard A and Raiford, Mattie and Isales, Carlos M and Shikany, James M and Coughlin, Steven S and Carbone, Laura D} } @article {7967, title = {Association of Dietary Niacin Intake With Incident Hip Fracture, BMD, and Body Composition: The Cardiovascular Health Study.}, journal = {J Bone Miner Res}, year = {2019}, month = {2019 Jan 19}, abstract = {

Interest in niacin has increased in the setting of reports suggesting that niacin plays a role in diseases of aging. No study to date has examined the association of dietary niacin intake with multiple skeletal health parameters including bone mineral density (BMD), hip fractures, and body composition, and none have included both African American and white men and women. Participants included 5187 men and women >=65 years from the Cardiovascular Health Study (CHS). Mean daily dietary niacin intake was 32.6 mg, with quartiles 1 through 4 defined as 3.6 to 21.8 mg/day, 21.9 to 30.2 mg/day, 30.3 to 40.9 mg/day, and 41.0 to 102.4 mg/day, respectively. Risk of incident hip fracture per 10 mg increment of daily dietary niacin intake was estimated using proportional hazards models. During a median follow-up of 13 years, 725 participants had an incident hip fracture. In models adjusted for demographic and clinical characteristics and diet, dietary niacin intake was significantly associated with an increased risk of hip fractures (hazard ratio [HR] 1.12; 95\% CI, 1.01 to 1.24) with spline models suggesting a U-shaped association. In post hoc analyses, both the lowest (HR 1.31; 95\% CI, 1.04 to 1.66) and highest (HR 1.53; 95\% CI, 1.20 to 1.95) quartiles of niacin intake were associated with an increased risk of incident hip fracture versus quartiles 2 and 3. There was a trend for a significant inverse association of dietary niacin intake with hip BMD (p = 0.06), but no significant association with total body BMD or any body composition measures. In this cohort of elderly, community-dwelling African American and white men and women, both high and low dietary niacin intakes were associated with a significantly increased risk of subsequent hip fracture, suggesting a possible U-shaped association. By comparison, dietary niacin may have an inverse linear association with hip BMD. {\textcopyright} 2018 American Society for Bone and Mineral Research.

}, issn = {1523-4681}, doi = {10.1002/jbmr.3639}, author = {Carbone, Laura D and B{\r u}zkov{\'a}, Petra and Fink, Howard A and Raiford, Mattie and Le, Brian and Isales, Carlos M and Shikany, James M and Coughlin, Steven S and Robbins, John A} } @article {7974, title = {Disentangling the genetics of lean mass.}, journal = {Am J Clin Nutr}, volume = {109}, year = {2019}, month = {2019 Feb 01}, pages = {276-287}, abstract = {

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n~=~38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

}, issn = {1938-3207}, doi = {10.1093/ajcn/nqy272}, author = {Karasik, David and Zillikens, M Carola and Hsu, Yi-Hsiang and Aghdassi, Ali and {\r A}kesson, Kristina and Amin, Najaf and Barroso, In{\^e}s and Bennett, David A and Bertram, Lars and Bochud, Murielle and Borecki, Ingrid B and Broer, Linda and Buchman, Aron S and Byberg, Liisa and Campbell, Harry and Campos-Obando, Natalia and Cauley, Jane A and Cawthon, Peggy M and Chambers, John C and Chen, Zhao and Cho, Nam H and Choi, Hyung Jin and Chou, Wen-Chi and Cummings, Steven R and de Groot, Lisette C P G M and De Jager, Phillip L and Demuth, Ilja and Diatchenko, Luda and Econs, Michael J and Eiriksdottir, Gudny and Enneman, Anke W and Eriksson, Joel and Eriksson, Johan G and Estrada, Karol and Evans, Daniel S and Feitosa, Mary F and Fu, Mao and Gieger, Christian and Grallert, Harald and Gudnason, Vilmundur and Lenore, Launer J and Hayward, Caroline and Hofman, Albert and Homuth, Georg and Huffman, Kim M and Husted, Lise B and Illig, Thomas and Ingelsson, Erik and Ittermann, Till and Jansson, John-Olov and Johnson, Toby and Biffar, Reiner and Jordan, Joanne M and Jula, Antti and Karlsson, Magnus and Khaw, Kay-Tee and Kilpel{\"a}inen, Tuomas O and Klopp, Norman and Kloth, Jacqueline S L and Koller, Daniel L and Kooner, Jaspal S and Kraus, William E and Kritchevsky, Stephen and Kutalik, Zolt{\'a}n and Kuulasmaa, Teemu and Kuusisto, Johanna and Laakso, Markku and Lahti, Jari and Lang, Thomas and Langdahl, Bente L and Lerch, Markus M and Lewis, Joshua R and Lill, Christina and Lind, Lars and Lindgren, Cecilia and Liu, Yongmei and Livshits, Gregory and Ljunggren, Osten and Loos, Ruth J F and Lorentzon, Mattias and Luan, Jian{\textquoteright}an and Luben, Robert N and Malkin, Ida and McGuigan, Fiona E and Medina-G{\'o}mez, Carolina and Meitinger, Thomas and Melhus, H{\r a}kan and Mellstr{\"o}m, Dan and Micha{\"e}lsson, Karl and Mitchell, Braxton D and Morris, Andrew P and Mosekilde, Leif and Nethander, Maria and Newman, Anne B and O{\textquoteright}Connell, Jeffery R and Oostra, Ben A and Orwoll, Eric S and Palotie, Aarno and Peacock, Munro and Perola, Markus and Peters, Annette and Prince, Richard L and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Ralston, Stuart H and Ripatti, Samuli and Rivadeneira, Fernando and Robbins, John A and Rotter, Jerome I and Rudan, Igor and Salomaa, Veikko and Satterfield, Suzanne and Schipf, Sabine and Shin, Chan Soo and Smith, Albert V and Smith, Shad B and Soranzo, Nicole and Spector, Timothy D and Stan{\v c}{\'a}kov{\'a}, Alena and Stefansson, Kari and Steinhagen-Thiessen, Elisabeth and Stolk, Lisette and Streeten, Elizabeth A and Styrkarsdottir, Unnur and Swart, Karin M A and Thompson, Patricia and Thomson, Cynthia A and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tikkanen, Emmi and Tranah, Gregory J and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and van Schoor, Natasja M and Vandenput, Liesbeth and Vollenweider, Peter and V{\"o}lzke, Henry and Wactawski-Wende, Jean and Walker, Mark and J Wareham, Nicholas and Waterworth, Dawn and Weedon, Michael N and Wichmann, H-Erich and Widen, Elisabeth and Williams, Frances M K and Wilson, James F and Wright, Nicole C and Yerges-Armstrong, Laura M and Yu, Lei and Zhang, Weihua and Zhao, Jing Hua and Zhou, Yanhua and Nielson, Carrie M and Harris, Tamara B and Demissie, Serkalem and Kiel, Douglas P and Ohlsson, Claes} } @article {8259, title = {Higher albumin:creatinine ratio and lower estimated glomerular filtration rate are potential risk factors for decline of physical performance in the elderly: the Cardiovascular Health Study.}, journal = {Clin Kidney J}, volume = {12}, year = {2019}, month = {2019 Dec}, pages = {788-794}, abstract = {

Introduction: Mildly reduced renal function and elevated urine protein levels are each prospectively associated with hip fracture risk in older adults. Here we determine whether these markers are associated with reduced appendicular muscle performance.

Methods: We prospectively examined the associations of urine albumin:creatinine ratio (ACR) and reduced estimated glomerular filtration rate (eGFR) with longitudinal changes in grip strength and gait speed >2 years in 2317 older community-dwelling men and women (median age 77 years). The median ACR was 9.8 [interquartile range (IQR) 5.40-21.50]~mg/g creatinine and the median eGFR was 71.6 (IQR 59.1-83.56)~mL/min/1.73~m. Models were adjusted for demographic factors, clinical history and biochemical measures in four candidate pathways: diabetes, oxidative stress, inflammation and fibrosis.

Results: In demographic- and covariate-adjusted models, a 2-fold higher baseline urine ACR was associated with longitudinal changes of -0.17 kg [95\% confidence interval (CI) -0.29 to -0.06)~in grip strength and -1.10 cm/s (95\% CI -1.67 to -0.53) gait speed per year. Corresponding estimates for a 10 mL/min/1.73~m lower baseline eGFR were -0.13 kg (95\% CI -0.23 to -0.04)~and -0.89 cm/s (95\% CI -1.37 to -0.40), respectively. The associations of a 2-fold higher baseline ACR and a 10 mL/min/1.73~m lower baseline eGFR using cystatin C with grip strength and gait speed were equivalent to \~{}1.2-1.9 additional years of age. Adjustment for covariates in candidate pathways did not attenuate these estimates.

Conclusions: In older adults, higher ACR and lower eGFR are potential risk factors for a decline of physical performance >2 years.

}, issn = {2048-8505}, doi = {10.1093/ckj/sfz024}, author = {B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I and Fink, Howard A and Robbins, John A and Cauley, Jane A and Ix, Joachim H and Mukamal, Kenneth J} } @article {8627, title = {Association of skeletal muscle mass, kidney disease and mortality in older men and women: the cardiovascular health study.}, journal = {Aging (Albany NY)}, volume = {12}, year = {2020}, month = {2020 11 02}, pages = {21023-21036}, abstract = {

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.

}, issn = {1945-4589}, doi = {10.18632/aging.202135}, author = {Kruse, Nicholas T and B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I and Valderr{\'a}bano, Rodrigo J and Robbins, John A and Fink, Howard A and Jalal, Diana I} } @article {9004, title = {Cardiovascular autonomic nervous system function and hip fracture risk: the Cardiovascular Health Study.}, journal = {Arch Osteoporos}, volume = {16}, year = {2021}, month = {2021 10 31}, pages = {163}, abstract = {

Among 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15~years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants.

PURPOSE: Autonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans.

METHODS: Participants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8~years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7~years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95\% confidence intervals, CI).

RESULTS: There were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24~h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR [Formula: see text] 0.80; 95\% CI 0.65-0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR [Formula: see text] 0.82; 95\% CI, 0.66-1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other{\textquoteright}s association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95\% CI, 0.50-0.99; p = 0.05). No HRV variables were associated with hip fracture in men.

CONCLUSIONS: In older women, increased heart rate variation is associated with hip fracture risk.

}, keywords = {Aged, Autonomic Nervous System, Female, Heart Rate, Hip Fractures, Humans, Osteoporosis, Proportional Hazards Models}, issn = {1862-3514}, doi = {10.1007/s11657-021-01028-y}, author = {Stein, Phyllis K and B{\r u}zkov{\'a}, Petra and Fink, Howard A and Robbins, John A and Mukamal, Kenneth J and Cauley, Jane A and Carbone, Laura and Elam, Rachel and McMillan, David W and Valderrabano, Rodrigo and Barzilay, Joshua I} } @article {9087, title = {The Association of Lipids and Lipoproteins with Hip Fracture Risk the Cardiovascular Health Study.}, journal = {Am J Med}, year = {2022}, month = {2022 Jun 06}, abstract = {

BACKGROUND: It is uncertain if lipids or lipoproteins are associated with osteoporotic fractures. In this study, incident hip fracture risk according to conventional lipid levels and lipoprotein levels and sizes was examined.

METHODS: We followed 5832 participants aged >=65 years from the Cardiovascular Health Study for hip fracture for a mean of 13.5 (SD 5.7) years. Standard enzymatic methods were used to determine lipid levels (HDL-c, LDL-c, triglycerides). Nuclear magnetic resonance spectroscopy was used to measure lipoprotein fractions (VLDL-P, LDL-P, HDL-P) in a subset of 1849 participants.

RESULTS: We documented 755 incident hip fractures among women (1.19 fractures per 100 participant years [95\% CI, 1.04, 1.35]) and 197 among men (0.67 fractures per 100 participant years [95\% CI, 0.41, 1.10]) over an average follow-up. HDL-c and LDL-c levels had statistically significant non-linear U-shaped relationships with hip fracture risk (HDL-c, p=0.009; LDL-c, p=0.02). Triglyceride levels were not significantly associated with hip fracture risk. In fully adjusted conjoint models, higher VLDL-P concentration [HR per 1-standard (SD) increment 1.47 (1.13, 1.91)] and size [HR per 1-SD increment 1.24 [1.05, 1.46]) and higher HDL-P size (HR per 1-SD increment 1.81 [1.25, 2.62]) were all associated with higher hip fracture risk.

CONCLUSIONS: Lipids and lipoproteins are associated with hip fracture risk in older adults. The associations are complex. Mechanistic studies are needed to understand these findings.

}, issn = {1555-7162}, doi = {10.1016/j.amjmed.2022.05.024}, author = {Barzilay, Joshua I and B{\r u}zkov{\'a}, Petra and Kuller, Lewis H and Cauley, Jane A and Fink, Howard A and Sheets, Kerry and Robbins, John A and Carbone, Laura D and Elam, Rachel E and Mukamal, Kenneth J} } @article {9089, title = {Trimethylamine N-oxide and hip fracture and bone mineral density in older adults: The cardiovascular health study.}, journal = {Bone}, volume = {161}, year = {2022}, month = {2022 08}, pages = {116431}, abstract = {

CONTEXT: Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) may adversely affect bone by inducing oxidative stress. Whether this translates into increased fracture risk in older adults is uncertain.

OBJECTIVE: Determine the associations of plasma TMAO with hip fracture and bone mineral density (BMD) in older adults.

DESIGN AND SETTING: Cox hazard models and linear regression stratified by sex examined the associations of TMAO with hip fracture and BMD in the longitudinal cohort of the Cardiovascular Health Study.

PARTICIPANTS: 5019~U.S. adults aged >=65~years.

EXPOSURE: Plasma TMAO.

MAIN OUTCOME MEASURES: Incident hip fractures; total hip BMD dual x-ray absorptiometry in a subset (n~=~1400).

RESULTS: Six hundred sixty-six incident hip fractures occurred during up to 26~years of follow-up (67,574 person-years). After multivariable adjustment, TMAO was not significantly associated with hip fracture (women: hazard ratio (HR) [95\% confidence interval (CI)] of 1.00[0.92,1.09] per TMAO doubling; men: 1.12[0.95,1.33]). TMAO was also not associated with total hip BMD (women: BMD difference [95\% CI] of 0.42~g/cm*100 [-0.34,1.17] per TMAO doubling; men: 0.19[-1.04,1.42]). In exploratory analyses, we found an interaction between body mass index (BMI) and the association of TMAO with hip fracture (P~<~0.01). Higher TMAO was significantly associated with risk of hip fracture in adults with overweight or obesity (BMI~>=~25) (HR [95\% CI]:1.17[1.05,1.31]), but not normal or underweight.

CONCLUSIONS: Among older US men and women, TMAO was not significantly associated with risk of hip fracture or BMD overall. Exploratory analyses suggested a significant association between higher TMAO and hip fracture when BMI was elevated, which merits further study.

}, keywords = {Absorptiometry, Photon, Aged, Bone Density, Female, Hip Fractures, Humans, Male, Methylamines, Risk Factors}, issn = {1873-2763}, doi = {10.1016/j.bone.2022.116431}, author = {Elam, Rachel E and B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I and Wang, Zeneng and Nemet, Ina and Budoff, Matthew J and Cauley, Jane A and Fink, Howard A and Lee, Yujin and Robbins, John A and Wang, Meng and Hazen, Stanley L and Mozaffarian, Dariush and Carbone, Laura D} } @article {9318, title = {Age-Related Factors Associated with Hip Fracture Risk.}, journal = {Endocr Pract}, year = {2023}, month = {2023 Mar 06}, abstract = {

OBJECTIVES: Advancing age is a powerful risk factor for hip fracture. The biological mechanisms through which aging impacts hip fracture risk have not been well studied.

METHODS: Biological factors associated with "advancing age" that help to explain how aging is associated with hip fracture risk are reviewed. The findings are based on analyses of the Cardiovascular Health Study, an ongoing observational study of adults ages >65 years with 25 years of follow up.

RESULTS: Five age-related factors were found to be significantly associated with hip fracture risk: (1) microvascular disease of the kidney (albuminuria and / or elevated urine albumin to creatinine ratio) and of the brain (abnormal white matter disease on brain MRI); (2) increased serum levels of carboxymethyl-lysine (CML), an advanced glycation end-product that reflects glycation and oxidative stress; (3) reduced parasympathetic tone, as derived from 24-hour Holter monitoring; (4) carotid artery atherosclerosis in the absence of clinical cardiovascular disease; and (5) increased trans-fatty acid levels in the blood. Each of these factors was associated with a 10-25\%. increased risk of fracture. These associations were independent of traditional risk factors for hip fracture.

CONCLUSION: Several factors associated with older age help to explain how "aging" may be associated with hip fracture risk. These same factors may also explain the high risk for mortality following hip fracture.

}, issn = {1530-891X}, doi = {10.1016/j.eprac.2023.03.001}, author = {B{\r u}zkov{\'a}, Petra and Cauley, Jane A and Fink, Howard A and Robbins, John A and Mukamal, Kenneth J and Barzilay, Joshua I} } @article {9478, title = {Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study.}, journal = {Calcif Tissue Int}, year = {2023}, month = {2023 Aug 31}, abstract = {

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.

}, issn = {1432-0827}, doi = {10.1007/s00223-023-01126-8}, author = {Elam, Rachel E and B{\r u}zkov{\'a}, Petra and Delaney, Joseph A C and Fink, Howard A and Barzilay, Joshua I and Carbone, Laura D and Saha, Rick and Robbins, John A and Mukamal, Kenneth J and Valderr{\'a}bano, Rodrigo J and Psaty, Bruce M and Tracy, Russell P and Olson, Nels C and Huber, Sally A and Doyle, Margaret F and Landay, Alan L and Cauley, Jane A} } @article {9499, title = {The Association of Tryptophan and Its Metabolites With Incident Hip Fractures, Mortality, and Prevalent Frailty in Older Adults: The Cardiovascular Health Study.}, journal = {JBMR Plus}, volume = {7}, year = {2023}, month = {2023 Oct}, pages = {e10801}, abstract = {

Amino acids are the building blocks of proteins, and sufficient protein intake is important for skeletal health. We utilized stored serum from the Cardiovascular Health Study in 1992-1993 to examine the relationship between levels of the essential amino acid tryptophan (trp) and its oxidized and nonoxidized metabolites to risk for incident hip fractures and mortality over 12 years of follow-up. We included 131 persons who sustained a hip fracture during this time period and 131 without a hip fracture over these same 12 years of follow-up; 58\% female and 95\% White. Weighted multivariable Cox hazards models were used to estimate the hazard ratios (HR) and 95\% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher trp or its metabolites exposure. Relative risk regression was used to evaluate the cross-sectional association of trp and its metabolites with frailty. Higher serum levels of trp were significantly associated with lower risk of incident hip fractures (HR = 0.75 per SD of trp (95\% CI 0.57-0.99) but were not significantly associated with mortality or frailty status by Freid{\textquoteright}s frailty index. There were no statistically significant associations between any of the oxidized or nonoxidized products of trp with incident hip fractures ( >= 0.64), mortality ( >= 0.20), or cross-sectional frailty status ( >= 0.13) after multiple testing adjustment. Randomized clinical trials examining whether increasing trp intake is beneficial for osteoporosis are needed. {\textcopyright} 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

}, issn = {2473-4039}, doi = {10.1002/jbm4.10801}, author = {Carbone, Laura and B{\r u}zkov{\'a}, Petra and Fink, Howard A and Robbins, John A and Barzilay, Joshua I and Elam, Rachel E and Isales, Carlos} } @article {9316, title = {The associations of markers of endothelial dysfunction with hip fracture risk.}, journal = {Arch Osteoporos}, volume = {18}, year = {2023}, month = {2023 Mar 02}, pages = {39}, abstract = {

UNLABELLED: Endothelial dysfunction underlies the development of atherosclerotic vascular disease, which in turn is associated with osteoporotic fractures. Here, we examined the association of two markers of endothelial dysfunction with incident hip fracture risk in older adults but found no statistically significant associations between them.

PURPOSE/INTRODUCTION: Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk.

METHODS: Participants for this study were 2792 individuals (mean age 78.6~years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3~years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7~years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group.

RESULTS: In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1\% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80\% of FMD (<= 4.5\%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20\% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable.

CONCLUSIONS: Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.

}, keywords = {Aged, Forearm, Hip Fractures, Humans, Osteoporotic Fractures, Vascular Diseases}, issn = {1862-3514}, doi = {10.1007/s11657-023-01226-w}, author = {Barzilay, Joshua I and B{\r u}zkov{\'a}, Petra and Fink, Howard A and Cauley, Jane A and Carbone, Laura and Elam, Rachel and Robbins, John A and Stein, Phyllis and Sheets, Kerry and Jalal, Diana and Mukamal, Kenneth J} } @article {9384, title = {Mortality Following Hip Fracture in Older Adults With and Without Coronary Heart Disease.}, journal = {Am J Med}, year = {2023}, month = {2023 Apr 24}, abstract = {

BACKGROUND: Comorbidities like coronary heart disease are common among older people who sustain an osteoporotic hip fracture. However, their impact on short- and long-term mortality post-hip fracture is not well quantified.

METHODS: We examined 4092 and 1173 older adults without and with prevalent coronary heart disease, respectively. Post-hip fracture mortality rates were computed with Poisson models and hazard ratios with Cox regression. For perspective, we compared mortality rates among participants with prevalent coronary heart disease who had either a hip fracture or incident heart failure (but no hip fracture).

RESULTS: Among participants without prevalent coronary heart disease, the mortality rate post-hip fracture was 21.83 per 100 participant years, including 49.27 per 100 participant years in the first 6 months following hip fracture. Among participants with prevalent coronary heart disease, the corresponding mortality rates were 32.52 and 79.44 per 100 participant years, respectively. Participants with prevalent coronary heart disease and incident heart failure (but no hip fracture) had corresponding post-incident heart failure mortality rates per 100 participant years of 25.62 overall and 46.4 in the first 6 months. In all 3 groups, the hazard ratio for mortality was similarly elevated: 5- to 7-fold at 6 months and 1.7- to 2.5-fold beyond 5 years.

CONCLUSION: As a case study in the absolute effects of a comorbidity on post-hip fracture mortality, hip fracture in a person with coronary heart disease carries an exceedingly high mortality rate, even higher than that following incident heart failure in individuals with coronary heart disease.

}, issn = {1555-7162}, doi = {10.1016/j.amjmed.2023.03.036}, author = {Robbins, John A and B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I and Cauley, Jane A and Fink, Howard A and Carbone, Laura D and Chen, Zhao and Stein, Phyllis K and Elam, Rachel and Sheets, Kerry and Mukamal, Kenneth J} } @article {9375, title = {Plasma Levels of Branched Chain Amino Acids, Incident Hip Fractures and Bone Mineral Density of the Hip and Spine.}, journal = {J Clin Endocrinol Metab}, year = {2023}, month = {2023 May 18}, abstract = {

OBJECTIVE: Branched chain amino acids (BCAA) are building blocks for protein, an essential component of bone. However, the association of plasma levels of BCAA with fractures in populations outside of Hong Kong or with hip fractures in particular is not known. The purpose of these analyses was to determine the relationship of BCAA including valine, leucine and isoleucine and total BCAA (standard deviation of the sum of Z-scores for each BCAA) with incident hip fractures and bone mineral density (BMD) of the hip and lumbar spine in older African American and Caucasian men and women in the Cardiovascular Health Study (CHS).

DESIGN: Longitudinal analyses of association of plasma levels of BCAA with incident hip fractures and cross-sectional BMD of the hip and lumbar spine from the CHS.

SETTING: Community.

PARTICIPANTS: 1850 men (38\% of cohort) and women; mean age 73.

MAIN OUTCOME MEASURES: Incident hip fractures and cross-sectional BMD of the total hip, femoral neck and lumbar spine.

RESULTS: In fully adjusted models, over 12 years of follow-up, we observed no significant association between incident hip fracture and plasma values of valine, leucine, isoleucine or total BCAA per 1 standard deviation higher of each BCAA. Plasma values of leucine but not valine, isoleucine or total BCAA, were positively and significantly associated with BMD of the total hip (p = 0.03) and femoral neck (p = 0.02), but not the lumbar spine (p = 0.07).

CONCLUSIONS: Plasma levels of the BCAA leucine may be associated with higher BMD in older men and women. However, given lack of a significant association with hip fracture risk, further information is needed to determine whether BCAAs would be novel targets for osteoporosis therapies.

}, issn = {1945-7197}, doi = {10.1210/clinem/dgad275}, author = {Carbone, Laura and B{\r u}zkov{\'a}, Petra and Fink, Howard A and Robbins, John A and Barzilay, Joshua I and Elam, Rachel E and Isales, Carlos and Connelly, Margery A and Mukamal, Kenneth J} } @article {9635, title = {Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.}, journal = {J Bone Miner Res}, year = {2024}, month = {2024 Jan 04}, abstract = {

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 Tr{\o}ndelag 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 {\texttimes} 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.

}, issn = {1523-4681}, doi = {10.1093/jbmr/zjad011}, author = {Austin, Thomas R and Fink, Howard A and Jalal, Diana I and T{\"o}rnqvist, Anna E and B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I and Lu, Tianyuan and Carbone, Laura and Gabrielsen, Maiken E and Grahnemo, Louise and Hveem, Kristian and Jonasson, Christian and Kizer, Jorge R and Langhammer, Arnulf and Mukamal, Kenneth J and Gerszten, Robert E and Nethander, Maria and Psaty, Bruce M and Robbins, John A and Sun, Yan V and Skogholt, Anne Heidi and {\r A}svold, Bj{\o}rn Olav and Valderr{\'a}bano, Rodrigo J and Zheng, Jie and Richards, J Brent and Coward, Eivind and Ohlsson, Claes} }