@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 {7344, title = {Bone Mineral Density and Risk of Heart Failure in Older Adults: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {6}, year = {2017}, month = {2017 Mar 13}, abstract = {

BACKGROUND: Despite increasing evidence of a common link between bone and heart health, the relationship between bone mineral density (BMD) and heart failure (HF) risk remains insufficiently studied.

METHODS AND RESULTS: We investigated whether BMD measured by dual-energy x-ray absorptiometry was associated with incident HF in an older cohort. Cox models were stratified by sex and interactions of BMD with race assessed. BMD was examined at the total hip and femoral neck separately, both continuously and by World Health Organization categories. Of 1250 participants, 442 (55\% women) developed HF during the median follow-up of 10.5~years. In both black and nonblack women, neither total hip nor femoral neck BMD was significantly associated with HF; there was no significant interaction by race. In black and nonblack men, total hip, but not femoral neck, BMD was significantly associated with HF, with evidence of an interaction by race. In nonblack men, lower total hip BMD was associated with higher HF risk (hazard ratio, 1.13 [95\% CI, 1.01-1.26] per 0.1~g/cm(2) decrement), whereas in black men, lower total hip BMD was associated with lower HF risk (hazard ratio, 0.74 [95\% CI, 0.59-0.94]). There were no black men with total hip osteoporosis. Among nonblack men, total hip osteoporosis was associated with higher HF risk (hazard ratio, 2.83 [95\% CI, 1.39-5.74]) compared with normal BMD.

CONCLUSIONS: Among older adults, lower total hip BMD was associated with higher HF risk in nonblack men but lower risk in black men, with no evidence of an association in women. Further research is needed to replicate these findings and to study potential underlying pathways.

}, issn = {2047-9980}, doi = {10.1161/JAHA.116.004344}, author = {Fohtung, Raymond B and Brown, David L and Koh, William J H and Bartz, Traci M and Carbone, Laura D and Civitelli, Roberto and Stein, Phyllis K and Chaves, Paulo H M and Kestenbaum, Bryan R and Kizer, Jorge R} } @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 {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 {9242, title = {Association of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study.}, journal = {Osteoporos Int}, volume = {34}, year = {2023}, month = {2023 Jan}, pages = {91-99}, abstract = {

UNLABELLED: Covert brain infarcts and white matter hyperintensities (WMHs), incidental markers of brain microvascular disease commonly seen on brain MRIs in older adults, have been associated with falls and lower bone mineral density. We found covert infarcts and WMHs may also be associated with an increased risk of future hip fracture.

INTRODUCTION: To determine whether covert infarcts and white matter hyperintensities (WMHs) are associated with increased risk of incident hip fracture.

METHODS: A prospective cohort of 3373 community-dwelling adults aged >= 65~years enrolled in the Cardiovascular Health Study with a brain MRI (1992-1993) was analyzed. Covert infarcts were categorized by number of infarcts and largest infarct size. WMH burden was assessed by radiologists and graded qualitatively from 0 (no WMHs) to 9 (extensive).

RESULTS: Participants had 465 incident hip fractures during a mean follow-up of 12.8~years. The demographic-adjusted hazard of incident hip fracture was 32\% higher among participants with >= 1 covert infarct compared to those without infarcts (hazard ratio (HR) 1.32; 95\% CI, 1.08-1.62). The hazard of incident hip fracture was similar after further adjustment for medications and medical history (HR = 1.34; 95\% CI, 1.08-1.65), but attenuated following additional adjustment for functional status, frailty, and falls (HR = 1.25; 95\% CI, 0.99-1.57). Fully adjusted hazard of incident hip fracture per increase in infarct number was 1.10 (95\% CI, 0.98-1.23); risk in individuals whose largest infarct was >= 20~mm versus 3 to < 20~mm was similar. Compared with WMH grades 0-1, the demographic-adjusted hazard of hip fracture was 1.34 (95\% CI, 1.09-1.66) and 1.83 (95\% CI, 1.37-2.46), respectively, for WMH grades 2-3 and 4-9. The hazard was similar following adjustment for medications and medical history (grades 2-3: HR = 1.32; 95\% CI, 1.05-1.64; grades 4-9: HR = 1.69; 95\% CI, 1.23-2.30), but attenuated following additional adjustment for functional status, frailty, and falls (grades 2-3: HR = 1.24; 95\% CI, 0.98-1.56; grades 4-9: HR = 1.34; 95\% CI, 0.95-1.90).

CONCLUSION: Older, community-dwelling adults with covert infarcts or WMHs may be at increased risk of hip fracture.

}, keywords = {Aged, Brain Infarction, Frailty, Hip Fractures, Humans, Prospective Studies, Risk Factors, White Matter}, issn = {1433-2965}, doi = {10.1007/s00198-022-06565-x}, author = {Sheets, Kerry M and B{\r u}zkov{\'a}, Petra and Chen, Zhao and Carbone, Laura D and Cauley, Jane A and Barzilay, Joshua I and Starks, Jamie L and Miller, Lindsay M and Fink, Howard A} } @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 {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} }