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Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy: Secondary Analysis From the FOURIER Randomized Clinical Trial.
Deedwania, P, Murphy, SA, Scheen, A, Badariene, J, Pineda, AL, Honarpour, N, Keech, AC, Sever, PS, Pedersen, TR, Sabatine, MS, et al
JAMA cardiology. 2021;(2):139-147
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Abstract
IMPORTANCE The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Patients with metabolic syndrome (MetS) are at increased cardiovascular risk. OBJECTIVE To investigate outcomes with evolocumab in patients with and without MetS. DESIGN, SETTING, AND PARTICIPANTS The FOURIER trial randomized patients worldwide with stable atherosclerotic cardiovascular disease receiving statin to evolocumab vs placebo with follow-up for a median of 2.2 years. Data were collected February 2013 to November 2016. For this prespecified analysis, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria; in secondary analyses, patients were further substratified by diabetes at baseline. Analysis was intention to treat. Analysis began March 2018 and ended April 2020. INTERVENTIONS Patients were randomized to evolocumab or placebo. MAIN OUTCOMES AND MEASURES The primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was cardiovascular death, myocardial infarction, or stroke. RESULTS Of 27 342 patients (mean [SD] age, 63 [9] years; 20 623 men [75.4%]) included in this analysis, 16 361 (59.8%) with baseline MetS were, when compared with patients without MetS, at higher risk of cardiovascular events (adjusted hazard ratio [95% CI], 1.31 [1.18-1.46]; P < .001 for the primary and 1.38 [1.20-1.57]; P < .001 for the key secondary end point). Evolocumab reduced low-density lipoprotein cholesterol similarly in patients with MetS (median [interquartile range], 92 [79-109] mg/dL vs 30 [19-48] mg/dL; P < .001) and without MetS (median [interquartile range], 92 [81-108] mg/dL vs 29 [18-44] mg/dl; P < .001). For the primary end point, the hazard ratios (95% CI) with evolocumab vs placebo were 0.83 (0.76-0.91) and 0.89 (0.79-1.01) in patients with and without MetS (P for interaction = .39). For the key secondary end point, the corresponding hazard ratios (95% CIs) were 0.76 (0.68-0.86) and 0.86 (0.74-1.01) (P for interaction = .23), respectively. Evolocumab did not increase the risk of new-onset diabetes or other major safety outcomes including worsening glycemic control, compared with placebo in patients with MetS. CONCLUSIONS AND RELEVANCE Patients with atherosclerotic cardiovascular disease and MetS have substantial residual risk of cardiovascular events despite statin therapy. Evolocumab significantly reduced low-density lipoprotein cholesterol and cardiovascular risk in patients with MetS without increasing new-onset diabetes, worsening glycemic control, or other major safety events. These data suggest the addition of evolocumab to statin therapy in patients with atherosclerotic cardiovascular disease and MetS is safe and efficacious to reduce residual cardiovascular risk. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01764633.
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Associations of body composition and physical fitness with gestational diabetes and cardiovascular health in pregnancy: Results from the HealthyMoms trial.
Henriksson, P, Sandborg, J, Söderström, E, Leppänen, MH, Snekkenes, V, Blomberg, M, Ortega, FB, Löf, M
Nutrition & diabetes. 2021;(1):16
Abstract
The aim of this study was to examine associations of body composition (fat mass index, % fat mass, fat-free mass index, body mass index) and physical fitness (cardiorespiratory fitness and handgrip strength) with gestational diabetes and cardiovascular health in early pregnancy. This cross-sectional study utilized baseline data (n = 303) collected in early pregnancy from the HealthyMoms trial. Body composition was measured using air-displacement plethysmography, cardiorespiratory fitness was assessed by means of the 6-min walk test and handgrip strength using a dynamometer. Logistic regression was used to estimate odds ratios (ORs) for gestational diabetes as well as high (defined as 1 SD above the mean) blood pressure, homeostatic model assessment for insulin resistance (HOMA-IR), and metabolic syndrome score (MetS score) per 1 SD increase in body composition and fitness variables. Fat mass index, % fat mass and body mass index were all strongly associated with gestational diabetes (ORs: 1.72-2.14, P ≤ 0.003), HOMA-IR (ORs: 3.01-3.80, P < 0.001), blood pressure (ORs: 1.81-2.05, P < 0.001) and MetS score (ORs: 3.29-3.71, P < 0.001). Associations with fat-free mass index were considerably weaker (ORs: 1.26-1.82, P = 0.001-0.15) and were strongly attenuated after adjustments for fat mass index (ORs: 0.88-1.54, P = 0.039-0.68). Finally, greater cardiorespiratory fitness was associated with lower risk of high HOMA-IR and MetS score (ORs: 0.57-0.63, P ≤ 0.004) although these associations were attenuated when accounting for fat mass index (ORs: 1.08-1.11, P ≥ 0.61). In conclusion, accurately measured fat mass index or % fat mass were strongly associated with gestational diabetes risk and markers of cardiovascular health although associations were not stronger than the corresponding ones for body mass index. Fat-free mass index had only weak associations with gestational diabetes and cardiovascular health which support that the focus during clinical care would be on excess fat mass and not fat-free mass.
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The Effect of Gum Arabic (Acacia Senegal) on Cardiovascular Risk Factors and Gastrointestinal Symptoms in Adults at Risk of Metabolic Syndrome: A Randomized Clinical Trial.
Jarrar, AH, Stojanovska, L, Apostolopoulos, V, Feehan, J, Bataineh, MF, Ismail, LC, Al Dhaheri, AS
Nutrients. 2021;(1)
Abstract
Gum Arabic (GA) is a widely-used additive in food processing, but is also historically used in a number of traditional therapies. It has been shown to have a broad range of health benefits, particularly in improving important cardiovascular risk indicators. Metabolic syndrome and its associated cardiac outcomes are a significant burden on modern healthcare systems, and complementary interventions to aid in its management are required. We aimed to examine the effect of GA on those with, or at risk of, metabolic syndrome to identify an effect on improving important disease parameters related to cardiovascular outcomes. A single-blind, randomized, placebo-controlled trial was conducted to identify the effects of daily GA supplementation on metabolic and cardiovascular risk factors. A total of 80 participants were randomized to receive 20 g of GA daily (n = 40) or placebo (1 g pectin, n = 40) for 12 weeks. Key endpoints included body-anthropometric indices, diet and physical activity assessment, and blood chemistry (HbA1c, fasting glucose, and blood lipids). Of the 80 enrolled, 61 completed the study (intervention: 31, control: 30) with 19 dropping out due to poor treatment compliance. After 12 weeks, the participants receiving the GA showed significant decreases in systolic and diastolic blood pressure, fat-free body mass, energy and carbohydrate consumption, and fasting plasma glucose, as well as increased intake of dietary fiber. They also reported improvements in self-perceived bloating and quality of bowel movements, as well as a decreased appetite score following GA consumption. These results suggest that GA could be a safe and beneficial adjunct to other treatments for those with, or at risk of, metabolic syndrome.
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The Type and Amount of Dietary Fat Affect Plasma Factor VIIc, Fibrinogen, and PAI-1 in Healthy Individuals and Individuals at High Cardiovascular Disease Risk: 2 Randomized Controlled Trials.
Kris-Etherton, PM, Stewart, PW, Ginsberg, HN, Tracy, RP, Lefevre, M, Elmer, PJ, Berglund, L, Ershow, AG, Pearson, TA, Ramakrishnan, R, et al
The Journal of nutrition. 2020;(8):2089-2100
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Abstract
BACKGROUND Factor VIIc, fibrinogen, and plasminogen activator inhibitor 1 (PAI-1) are cardiovascular disease (CVD) risk factors and are modulated, in part, by fat type and amount. OBJECTIVE We evaluated fat type and amount on the primary outcomes: factor VIIc, fibrinogen, and PAI-1. METHODS In the Dietary Effects on Lipoproteins and Thrombogenic Activity (DELTA) Trial, 2 controlled crossover feeding studies evaluated substituting carbohydrate or MUFAs for SFAs. Study 1: healthy participants (n = 103) were provided with (8 wk) an average American diet [AAD; designed to provide 37% of energy (%E) as fat, 16% SFA], a Step 1 diet (30%E fat, 9% SFA), and a diet low in SFA (Low-Sat; 26%E fat, 5% SFA). Study 2: participants (n = 85) at risk for CVD and metabolic syndrome (MetSyn) were provided with (7 wk) an AAD, a step 1 diet, and a high-MUFA diet (designed to provide 37%E fat, 8% SFA, 22% MUFA). RESULTS Study 1: compared with AAD, the Step 1 and Low-Sat diets decreased mean factor VIIc by 1.8% and 2.6% (overall P = 0.0001), increased mean fibrinogen by 1.2% and 2.8% (P = 0.0141), and increased mean square root PAI-1 by 0.0% and 6.0% (P = 0.0037), respectively. Study 2: compared with AAD, the Step 1 and high-MUFA diets decreased mean factor VIIc by 4.1% and 3.2% (overall P < 0.0001), increased mean fibrinogen by 3.9% and 1.5% (P = 0.0083), and increased mean square-root PAI-1 by 2.0% and 5.8% (P = 0.1319), respectively. CONCLUSIONS Replacing SFA with carbohydrate decreased factor VIIc and increased fibrinogen in healthy and metabolically unhealthy individuals and also increased PAI-1 in healthy subjects. Replacing SFA with MUFA decreased factor VIIc and increased fibrinogen but less than carbohydrate. Our results indicate an uncertain effect of replacing SFA with carbohydrate or MUFA on cardiometabolic risk because of small changes in hemostatic factors and directionally different responses to decreasing SFA. This trial was registered at https://clinicaltrials.gov/ct2/show/NCT00000538?term=NCT00000538&rank=1 as NCT00000538.
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Adverse Effects of Low-Dose Methotrexate: A Randomized Trial.
Solomon, DH, Glynn, RJ, Karlson, EW, Lu, F, Corrigan, C, Colls, J, Xu, C, MacFadyen, J, Barbhaiya, M, Berliner, N, et al
Annals of internal medicine. 2020;(6):369-380
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Abstract
BACKGROUND Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred. OBJECTIVE To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo. DESIGN Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333). SETTING North America. PARTICIPANTS Adults with known cardiovascular disease and diabetes or metabolic syndrome. INTERVENTION Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week. MEASUREMENTS Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication. RESULTS After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]). LIMITATION The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period. CONCLUSION Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased. PRIMARY FUNDING SOURCE National Institutes of Health.
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A Randomized Crossover Intervention Study on the Effect a Standardized Maté Extract (Ilex paraguariensis A. St.-Hil.) in Men Predisposed to Cardiovascular Risk.
Gebara, KS, Gasparotto Junior, A, Palozi, RAC, Morand, C, Bonetti, CI, Gozzi, PT, de Mello, MRF, Costa, TA, Cardozo Junior, EL
Nutrients. 2020;(1)
Abstract
(1) Background: Due to its richness in chlorogenic acids (CGAs), Maté (Ilex paraguariensis A. St.-Hil.) could be of interest in the prevention of cardiometabolic diseases, however clinical evidence are lacking. This trial aimed to evaluate the impact of maté CGAs, consumed in a daily dose achievable through traditional maté beverages, on parameters related to cardiometabolic risk. (2) Design: Thirty-four male volunteers aged 45-65 years and with at most one criteria of metabolic syndrome, were recruited for a randomized, double-blind, placebo-controlled, and crossover study. The volunteers were assigned to consume an encapsulated dry maté extract for four-weeks, providing 580 mg of caffeoyl quinic acid derivatives (CQAs) daily, or a placebo, with a two weeks washout between intervention periods. Anthropometric variables, blood pressure, plasma glucose, lipids, endothelial, and inflammatory biomarkers were measured in overnight-fasted subjects and after a glucose load. (3) Results: We found no significant effects of treatment on these parameters and the response to the glucose load was also similar between the two interventions. However, a significant decrease in fasting glucose was observed between day 0 and day 28 for the maté group only (-0.57 ± 0.11 mmol/L, p < 0.0002). In subjects with an intermediate to high Framingham risk score, consumption of maté extract induced a 10% increase of high-density lipoprotein (HDL)-c from baseline. In a subgroup representative of the study population, significant decreases in the C-reactive protein (CRP) (-50%) and interleukin-6 (IL-6) (-19%) levels were observed. (4) Conclusions: These clinical observations suggest that maté, naturally rich in CGAs, could improve some cardiometabolic markers in subjects with a higher predisposition to metabolic syndrome, even if that remains to be confirmed in new trials specifically targeting this population.
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Effects of Exercise Training during Christmas on Body Weight and Cardiometabolic Health in Overweight Individuals.
Ramirez-Jimenez, M, Morales-Palomo, F, Ortega, JF, Moreno-Cabañas, A, Guio de Prada, V, Alvarez-Jimenez, L, Mora-Rodriguez, R
International journal of environmental research and public health. 2020;(13)
Abstract
: Individuals with abdominal obesity and metabolic syndrome (MetS) have augmented risk of all-cause mortality. Lifestyle interventions are effective to treat MetS, however, there are periods during the year in which exercise programs are discontinued and improper dietary habits reappear (e.g., Christmas holidays). We aimed to analyze if exercise-training during Christmas holidays would avoid body-weight gains and cardiometabolic deterioration in MetS individuals, using a randomized control trial. Thirty-eight men with MetS undergoing exercise training were randomly allocated to either continue (TRAIN group, n = 16) or discontinue (HOLID group, n = 22) training, during the three weeks of Christmas. Anthropometrics (body weight, fat, and waist circumference), fasting blood metabolites (glucose, insulin, triglycerides, and cholesterol concentrations) and exercise maximal fat oxidation (FOMAX) and oxygen uptake (VO2PEAK) were determined before and after Christmas. Both groups were similar at baseline in all parameters (p > 0.05). HOLID group increased body weight (91.3 ± 13.0 to 92.0 ± 13.4 kg, p = 0.004), mean arterial pressure (94.0 ± 10.6 to 97.1 ± 8.9 mmHg, p = 0.026), blood insulin (10.2 ± 3.8 to 12.5 ± 5.4 µIU·mL-1, p = 0.003) and HOMA (3.2 ± 1.3 to 4.1 ± 2.3, p = 0.003). In contrast, TRAIN prevented those disarrangements and reduced total (170.6 ± 30.6 to 161.3 ± 31.3 mg·dL-1, p = 0.026) and low-density lipoprotein cholesterol (i.e., LDL-C, 104.8 ± 26.1 to 95.6 ± 21.7 mg·dL-1, p = 0.013). TRAIN also prevented the reductions in exercise FOMAX and VO2PEAK that was observed in the HOLID group (p = 0.002). In conclusion, exercise training during Christmas, prevents body weight gains and the associated cardiovascular (increase in blood pressure and LDL-C) and metabolic (reduced insulin sensitivity) health risks are an optimal non-pharmacological therapy for that period of the year.
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Socio-economic status and behavioural and cardiovascular risk factors in Papua New Guinea: A cross-sectional survey.
Rarau, P, Pulford, J, Gouda, H, Phuanukoonon, S, Bullen, C, Scragg, R, Pham, BN, McPake, B, Oldenburg, B
PloS one. 2019;(1):e0211068
Abstract
BACKGROUND Risk factors for cardiovascular disease (CVD) are negatively correlated with socio-economic status (SES) in high-income countries (HIC) but there has been little research on their distribution by household SES within low-and middle-income countries (LMICs). Considering the limited data from LMICs, this paper examines the association between behavioural and cardiovascular risk factors and household SES in Papua New Guinea (PNG). METHODS Reported here are results of 671 participants from the 900 randomly selected adults aged 15-65 years. These adults were recruited from three socioeconomically and geographically diverse surveillance sites (peri-urban community, rural Highland and an Island community) in PNG in 2013-2014. We measured their CVD risk factors (behavioural and metabolic) using a modified WHO STEPS risk factor survey and analysis of blood samples. We assessed SES by education, occupation and creating a household wealth index based on household assets. We calculated risk ratios (RR) and their 95% confidence intervals (CI) using a generalized linear model to assess the associations between risks and SES. FINDINGS Elevated CVD risk factors were common in all SES groups but the CVD metabolic risk factors were most prevalent among homemakers, peri-urban and rural highlands, and the highest (4th and 5th) wealth quintile population. Adults in the highest wealth quintile had high risks of obesity, elevated HbA1c and metabolic syndrome (MetS) that were greater than those in the lowest quintile although those in the highest wealth quintiles were less likely to smoke tobacco. Compared to people from the Island community, peri-urban residents had increased risks of increased waist circumference (WC) (RR: 1.67, 95%CI: 1.21-2.31), hypertension (RR: 2∙29, 95%CI: 1∙89-4.56), high cholesterol (RR: 2∙22, 95%CI: 1∙20-4∙10), high triglycerides (RR: 1∙49, 95%CI: 1∙17-1∙91), elevated HbA1c (RR: 5∙54, 95%CI: 1∙36-21∙56), and Metabolic syndrome (MetS) (RR: 2∙04, 95%CI: 1∙25-3∙32). Similarly, Rural Highland residents had increased risk of obesity (Waist Circumference RR: 1∙70, 95%CI: 1∙21-3∙38, Waist-Hip-Ratio RR:1∙48, 95%CI: 1∙28-1∙70), hypertension (RR: 2∙60, 95%CI: 1∙71-3∙95), high triglycerides (RR: 1∙34, 95%CI: 1∙06-1∙70) and MetS (RR: 1∙88, 95%CI: 1∙12-3∙16) compared to those in the rural Island site. INTERPRETATION CVD risk factors are common in PNG adults but their association with SES varies markedly and by location. Our findings show that all community members are at risk of CVD weather they are part of high or low SES groups. These results support the notion that the association between CVD risk factors and SES differ greatly accordingly to the type of SES measure used, risk factors and the population studied. In addition, our findings contribute further to the limited literature in LMIC. Longitudinal studies are needed to monitor changes in rapidly changing societies such as PNG to inform public health policy for control and prevention of NCDs in the country.
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Comparison of the Effects of Brazil Nut Oil and Soybean Oil on the Cardiometabolic Parameters of Patients with Metabolic Syndrome: A Randomized Trial.
Costa E Silva, LM, Pereira de Melo, ML, Faro Reis, FV, Monteiro, MC, Dos Santos, SM, Quadros Gomes, BA, Meller da Silva, LH
Nutrients. 2019;(1)
Abstract
Recent evidence suggests that replacing saturated fat with unsaturated fat is beneficial for cardiovascular health. This study compared the effects of Brazil nut oil (BNO) and soybean oil (SO) supplementation for 30 days on anthropometric, blood pressure, biochemical, and oxidative parameters in patients with metabolic syndrome (MS). Thirty-one patients with MS were randomly allocated to receive 30 sachets with 10 mL each of either BNO (n = 15) or SO (n = 16) for daily supplementation. Variables were measured at the beginning of the study and after 30 days of intervention. No change in anthropometric and blood pressure variables were observed (p > 0.05). Total (p = 0.0253) and low-density lipoprotein (p = 0.0437) cholesterol increased in the SO group. High-density lipoprotein cholesterol decreased (p = 0.0087) and triglycerides increased (p = 0.0045) in the BNO group. Malondialdehyde levels decreased in the BNO group (p = 0.0296) and total antioxidant capacity improved in the SO group (p = 0.0110). Although the addition of oils without lifestyle interventions did not affect anthropometric findings or blood pressure and promoted undesirable results in the lipid profile in both groups, daily supplementation of BNO for 30 days decreased lipid peroxidation, contributing to oxidative stress reduction.
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Effect of Exercise Modality During Weight Loss on Bone Health in Older Adults With Obesity and Cardiovascular Disease or Metabolic Syndrome: A Randomized Controlled Trial.
Beavers, KM, Walkup, MP, Weaver, AA, Lenchik, L, Kritchevsky, SB, Nicklas, BJ, Ambrosius, WT, Stitzel, JD, Register, TC, Shapses, SA, et al
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2018;(12):2140-2149
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Abstract
The objective of this study was to determine the ability of either aerobic or resistance training to counter weight-loss-associated bone loss in older adults. There were 187 older adults (67 years, 70% women, 64% white) with obesity (BMI = 34.5 ± 3.7 kg/m2 ) and cardiovascular disease and/or metabolic syndrome who were randomized to participate in an 18-month, community-based trial, with a follow-up assessment at 30 months. Intervention arms included: weight loss alone (WL; 7% to 10% baseline weight), WL plus aerobic training (WL + AT), and WL plus resistance training (WL + RT), as well as DXA-acquired total hip, femoral neck, and lumbar spine areal bone mineral density (aBMD), and trabecular bone score (TBS). Biomarkers of bone turnover (procollagen type 1 N-terminal propeptide, C-terminal telopeptide of type 1 collagen) were measured at baseline, 6, 18, and 30 (aBMD and TBS only) months. CT-acquired hip and spine volumetric BMD (vBMD), cortical thickness, and bone strength were measured in a subset at baseline (n = 55) and 18 months. Total hip aBMD was reduced by 2% in all groups at 18 months, with a primary analysis showing no significant treatment effects for any DXA, biomarker, or CT outcome. After adjustment for WL and follow-up at 30 months, secondary analyses revealed that total hip [-0.018 (-0.023 to -0.012) g/cm2 versus -0.025 (-0.031 to -0.019) g/cm2 ; p = 0.05] and femoral neck [-0.01 (-0.009 to 0.008) g/cm2 versus -0.011 (-0.020 to -0.002) g/cm2 ; p = 0.06] aBMD estimates were modestly attenuated in the WL + RT group compared with the WL group. Additionally, lumbar spine aBMD was increased in the WL [0.015 (0.007 to 0.024) g/cm2 ] and the WL + RT [0.009 (0.000 to 0.017) g/cm2 ] groups compared with the WL + AT [-0.003 (-0.012 to 0.005)g/cm2 ] group; both p ≤ 0.01. Community-based exercise does not prevent bone loss during active WL in older adults; however, adding RT may help minimize long-term hip bone loss. © 2018 American Society for Bone and Mineral Research.