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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/cm2*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

ObjectivesElevated Lipoprotein(a) (Lp[a]) is a well-known risk factor for cardiovascular disease. However, its roles in bone metabolism and fracture risk are unclear. We therefore investigated whether plasma Lp(a) levels were associated with bone mineral density (BMD) and incident hip fractures in a large cohort of postmenopausal women.DesignPost hoc analysis of data from the Women's Health Initiative (WHI), USA.Setting40 clinical centres in the USA.ParticipantsThe current analytical cohort consisted of 9698 white, postmenopausal women enrolled in the WHI, a national prospective study investigating determinants of chronic diseases including heart disease, breast and colorectal cancers and osteoporotic fractures among postmenopausal women. Recruitment for WHI took place from 1 October 1993 to 31 December 1998.ExposuresPlasma Lp(a) levels were measured at baseline.Outcome measuresIncident hip fractures were ascertained annually and confirmed by medical records with follow-up through 29 August 2014. BMD at the femoral neck was measured by dual X-ray absorptiometry in a subset of participants at baseline.Statistical analysesCox proportional hazards and logistic regression models were used to evaluate associations of quartiles of plasma Lp(a) levels with hip fracture events and hip BMD T-score, respectively.ResultsDuring a mean follow-up of 13.8 years, 454 incident cases of hip fracture were observed. In analyses adjusting for confounding variables including age, body mass index, history of hysterectomy, smoking, physical activity, diabetes mellitus, general health status, cardiovascular disease, use of menopausal hormone therapy, use of bisphosphonates, calcitonin or selective-oestrogen receptor modulators, baseline dietary and supplemental calcium and vitamin D intake and history of fracture, no significant association of plasma Lp(a) levels with low hip BMD T-score or hip fracture risk was detected.ConclusionsThese findings suggest that plasma Lp(a) levels are not related to hip BMD T-score or hip fracture events in postmenopausal women.Trial registration numberNCT00000611; Post-results.

Studies of the associations of sodium and potassium intakes with cardiovascular disease incidence often rely on self-reported dietary data. In the present study, self-reported intakes from postmenopausal women at 40 participating US clinical centers are calibrated using 24-hour urinary excretion measures in cohorts from the Women's Health Initiative, with follow-up from 1993 to 2010. The incidence of hypertension was positively related to (calibrated) sodium intake and to the ratio of sodium to potassium. The sodium-to-potassium ratio was associated with cardiovascular disease incidence during an average follow-up period of 12 years. The estimated hazard ratio for a 20% increase in the sodium-to-potassium ratio was 1.13 (95% confidence interval (CI): 1.04, 1.22) for coronary heart disease, 1.20 (95% CI: 1.01, 1.42) for heart failure, and 1.11 (95% CI: 1.04, 1.19) for a composite cardiovascular disease outcome. The association with total stroke was not significant, but it was positive for ischemic stroke and inverse for hemorrhagic stroke. Aside from hemorrhagic stroke, corresponding associations of cardiovascular disease with sodium and potassium jointly were positive for sodium and inverse for potassium, although some were not statistically significant. Specifically, for coronary heart disease, the hazard ratios for 20% increases were 1.11 (95% CI: 0.95, 1.30) for sodium and 0.85 (95% CI: 0.73, 0.99) for potassium; and corresponding values for heart failure were 1.36 (95% CI: 1.02, 1.82) for sodium and 0.90 (95% CI: 0.69, 1.18) for potassium.

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

ObjectiveThis study aims to test the added value of calcium and vitamin D (CaD) in fracture prevention among women taking postmenopausal hormone therapy (HT).MethodsThis is a prospective, partial-factorial, randomized, controlled, double-blind trial among Women's Health Initiative postmenopausal participants aged 50 to 79 years at 40 centers in the United States with a mean follow-up of 7.2 years. A total of 27,347 women were randomized to HT (0.625 mg of conjugated estrogens alone, or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily), and 36,282 women were randomized to 1,000 mg of elemental calcium (carbonate) plus 400 IU of vitamin D3 daily, each compared with placebo. A total of 16,089 women participated in both arms. The predefined outcomes were adjudicated hip fractures and measured bone mineral density.ResultsInteraction between HT and CaD on hip fracture (P interaction = 0.01) was shown. The effect of CaD was stronger among women assigned to HT (hazard ratio [HR], 0.59; 95% CI, 0.38-0.93) than among women assigned to placebo (HR, 1.20; 95% CI, 0.85-1.69). The effect of HT on hip fracture was stronger among women assigned to active CaD (HR, 0.43; 95% CI, 0.28-0.66) than among women assigned to placebo (HR, 0.87; 95% CI, 0.60-1.26). CaD supplementation enhanced the antifracture effect of HT at all levels of personal calcium intake. There was no interaction between HT and CaD on change in hip or spine bone mineral density.ConclusionsPostmenopausal women at normal risk for hip fracture who are on CaD supplementation experience significantly reduced incident hip fractures beyond HT alone at all levels of personal baseline total calcium intake.

ObjectivesTo identify factors that predicted incident use of assistive walking devices (AWDs) and to explore whether AWD use was associated with changes in osteoarthritis of the knee.DesignProspective cohort study.SettingCommunity.ParticipantsOlder adults (N=2639) in the Health, Aging and Body Composition (Health ABC) Study including a subset of 874 patients with prevalent knee pain.InterventionsNot applicable.Main outcome measuresIncident use of AWDs, mean Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores, and the frequency of joint space narrowing on knee radiographs over a 3-year time period.ResultsAWD use was initiated by 9% of the entire Health ABC cohort and 12% of the knee pain subset. Factors that predicted use in both groups were age ≥73 (entire cohort: odds ratio [OR]=2.07; 95% confidence interval [CI], 1.43-3.01; knee pain subset: OR=1.87; 95% CI, 1.16-3.03), black race (entire cohort: OR=2.95; 95% CI, 2.09-4.16; knee pain subset: OR=3.21; 95% CI, 2.01-5.11), and lower balance ratios (entire cohort: OR=3.18; 95% CI, 2.21-4.59; knee pain subset: OR=3.77; 95% CI, 2.34-6.07). Mean WOMAC pain scores decreased slightly over time in both AWD and non-AWD users. Twenty percent of non-AWD users and 28% of AWD users had radiographic progression in joint space narrowing of the tibiofemoral joint in at least 1 knee. Fourteen percent of non-AWD users and 12% of AWD users had radiographic progression in joint space narrowing in the patellofemoral joint in at least 1 knee.ConclusionsAWDs are frequently used by older adults. Knee pain and balance problems are significant reasons why older adults initiate use of an AWD. In an exploratory analysis, there was no consistent relation between the use or nonuse of an AWD and WOMAC pain scores or knee joint space narrowing progression. Further studies of the relation of use of AWDs to changes in knee osteoarthritis are needed.

Antiepileptic drugs (AEDs) are used increasingly in clinical practice to treat a number of conditions. However, the relationship between the use of these medications, particularly the newer AEDs, and fracture risk has not been well characterized. We used data from the Women's Health Initiative (WHI) to determine the relationship bewteen the use of AEDs and falls, fractures, and bone mineral density (BMD) over an average of 7.7 years of follow-up. We included 138,667 women (1,385 users of AEDs and 137,282 nonusers) aged 50 to 79 years in this longitudinal cohort analyses. After adjustment for covariates, use of AEDs was positively associated with total fractures [hazard ratio (HR) = 1.44, 95% confidence interval (CI) 1.30-1.61], all site-specific fractures including the hip (HR = 1.51, 95% CI 1.05-2.17), clinical vertebral fractures (HR = 1.60, 95% CI 1.20-2.12), lower arm or wrist fractures (HR = 1.40, 95% CI 1.11-1.76), and other clinical fractures (HR = 1.46, 95% CI 1.29-1.65) and two or more falls (HR = 1.62, 95% CI 1.50-1.74) but not with baseline BMD or changes in BMD (p > or = .064 for all sites). Use of more than one and use of enzyme-inducing AEDs were significantly associated with total fractures (HR = 1.55, 95% CI 1.15-2.09 and HR = 1.36, 95% CI 1.09-1.69, respectively). We conclude that in clinical practice, postmenopausal women who use AEDs should be considered at increased risk for fracture, and attention to fall prevention may be particularly important in these women.

BackgroundThe relationship of loop diuretics to bone mineral density (BMD), falls, and fractures in postmenopausal women has not been established.MethodsWe examined whether loop diuretics are associated with changes in BMD, falls, and fractures in women enrolled in the Women's Health Initiative. We included the 133,855 women (3411 users and 130,444 nonusers of loop diuretics) who were enrolled in the WHI from October 29, 1993 to December 31, 1998 and determined incident falls and fractures for a mean of 7.7 years. Women who had BMD measurements at baseline and at year 3 (300 users and 9124 nonusers of loop diuretics) were also examined.ResultsAfter adjustment for covariates, no significant association was found between ever use of loop diuretics and total (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.00-1.19), hip (HR, 1.21; 95% CI, 0.91-1.60), and clinical vertebral fractures (HR, 1.17; 95% CI, 0.92-1.48) and falls (1.02; 0.96-1.08). An increased risk was found for other clinical fractures (1.16; 1.01-133) and total fractures (1.16; 1.03-1.31) with more than 3 years' use of loop diuretics. The BMD changes were not associated with loop diuretic use.ConclusionsAfter adjustment for confounding variables, no significant association was found between ever use of loop diuretics and changes in BMD, falls, and fractures. Loop diuretics were used by women in poor health who were already at risk for fractures. However, prolonged use of loop diuretics was associated with higher fracture risk in postmenopausal women.