Joshua R. Lewis

Calcium supplementation and the risks of atherosclerotic vascular disease in older women: Results of a 5-year RCT and a 4.5-year follow-up

Concern has been expressed that calcium supplementation, a key intervention for preventing osteoporotic fracture in older women, may increase the risk of atherosclerotic vascular disease. To evaluate the risk further, an examination of complete verified atherosclerotic vascular hospitalization and mortality data from a 5‐year randomized, controlled trial (RCT) of calcium carbonate and 4.5 years of posttrial follow‐up was undertaken. This study used data from a published 5‐year randomized, double‐blinded, placebo‐controlled trial [Calcium Intake Fracture Outcome Study (CAIFOS)]. The participants were 1460 women aged 75.1 ± 2.7 years at baseline (1998) recruited from the general population and randomized to receive 1200 mg of calcium carbonate daily or an identical placebo. All hospital admission and deaths during the 5‐year study and the 4.5‐year follow‐up were derived from the Western Australian Data Linkage Service (WADLS). Hazard ratios (HRs) for the combined endpoint of atherosclerotic vascular mortality or first hospitalization were calculated using prespecified intention‐to‐treat and per‐protocol models. The intervention group that received calcium supplementation did not have a higher risk of death or first‐time hospitalization from atherosclerotic vascular disease in either the 5‐year RCT [multivariate‐adjusted HR = 0.938, 95% confidence interval (CI) 0.690–1.275] or during the 9.5 years of observational study (multivariate‐adjusted HR = 0.919, 95% CI 0.737–1.146). Further analysis suggested that calcium supplementation may reduce the risk of hospitalization and mortality in patients with preexisting atherosclerotic cardiovascular disease. This trial provides compelling evidence that calcium supplementation of 1200 mg daily does not significantly increase the risk of atherosclerotic vascular disease in elderly women.

Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: A randomized controlled trial

Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3‐monthly vitamin D therapy on falls, muscle strength, and mobility, we conducted a 9‐month randomized, double‐blind, placebo‐controlled trial in 686 community‐dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n = 353) or an identical placebo (n = 333). All participants were advised to increase dietary calcium intake. Falls data were collected 3‐monthly. At baseline, 3, 6, and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7 ± 4.1 years. The average serum 25OHD value at baseline was 65.8 ± 22.7 nmol/L. By 3, 6, and 9 months after supplementation, 25OHD levels of the vitamin D group were approximately 15 nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864 ± 412 mg/day) and 9 months (855 ± 357 mg/day). Faller rates in the two groups did not differ: vitamin D group, 102 of 353 (29%); placebo group, 89 of 333 (27%). At 9 months, compared to placebo or baseline, muscle strength, and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered 3‐monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high‐dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures.

Association between yogurt, milk, and cheese consumption and common carotid artery intima-media thickness and cardiovascular disease risk factors in elderly women

BACKGROUND Despite the contribution of dairy foods to total dietary saturated fat intake, available data indicate that dairy consumption may lower the risk of cardiovascular disease. OBJECTIVE The objective of this study was to investigate the relation between consumption of milk, cheese, and yogurt and common carotid artery intima-media thickness (CCA-IMT) in a cohort of elderly women. DESIGN Dairy consumption was assessed with a validated food-frequency questionnaire in 1080 participants randomly selected from ambulant white women aged >70 y living in Perth, Western Australia. CCA-IMT was assessed by using B-mode carotid ultrasound 3 y later. Cardiovascular disease risk factors, including serum lipids and blood pressure, were assessed at baseline. RESULTS Total dairy product, milk, and cheese consumption was not associated with CCA-IMT (P > 0.05), whereas yogurt consumption was negatively associated with CCA-IMT (unadjusted standardized β = -0.081, P = 0.008; baseline risk factor-adjusted standardized β = -0.075, P = 0.015). Participants who consumed >100 g yogurt/d had a significantly lower CCA-IMT than did participants with lower consumption (unadjusted = -0.024 mm, P = 0.002). This relation remained significant after adjustment for baseline, dietary, and lifestyle risk factors (multivariable analysis = -0.023 mm, P = 0.003). CONCLUSION Increased consumption of yogurt, but not of other dairy products, is associated with a lower CCA-IMT, independent of other risk factors.

Adverse events from calcium supplementation: relationship to errors in myocardial infarction self-reporting in randomized controlled trials of calcium supplementation.

The clinical effects of calcium supplements on adverse events reporting have not been well described. This study reviews randomized controlled trial (RCT) evidence of adverse events to clarify the epidemiology of these events. The hypothesis that patient self‐report of myocardial infarction (MI) is increased in individuals receiving calcium supplementation is because of an increase in non‐MI events incorrectly perceived by the patient as being because of MI, is examined. In seven RCTs summary self‐reported gastrointestinal (GI) adverse event rates were more common in participants receiving calcium. These were described as constipation, excessive abdominal cramping, bloating, upper GI events, GI disease, GI symptoms, and severe diarrhoea or abdominal pain (calcium 14.1%, placebo 10.0%), relative risk (RR) 1.43 95% confidence interval (CI) 1.28 to 1.59, p < 0.001. Adjudicated functional GI hospitalizations in one study were calcium 6.8%, placebo 3.6% (RR 1.92, 95% CI 1.21–3.05, p = 0.006). Direct comparison of self‐reported and adjudicated MI events in the two trials of dietary calcium supplementation showed self‐reported MI rates of 3.6% in the calcium group and 2.1% in the placebo group. After adjudication the MI rates were 2.4% in the calcium group and 1.6% in the placebo group (RR 1.45, 95% CI 0.88–2.45, p = 0.145). These data support the hypothesis that calcium tablets increase the incidence of adverse GI events, which may account for an increase in self‐reported MI in calcium treated patients but not controls.

The Effects of Calcium Supplementation on Verified Coronary Heart Disease Hospitalization and Death in Postmenopausal Women: A Collaborative Meta‐Analysis of Randomized Controlled Trials

Calcium supplementation, particularly with vitamin D, has been an approved public health intervention to reduce fracture risk. Enthusiasm for this intervention has been mitigated by meta‐analyses suggesting that calcium supplementation with or without vitamin D increases myocardial infarction (MI) risk; however, concern has been raised over the design of these meta‐analyses. We, therefore, undertook a meta‐analysis of randomized controlled trials with placebo or no‐treatment control groups to determine if these supplements increase all‐cause mortality and coronary heart disease (CHD) risk including MI, angina pectoris and acute coronary syndrome, and chronic CHD verified by clinical review, hospital record, or death certificate in elderly women. The Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases were searched from January 1, 1966, to May 24, 2013, for potentially eligible studies, reference lists were checked, and trial investigators were contacted where additional unpublished data were required. The search yielded 661 potentially eligible reports of which 18 met the inclusion criteria and contributed information on 63,563 participants with 3390 CHD events and 4157 deaths. Two authors extracted the data independently with trial data combined using random‐effects meta‐analysis to calculate the relative risk (RR). Five trials contributed CHD events with pooled relative RR of 1.02 (95% confidence interval [CI], 0.96–1.09; p = 0.51). Seventeen trials contributed all‐cause mortality data with pooled RR of 0.96 (95% CI, 0.91–1.02; p = 0.18). Heterogeneity among the trials was low for both primary outcomes (I2 = 0%). For secondary outcomes, the RR for MI was 1.08 (95% CI, 0.92–1.26; p = 0.32), angina pectoris and acute coronary syndrome 1.09 (95% CI, 0.95–1.24; p = 0.22) and chronic CHD 0.92 (95% CI, 0.73–1.15; p = 0.46). In conclusion, current evidence does not support the hypothesis that calcium supplementation with or without vitamin D increases coronary heart disease or all‐cause mortality risk in elderly women.

Flavonoid intake and all-cause mortality

BACKGROUND Flavonoids are bioactive compounds found in foods such as tea, chocolate, red wine, fruit, and vegetables. Higher intakes of specific flavonoids and flavonoid-rich foods have been linked to reduced mortality from specific vascular diseases and cancers. However, the importance of flavonoids in preventing all-cause mortality remains uncertain. OBJECTIVE The objective was to explore the association between flavonoid intake and risk of 5-y mortality from all causes by using 2 comprehensive food composition databases to assess flavonoid intake. DESIGN The study population included 1063 randomly selected women aged >75 y. All-cause, cancer, and cardiovascular mortalities were assessed over 5 y of follow-up through the Western Australia Data Linkage System. Two estimates of flavonoid intake (total flavonoidUSDA and total flavonoidPE) were determined by using food composition data from the USDA and the Phenol-Explorer (PE) databases, respectively. RESULTS During the 5-y follow-up period, 129 (12%) deaths were documented. Participants with high total flavonoid intake were at lower risk [multivariate-adjusted HR (95% CI)] of 5-y all-cause mortality than those with low total flavonoid consumption [total flavonoidUSDA: 0.37 (0.22, 0.58); total flavonoidPE: 0.36 (0.22, 0.60)]. Similar beneficial relations were observed for both cardiovascular disease mortality [total flavonoidUSDA: 0.34 (0.17, 0.69); flavonoidPE: 0.32 (0.16, 0.61)] and cancer mortality [total flavonoidUSDA: 0.25 (0.10, 0.62); flavonoidPE: 0.26 (0.11, 0.62)]. CONCLUSIONS Using the most comprehensive flavonoid databases, we provide evidence that high consumption of flavonoids is associated with reduced risk of mortality in older women. The benefits of flavonoids may extend to the etiology of cancer and cardiovascular disease.

Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study.

Proton pump inhibitors (PPIs) are widely used in the elderly. Recent studies have suggested that long‐term PPI therapy is associated with fractures in the elderly, however the mechanism remains unknown. We investigated the association between long‐term PPI therapy ≥1 year and fracture risk factors including bone structure, falls, and balance‐related function in a post hoc analysis of a longitudinal population‐based prospective cohort of elderly postmenopausal women and replicated the findings in a second prospective study of falling in elderly postmenopausal women. Long‐term PPI therapy was associated with increased risk of falls and fracture‐related hospitalizations; adjusted odds ratio (AOR) 2.17; 95% CI, 1.25–3.77; p = 0.006 and 1.95; 95% CI, 1.20–3.16; p = 0.007, respectively. In the replication study, long‐term PPI use was associated with an increased risk of self‐reported falling; AOR, 1.51; 95% CI, 1.00–2.27; p = 0.049. No association of long‐term PPI therapy with bone structure was observed; however, questionnaire‐assessed falls‐associated metrics such as limiting outdoor activity (p = 0.002) and indoor activity (p = 0.001) due to fear of falling, dizziness (p < 0.001) and numbness of feet (p = 0.017) and objective clinical measurement such as Timed Up and Go (p = 0.002) and Romberg eyes closed (p = 0.025) tests were all significantly impaired in long‐term PPI users. Long‐term PPI users were also more likely to have low vitamin B12 levels than non‐users (50% versus 21%, p = 0.003). In conclusion, similar to previous studies, we identified an increased fracture risk in subjects on long‐term PPI therapy. This increase in fracture risk in elderly women, already at high risk of fracture, appears to be mediated via increased falls risk and falling rather than impaired bone structure and should be carefully considered when prescribing long‐term PPI therapy.

Timed up and go test and bone mineral density measurement for fracture prediction

BACKGROUND Two major factors associated with skeletal fracture in older persons are intrinsic bone strength and risk of falling. This study examined the role of Timed Up and Go (TUG) test performance, a validated predictor of falling, and hip areal bone mineral density (BMD), a validated predictor of bone strength in fracture prediction in a 10-year longitudinal study. METHODS The study participants were 1126 women (mean [SD] age at baseline, 75.0 [2.6] years) living in Perth, Western Australia. Assessments included TUG test at baseline and dual-energy x-ray absorptiometry total hip areal BMD measurement at year 1. Incident clinical osteoporotic fracture over 10 years was confirmed by radiographic records. Complete incident hip fracture data were obtained from a hospital morbidity database. RESULTS One-third (32.7%) of participants had slow TUG test performance (>10.2 seconds), and 54.2% of participants had low hip areal BMD (T-score of less than -1). Relative to risks among participants having normal TUG test performance and normal BMD, risks of nonvertebral fracture and hip fracture were significantly higher among participants who had slow TUG test performance and normal hip BMD (nonvertebral fracture hazard ratio [HR], 1.84; hip fracture HR, 2.48) or both slow TUG test performance and low hip BMD (nonvertebral fracture HR, 2.51; hip fracture HR, 4.68). For nonvertebral fracture and hip fracture, the population-attributable risks of slow TUG test performance with normal hip BMD were 19.3% and 32.3%, of normal TUG test performance with low hip BMD were 31.3% and 50.3%, and of both slow TUG test performance and low hip BMD were 30.1% and 55.9%, respectively. CONCLUSION TUG test performance is an independent risk factor for incident nonvertebral fracture and a feasible inexpensive physical performance assessment for use in clinical practice to screen patients with increased risk of fracture.

The effects of probiotic bacteria on glycaemic control in overweight men and women: a randomised controlled trial

Background/Objectives:Evidence from animal and in vitro models suggest a role of probiotic bacteria in improving glycaemic control and delaying the onset of type 2 diabetes. However, the evidence from controlled trials in humans is limited. The objective was to determine if the probiotic bacteria L. acidophilus La5 and B. animalis subsp lactis Bb12, supplemented in a whole food (yoghurt) or isolated (capsules) form, can improve biomarkers of glycaemic control.Subjects/methods:Following a 3-week washout period, 156 overweight men and women over 55 years (mean age: 67±8 years; mean body mass index (31±4 kg/m2) were randomized to a 6-week double-blinded parallel study. The four intervention groups were: (A) probiotic yoghurt plus probiotic capsules; (B) probiotic yoghurt plus placebo capsules; (C) control milk plus probiotic capsules; and (D) control milk plus placebo capsules. Outcome measurements, including fasting glucose, insulin, glycated haemoglobin and Homoeostasis Model Assessment of Insulin Resistance (HOMA-IR), were performed at baseline and week 6.Results:Relative to the milk-control group, probiotic yoghurt resulted in a significantly higher HOMA-IR (0.32±0.15, P=0.038), but did not have a significant effect on the other three measures of glycaemic control (P>0.05). Relative to placebo capsules, probiotic capsules resulted in a significantly higher fasting glucose (0.15±0.07 mmol/l, P=0.037), with no significant effect on the other three measures of glycaemic control (P>0.05). Further analyses did not identify other variables as contributing to these adverse findings.Conclusions:Data from this study does not support the hypothesis that L. acidophilus La5 and B. animalis subsp lactis Bb12, either in isolated form or as part of a whole food, benefit short-term glycaemic control. Indeed, there is weak data for an adverse effect of these strains on glucose homoeostasis.

Effect of vitamin D supplementation alone or with calcium on adiposity measures: a systematic review and meta-analysis of randomized controlled trials

CONTEXT The independent or interactive effects of vitamin D and calcium on adiposity remain inconclusive. OBJECTIVE The objective of this systematic review and meta-analysis was to assess whether vitamin D and calcium supplements cause changes in adiposity. DATA SOURCES MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases were searched for literature published from 1966 to March 2014. STUDY SELECTION A systematic search was conducted for randomized clinical trials with ≥ 50 participants aged ≥ 18 years at baseline who had received at least 12 weeks of treatment. Among the inclusion criteria were supplementation with vitamin D with or without calcium and measurement of adiposity (weight, body mass index [BMI], and/or fat mass). DATA EXTRACTION The primary endpoints assessed were changes in weight, BMI, or fat mass. DATA SYNTHESIS Of 953 trials identified, 26 randomized clinical trials (n = 12, vitamin D alone; n = 10, vitamin D plus calcium versus calcium control; n = 4, vitamin D plus calcium versus placebo) with a total of 42,430 participants (median duration, 12 months) met the inclusion criteria. When compared with placebo, vitamin D supplementation had no significant effect on BMI (weighted mean difference [WMD], -0.06 kg/m(2); 95% confidence interval [95%CI], -0.14 to 0.03), weight (WMD, -0.05 kg; 95%CI, -0.32 to 0.23), or fat mass (WMD, -0.43 kg; 95%CI, -1.69 to 0.84). Likewise, no significant reduction in BMI (WMD, 0.02 kg/m(2); 95%CI, -0.11 to 0.14), weight (WMD, 0.12 kg; 95%CI, -0.24 to 0.49), or fat mass (WMD, 0.12 kg; 95%CI, -0.22 to 0.45) was observed in participants who received vitamin D plus calcium compared with those who received calcium control. CONCLUSIONS Supplementation with vitamin D showed no effect on adiposity measures in adults.