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The additive effect of vitamin K supplementation and bisphosphonate on fracture risk in post-menopausal osteoporosis: a randomised placebo controlled trial.
Moore, AE, Dulnoan, D, Voong, K, Ayis, S, Mangelis, A, Gorska, R, Harrington, DJ, Tang, JCY, Fraser, WD, Hampson, G
Archives of osteoporosis. 2023;18(1):83
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Osteoporosis is the most common bone disease leading to weakening of the bones and is particularly prevalent in postmenopausal women. Osteoporosis-related fractures cause severe pain and disability, and strains on the healthcare systems. The typical treatment in postmenopausal osteoporosis involves the prescription of oral bisphosphonate medications. An important regulator in bone health is Vitamin K. Low vitamin K levels and intake are linked to reduced bone mineral density (BMD) and increased fractures. Some findings suggest that a combination treatment of bisphosphonate and vitamin K2 (MK-4) may enhance treatment efficacy and hence this randomised placebo-controlled trial sought further evidence. The study enrolled 105 women, between 55–85 years old, with osteoporosis and low vitamin K status. The women received either vitamin K1 (1 mg/day), vitamin K2 arm (MK-4; 45 mg/day) or a placebo for 18 months, alongside oral bisphosphonate and calcium and/or vitamin D treatment. Outcomes were measured in bone mineral density (BMD), structural characteristics of the hips (hip geometry) and bone turnover markers (BTMs). 91 candidates completed the trial. The results showed that the combination of vitamin K1 or MK-4 and oral bisphosphonate did not lead to significant improvement in bone mineral density or bone turnover. However it showed significant changes in hip geometry in the vitamin K1 group, suggesting a potential synergy here. Whereby there were positive trends in BMD too with vitamin K1 supplementation, the results did not reach significance. In the discussion the authors review the outcomes in the context of existing research, suggesting that perhaps a longer duration of treatment with vitamin K may be required to boost mineralisation and BMD outcomes. The effect of MK-4 on bone cells may also have been hindered by its poor bioavailability and the suppression of bone remodelling caused by long-term bisphosphonate therapy. Larger and longer-term studies are needed to confirm the effects of Vitamin K on hip remodelling and prevention of bone fractures and help clarify the mixed results in existing research.
Abstract
UNLABELLED This study assessed whether vitamin K, given with oral bisphosphonate, calcium and/or vitamin D has an additive effect on fracture risk in post-menopausal women with osteoporosis. No difference in bone density or bone turnover was observed although vitamin K1 supplementation led to a modest effect on parameters of hip geometry. PURPOSE Some clinical studies have suggested that vitamin K prevents bone loss and may improve fracture risk. The aim was to assess whether vitamin K supplementation has an additive effect on bone mineral density (BMD), hip geometry and bone turnover markers (BTMs) in post-menopausal women with osteoporosis (PMO) and sub-optimum vitamin K status receiving bisphosphonate, calcium and/or vitamin D treatment. METHODS We conducted a trial in 105 women aged 68.7[12.3] years with PMO and serum vitamin K1 ≤ 0.4 µg/L. They were randomised to 3 treatment arms; vitamin K1 (1 mg/day) arm, vitamin K2 arm (MK-4; 45 mg/day) or placebo for 18 months. They were on oral bisphosphonate and calcium and/or vitamin D. We measured BMD by DXA, hip geometry parameters using hip structural analysis (HSA) software and BTMs. Vitamin K1 or MK-4 supplementation was each compared to placebo. Intention to treat (ITT) and per protocol (PP) analyses were performed. RESULTS Changes in BMD at the total hip, femoral neck and lumbar spine and BTMs; CTX and P1NP did not differ significantly following either K1 or MK-4 supplementation compared to placebo. Following PP analysis and correction for covariates, there were significant differences in some of the HSA parameters at the intertrochanter (IT) and femoral shaft (FS): IT endocortical diameter (ED) (% change placebo:1.5 [4.1], K1 arm: -1.02 [5.07], p = 0.04), FS subperiosteal/outer diameter (OD) (placebo: 1.78 [5.3], K1 arm: 0.46 [2.23] p = 0.04), FS cross sectional area (CSA) (placebo:1.47 [4.09],K1 arm: -1.02[5.07], p = 0.03). CONCLUSION The addition of vitamin K1 to oral bisphosphonate with calcium and/or vitamin D treatment in PMO has a modest effect on parameters of hip geometry. Further confirmatory studies are needed. TRIAL REGISTRATION The study was registered at Clinicaltrial.gov:NCT01232647.
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Effects of Synbiotic Supplement on Human Gut Microbiota, Body Composition and Weight Loss in Obesity.
Sergeev, IN, Aljutaily, T, Walton, G, Huarte, E
Nutrients. 2020;12(1)
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The gut microbiota plays a role in the development of obesity and associated diseases. Whilst energy-restricted, low-carbohydrate, high-protein diets can facilitate substantial weight-loss, they also have been linked to ill-effects and unfavourable changes in the gut microbiota from excess protein fermentation. Pro-and prebiotics (synbiotics) have become a promising intervention in the management of obesity. This small placebo-controlled clinical trial involved 20 obese adults following an energy-restricted (approx.950 kcal/day) low-carbohydrate, high-protein diet. The study examined whether a supplementary synbiotic contributed to additional changes in body composition and metabolic biomarkers. The synbiotic contained Lactobacilli spp. and Bifidobacteria spp. and a prebiotic mixture of galactooligosaccharides. Overall, at the end of the 3-month trial, there was no remarkable difference between the groups. Both experienced a significant and decreasing trend in body mass, waist circumference, body mass index, fat mass, fat percentage, and glucose level, affirming the known benefits of the described weight-loss diet. However, the synbiotic supplementation group had a greater decrease in HbA1C and significant alterations in gut microbiota, showing an increased abundance of gut bacteria associated with positive health effects. Due to the complexity of microbial species and host interactions, the authors advocate for more research to identify their significance and shed light on contradictory findings. This study identified that synbiotics may not contribute to additional changes in body composition when combined with an energy-restricted, low-carbohydrate, high-protein diet but they can offer additional health benefits by inducing favourable changes to the gut microbiota.
Abstract
Targeting gut microbiota with synbiotics (probiotic supplements containing prebiotic components) is emerging as a promising intervention in the comprehensive nutritional approach to reducing obesity. Weight loss resulting from low-carbohydrate high-protein diets can be significant but has also been linked to potentially negative health effects due to increased bacterial fermentation of undigested protein within the colon and subsequent changes in gut microbiota composition. Correcting obesity-induced disruption of gut microbiota with synbiotics can be more effective than supplementation with probiotics alone because prebiotic components of synbiotics support the growth and survival of positive bacteria therein. The purpose of this placebo-controlled intervention clinical trial was to evaluate the effects of a synbiotic supplement on the composition, richness and diversity of gut microbiota and associations of microbial species with body composition parameters and biomarkers of obesity in human subjects participating in a weight loss program. The probiotic component of the synbiotic used in the study contained Lactobacillus acidophilus, Bifidobacterium lactis, Bifidobacterium longum, and Bifidobacterium bifidum and the prebiotic component was a galactooligosaccharide mixture. The results showed no statistically significant differences in body composition (body mass, BMI, body fat mass, body fat percentage, body lean mass, and bone mineral content) between the placebo and synbiotic groups at the end of the clinical trial (3-month intervention, 20 human subjects participating in weight loss intervention based on a low-carbohydrate, high-protein, reduced energy diet). Synbiotic supplementation increased the abundance of gut bacteria associated with positive health effects, especially Bifidobacterium and Lactobacillus, and it also appeared to increase the gut microbiota richness. A decreasing trend in the gut microbiota diversity in the placebo and synbiotic groups was observed at the end of trial, which may imply the effect of the high-protein low-carbohydrate diet used in the weight loss program. Regression analysis performed to correlate abundance of species following supplementation with body composition parameters and biomarkers of obesity found an association between a decrease over time in blood glucose and an increase in Lactobacillus abundance, particularly in the synbiotic group. However, the decrease over time in body mass, BMI, waist circumstance, and body fat mass was associated with a decrease in Bifidobacterium abundance. The results obtained support the conclusion that synbiotic supplement used in this clinical trial modulates human gut microbiota by increasing abundance of potentially beneficial microbial species.
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Combined bioavailable isoflavones and probiotics improve bone status and estrogen metabolism in postmenopausal osteopenic women: a randomized controlled trial.
Lambert, MNT, Thybo, CB, Lykkeboe, S, Rasmussen, LM, Frette, X, Christensen, LP, Jeppesen, PB
The American journal of clinical nutrition. 2017;106(3):909-920
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Oestrogens play a vital role in maintaining bone health. The natural decline in oestrogen during menopause negatively impacts bone mineral density and increases the risk of osteoporosis and fractures. Standard interventions offered include calcium and vitamin D supplementation and hormone replacement therapy. As hormone replacement therapy is associated with increased cancer risk, there is a need to find effective treatments that display a suitable safety profile for long-term use. Isoflavones are compounds found in legume plants, many of which are dietary staples in some cultures. Isoflavones are phytoestrogens, substances that can selectively interact with human oestrogen receptors. Initial research on Isoflavones indicated that it reduces bone breakdown whilst showing protective effects for certain cancers. This randomized, double- blind, placebo-controlled trial compared the effectiveness of an lactic acid fermented, probiotic-rich isoflavone product from Red Clover (RCE) or a placebo, when given in addition to Calcium, Magnesium and Vitamin D (CMD) in postmenopausal women with osteopenia. Participants were monitored using blood tests assessing phytoestrogen activity and oestrogen metabolism, DXA scans to observe changes in bone structure and activity and dietary questionnaires. A total of 78 participants completed the study. The results showed that twice a day 60 mg isoflavones from RCE had a significant physiological impact on preventing bone loss associated with oestrogen deficiency, and was more effective in preserving bone density than CDM alone. The authors concluded that RCE was close to effectiveness to conventional bone-preserving treatments like hormone therapy but stood out due to its better safety profile and minimal side effects. Gut bacteria enhance the effectiveness of these isoflavones, which can be metabolised into compounds called equol. While before the study none of the participants could produce equol, in the end, half of the participants in the RCE group were able to produce equol, suggesting that the probiotic presence in the supplement positively influenced the participants' gut bacteria, creating favourable conditions. Additionally, RCE treatment led to favourable changes in urinary oestrogen metabolites associated with less carcinogenic oestrogen metabolism. In conclusion, the probiotic RCE, enhanced the effectiveness of CMD in preventing bone loss, whilst also increasing the ability to produce equol.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Fermented red clover extract, rich in bioavailable isoflavones with selective oestrogen receptor affinity and probiotics, combined with traditional supplementation (calcium, magnesium and vitamin D) improves bone mineral density and bone turnover compared to placebo in post menopausal women with osteopenia.
- Combining probiotics with isoflavones appears to enhance intestinal isoflavone uptake and isoflavone metabolism.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
This was a well-constructed randomised, parallel-design, placebo-controlled, double-blind trial over 12 months. The primary aim was to determine the effectiveness of a novel fermented red clover extract (RCE) containing isoflavones and probiotics combined with traditional calcium/magnesium/vitamin D supplementation, in comparison with traditional calcium/magnesium/vitamin D supplementation alone on bone mineral density (BMD) in postmenopausal women with osteopenia.
Methods
- The trial followed the guidelines of the Declaration of Helsinki and received ethics approval.
- Inclusion criteria: female; >=1 year postmenopause; age 60-85; and bone T score of -1 to -2.25.
- Exclusion criteria: medical treatment for osteopenia or hormone replacement therapy within the past 3 months; diet rich in or supplementation with isoflavones; supplementation with Vitamin K; medical history of stipulated conditions.
- 85 participants were eligible and randomised to either the control or treatment group.
- Treatment group received 95 mL of RCE twice daily, containing 60 mg isoflavone aglycones and probiotics, plus 1040mg calcium, 487mg magnesium and 25μg Vitamin D daily (CMD/d). Control group received masked RCE placebo plus CMD/d.
Results
- The change in BMD (p=0.043) and T score (p=0.045) showed a statistically significant greater decrease in the lumbar spine, femoral neck and hip of the control group than the RCE treatment group after 12 months of treatment.
- A statistically significant reduction in one bone resorption marker was found in the RCE group compared to control (p=0.045). All other bone biomarkers failed to reach significance.
- Plasma isoflavone concentration was elevated in the RCE treatment group compared to control (p=0.0094).
- The concentration ratios of urinary oestrogen metabolites 2-OH:16αOH was significantly increased in the RCE group compared to control (p=0.026).
Conclusion
Fermented RCE with CMD/d slowed oestrogen-deficient BMD loss and improved one marker of bone turnover in postmenopausal osteopenic women. Combining RCE with CMD/d was found to be more effective in preserving bone density than CMD/d alone in this target group. Probiotics in the fermented RCE appear to enhance intestinal isoflavone uptake, metabolism, and therapeutic effect.
Clinical practice applications:
- Healthcare practitioners working with women in post-menopause with osteopenia could consider the addition of fermented RCE with CMD/d for improved bone mineral density and bone turnover over 12 months.
- Given the positive impact of RCE intake over 12 months on 2-OH:16αOH oestrogen metabolite ratios, healthcare practitioners could consider fermented RCE when HRT is not an available option in relation to cancer risk.
- Based on these results, Nutritional Therapists working with post-menopausal women with osteopenia can focus on dietary isoflavone intake and pre and probiotic foods to support BMD, alongside supplementary options.
Considerations for future research:
- Given the length of time taken in bone remodelling cycles, a clinical trial of more than 2 years would strengthen the evidence provided by DXA scan.
- All trial participants were normotensive and healthy weight. Future studies could include women with hypertension and obesity to determine effects of RCE on bone and blood pressure/lipid markers in this group.
- Controlled feeding studies to determine the dietary effects of isoflavones and pre and probiotic foods would provide additional information in this area.
- Other fermented RCE products should be trialled to replicate findings.
Abstract
Background: Female age-related estrogen deficiency increases the risk of osteoporosis, which can be effectively treated with the use of hormone replacement therapy. However, hormone replacement therapy is demonstrated to increase cancer risk. Bioavailable isoflavones with selective estrogen receptor affinity show potential to prevent and treat osteoporosis while minimizing or eliminating carcinogenic side effects.Objective: In this study, we sought to determine the beneficial effects of a bioavailable isoflavone and probiotic treatment against postmenopausal osteopenia.Design: We used a novel red clover extract (RCE) rich in isoflavone aglycones and probiotics to concomitantly promote uptake and a favorable intestinal bacterial profile to enhance isoflavone bioavailability. This was a 12-mo, double-blind, parallel design, placebo-controlled, randomized controlled trial of 78 postmenopausal osteopenic women supplemented with calcium (1200 mg/d), magnesium (550 mg/d), and calcitriol (25 μg/d) given either RCE (60 mg isoflavone aglycones/d and probiotics) or a masked placebo [control (CON)].Results: RCE significantly attenuated bone mineral density (BMD) loss at the L2-L4 lumbar spine vertebra (P < 0.05), femoral neck (P < 0.01), and trochanter (P < 0.01) compared with CON (-0.99% and -2.2%; -1.04% and -3.05%; and -0.67% and -2.79, respectively). Plasma concentrations of collagen type 1 cross-linked C-telopeptide was significantly decreased in the RCE group (P < 0.05) compared with CON (-9.40% and -6.76%, respectively). RCE significantly elevated the plasma isoflavone concentration (P < 0.05), the urinary 2-hydroxyestrone (2-OH) to 16α-hydroxyestrone (16α-OH) ratio (P < 0.05), and equol-producer status (P < 0.05) compared with CON. RCE had no significant effect on other bone turnover biomarkers. Self-reported diet and physical activity were consistent and differences were nonsignificant between groups throughout the study. RCE was well tolerated with no adverse events.Conclusions: Twice daily RCE intake over 1 y potently attenuated BMD loss caused by estrogen deficiency, improved bone turnover, promoted a favorable estrogen metabolite profile (2-OH:16α-OH), and stimulated equol production in postmenopausal women with osteopenia. RCE intake combined with supplementation (calcium, magnesium, and calcitriol) was more effective than supplementation alone. This trial was registered at clinicaltrials.gov as NCT02174666.
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Effects of daily almond consumption on cardiometabolic risk and abdominal adiposity in healthy adults with elevated LDL-cholesterol: a randomized controlled trial.
Berryman, CE, West, SG, Fleming, JA, Bordi, PL, Kris-Etherton, PM
Journal of the American Heart Association. 2015;4(1):e000993
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Research has shown that almond consumption has a positive impact on cardiovascular risk factors and markers for inflammation. The aim of this randomised controlled trial was to compare a cholesterol lowering diet with almonds (1.5oz./day) with the same diet but substituting almonds with a calorie-matched food (i.e. a muffin) in a controlled-feeding setting. The study concluded that almonds reduce non high density lipoproteins, low-density lipoproteins and central adiposity in healthy individuals. The researchers suggest that it is likely to be almonds unique fatty acid profile and in particular, oleic acid that offers these cardiovascular protective effects. It recommended a daily intake of 1.5oz of almonds to replace high carbohydrate snacks.
Abstract
BACKGROUND Evidence consistently shows that almond consumption beneficially affects lipids and lipoproteins. Almonds, however, have not been evaluated in a controlled-feeding setting using a diet design with only a single, calorie-matched food substitution to assess their specific effects on cardiometabolic risk factors. METHODS AND RESULTS In a randomized, 2-period (6 week/period), crossover, controlled-feeding study of 48 individuals with elevated LDL-C (149±3 mg/dL), a cholesterol-lowering diet with almonds (1.5 oz. of almonds/day) was compared to an identical diet with an isocaloric muffin substitution (no almonds/day). Differences in the nutrient profiles of the control (58% CHO, 15% PRO, 26% total fat) and almond (51% CHO, 16% PRO, 32% total fat) diets were due to nutrients inherent to each snack; diets did not differ in saturated fat or cholesterol. The almond diet, compared with the control diet, decreased non-HDL-C (-6.9±2.4 mg/dL; P=0.01) and LDL-C (-5.3±1.9 mg/dL; P=0.01); furthermore, the control diet decreased HDL-C (-1.7±0.6 mg/dL; P<0.01). Almond consumption also reduced abdominal fat (-0.07±0.03 kg; P=0.02) and leg fat (-0.12±0.05 kg; P=0.02), despite no differences in total body weight. CONCLUSIONS Almonds reduced non-HDL-C, LDL-C, and central adiposity, important risk factors for cardiometabolic dysfunction, while maintaining HDL-C concentrations. Therefore, daily consumption of almonds (1.5 oz.), substituted for a high-carbohydrate snack, may be a simple dietary strategy to prevent the onset of cardiometabolic diseases in healthy individuals. CLINICAL TRIAL REGISTRATION URL www.clinicaltrials.gov; Unique Identifier: NCT01101230.
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Efficacy of exercise for treating overweight in children and adolescents: a systematic review.
Atlantis, E, Barnes, EH, Singh, MA
International journal of obesity (2005). 2006;30(7):1027-40
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The global number of overweight and obese children/adolescents is increasing at an alarming rate. This systematic review and meta-analysis aimed to assess the impact of exercise for overweight children/adolescents. Fourteen randomised controlled trials (RCTs) were included in the analysis. Overall the reduction in average body weight and central obesity was not significant. However, it was found that exercise did significantly reduce body fat percentage by 0.6% in studies that involved more exercise (more than 3 days a week) for children with an average age of 12. When results were grouped by exercise amount, it was found that higher amounts had greater effect. Additionally, trials with longer intervention length saw greater effects. None of the trials reached the level of exercise recommended for children by UK/US guidelines (at least 60 minutes a day). The author suggested further studies of longer duration in this area are required to clarify exercise amount response.
Abstract
BACKGROUND Overweight prevalence among children/adolescents is increasing, while adult obesity may potentially cause a decline in life expectancy. More exercise is uniformly recommended, although treatment efficacy remains unclear. OBJECTIVE To determine the efficacy of exercise alone for treating overweight in children/adolescents. DESIGN A systematic review and meta-analysis of randomized trials published in English were completed following multiple database searches performed on December 10, 2004. Studies of isolated or adjunctive exercise/physical activity treatment in overweight/obese children or adolescents which reported any overweight outcome were included. Literature searches identified 645 papers which were manually searched, of which 45 were considered for inclusion, of which 13 papers which reported 14 studies were included (N=481 overweight boys and girls, aged approximately 12 years). Two reviewers independently identified relevant papers for potential inclusion and assessed methodological quality. Principal measures of effects included the mean difference (MD) (between treatment and control groups), the weighted MD (WMD), and the standardized MD (SMD). RESULTS Few studies were of robust design. The pooled SMD was -0.4 (-0.7, -0.1, P=0.006) for percent body fat, and -0.2 (-0.6, 0.1, P=0.07) for central obesity outcomes, whereas the pooled WMD was -2.7 kg (-6.1 kg, 0.8 kg, P=0.07) for body weight, all of which favored exercise. Pooled effects on body weight were significant and larger for studies of higher doses, whereas nonsignificant and smaller effects were seen for studies of lower doses of exercise (155-180 min/weeks vs 120-150 min/weeks). CONCLUSIONS Based on the small number of short-term randomized trials currently available, an aerobic exercise prescription of 155-180 min/weeks at moderate-to-high intensity is effective for reducing body fat in overweight children/adolescents, but effects on body weight and central obesity are inconclusive. Recommendations for future study designs are discussed.