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Effect of a Hop Extract Standardized in 8-Prenylnaringenin on Bone Health and Gut Microbiome in Postmenopausal Women with Osteopenia: A One-Year Randomized, Double-Blind, Placebo-Controlled Trial.
Lecomte, M, Tomassi, D, Rizzoli, R, Tenon, M, Berton, T, Harney, S, Fança-Berthon, P
Nutrients. 2023;15(12)
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Osteoporosis is a bone condition characterized by weakened and brittle bones, leading to an increased risk of fractures. Oestrogens play a vital role in maintaining bone health, whereby oestrogen deficiency elevates the risk of osteoporosis and fractures, particularly in menopausal women due to the decline in oestrogen levels. Phytoestrogens, plant-derived compounds capable of interacting with human oestrogen receptors, have presented an intriguing non-pharmaceutical avenue for preventing bone loss. Other phytoestrogens have received some attention in the field, however, limited human research exists on prenylflavonoids, a phytoestrogens found in hops (Humulus lupulus). This randomized, double-blinded, placebo-controlled trial aimed to investigate the effects of a year-long supplementation of standardised hop extract (8-PN) Lifenol® on bone mineral density in postmenopausal women. Additionally, the study explored potential mechanisms, particularly focusing on changes in gut bacteria. Notably, gut bacteria play a role in bone metabolism and the pathogenesis of osteoporosis. They are also, along with the liver, responsible for converting hops phenols into active phytoestrogenic compounds. The trial was completed by 95 postmenopausal, women with Osteopenia aged 50 to 85. They all received calcium and vitamin D3 tablets in addition either a hop extract (100mcg) or a placebo for 48 weeks. Changes were monitored using DXA scans for bone mineral density (BMD) and bone metabolism, blood samples for markers for bone health, a quality of life questionnaire, gut microbiome testing, and tests for short-chain fatty acid (SCFA) levels. In conclusion, the intake of hop extract confirmed a previously observed trend of a slight increase in total bone mineral density (BMD), in addition to the benefits linked to calcium and vitamin D supplementation. Although there were no significant changes in the composition of gut bacteria and SCFA levels, the hop extract candidates had a higher abundance of specific genera associated with total body BMD, suggesting a potential positive impact. Larger studies are required to validate these findings.
Abstract
Estrogen deficiency increases the risk of osteoporosis and fracture. The aim of this study was to investigate whether a hop extract standardized in 8-prenylnaringenin (8-PN), a potent phytoestrogen, could improve bone status of osteopenic women and to explore the gut microbiome roles in this effect. In this double-blind, placebo-controlled, randomized trial, 100 postmenopausal, osteopenic women were supplemented with calcium and vitamin D3 (CaD) tablets and either a hop extract (HE) standardized in 8-PN (n = 50) or a placebo (n = 50) for 48 weeks. Bone mineral density (BMD) and bone metabolism were assessed by DXA measurements and plasma bone biomarkers, respectively. Participant's quality of life (SF-36), gut microbiome composition, and short-chain fatty acid (SCFA) levels were also investigated. In addition to the CaD supplements, 48 weeks of HE supplementation increased total body BMD (1.8 ± 0.4% vs. baseline, p < 0.0001; 1.0 ± 0.6% vs. placebo, p = 0.08), with a higher proportion of women experiencing an increase ≥1% compared to placebo (odds ratio: 2.41 ± 1.07, p < 0.05). An increase in the SF-36 physical functioning score was observed with HE versus placebo (p = 0.05). Gut microbiome α-diversity and SCFA levels did not differ between groups. However, a higher abundance of genera Turicibacter and Shigella was observed in the HE group; both genera have been previously identified as associated with total body BMD. These results suggest that an 8-PN standardized hop extract could beneficially impact bone health of postmenopausal women with osteopenia.
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Muscle Mass Changes After Daily Consumption of Protein Mix Supplemented With Vitamin D in Adults Over 50 Years of Age: Subgroup Analysis According to the Serum 25(OH)D Levels of a Randomized Controlled Trial.
Kang, Y, Kim, N, Lee, Y, An, X, Chung, YS, Park, YK
Clinical nutrition research. 2023;12(3):184-198
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Sarcopenia is an age-related decrease in muscle mass and strength and increases the risk of falls and death. Protein intake and vitamin D are important for the maintenance of muscle mass, and the amino acid leucine plays a role in the regulation of muscle protein turnover. The aim of this 12-week double-blind, randomised, placebo-controlled trial was to evaluate the efficacy of a supplement containing protein, vitamin D, leucine and calcium for maintaining muscle mass, strength and physical functioning in healthy Koreans aged 50-80 years. Increases in muscle mass were seen in those with low vitamin D levels (< 30 ng/ml) but not in those with higher vitamin D levels. No differences were observed in muscle strength and physical functioning. The authors concluded that a supplement containing protein, including high levels of leucine, vitamin D and calcium may be of benefit for muscle mass to middle-aged and older adults with low vitamin D levels.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Consider supplementing protein in combination with leucine, vitamin D and calcium in middle-aged or older adults with insufficient vitamin D levels for prevention of sarcopenia.
Evidence Category:
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X
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
- Sarcopenia increases the risk of falls and death
- Protein and vitamin D are important for maintaining muscle mass whilst leucine is involved in regulating muscle protein turnover
- The aim of this study was to evaluate the effects of a supplement containing protein, vitamin D, leucine and calcium on muscle mass, physical functioning, muscle strength, and physical ability in middle-aged and older adults.
Methods
- Double-blind, randomised, placebo-controlled trial, with a duration of 12 weeks. Included 120 healthy Koreans aged 50-80 years
- Participants were assigned to “insufficient” subgroup if vitamin D levels were <30ng/ml and to the “sufficient” subgroup if vitamin D was 30ng/ml or higher
- Intervention: 2.5g powder (containing 20g protein (90% milk/10% soya, incl. 3g leucine), 800 IU vitamin D, 300 mg calcium) mixed into beverage of choice twice a day. Control: isocaloric placebo powder
- Primary outcome: Muscle mass determined by dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA)
- Secondary outcomes: Muscle strength (femoral muscle and grip strength); physical functioning (short physical performance battery (SPPB), International Physical Activity Questionnaire (IPAQ)).
Results
- At baseline, age of participants in the “sufficient” intervention subgroup was higher than that of the “sufficient” control subgroup (p=0.02)
- Increase in vitamin D levels in intervention group relative to control group, in both sufficient and insufficient subgroups (difference in changes between groups 11.5 ng/ml and 13.9 ng/ml, respectively, both p=0.00)
- No difference in change in muscle index as measured by DXA between groups
- In the “insufficient” subgroup, BIA increases in muscle mass were seen when normalised by height (p=0.037) and weight (p=0.05)
- No differences in changes in physical functioning or muscle strength between groups.
Conclusion
- The authors conclude that a supplement containing protein, with high levels of leucine, vitamin D and calcium may be of benefit for muscle mass to middle-aged and older adults with insufficient vitamin D levels.
Clinical practice applications:
- Middle-aged and older adults with insufficient vitamin D levels may gain muscle mass through supplementation of protein, leucine, vitamin D and calcium
- Middle-age and older adults with sufficient vitamin D levels do not appear to benefit from the same intervention.
Considerations for future research:
- Longer-term studies may help identify whether increases in muscle mass lead to improved physical functioning over time
- A study combining supplementation and exercise may help identify additive or synergistic effects.
Abstract
UNLABELLED Early prevention of sarcopenia can be an important strategy for muscle maintenance, but most studies target subjects at slightly pre-sarcopenic state. Our previous paper describes the effect of protein supplements rich in leucine and vitamin D on muscle condition, and in this paper, we performed a sub-analysis to evaluate who benefitted the most in terms of improvement in muscle health. A 12-week randomized clinical trial of 120 healthy adults (aged 50 to 80) assigned to an intervention group (n = 60) or control group (n = 60) were analyzed. Subjects in the intervention group received, twice per day, a protein supplement containing (per serving) 800 IU of vitamin D, 20 g of protein (3 g of total leucine), 300 mg of calcium, 1.1 g of fat, and 2.5 g of carbohydrate. The subjects were classified into 'insufficient' and 'sufficient' groups at 25-hydroxyvitamin D (25[OH]D) value of 30 ng/mL. The skeletal muscle mass index normalized to the square of the skeletal muscle mass (SMM) height (kg/m2) increased significantly in the 'insufficient group' difference value of change between weeks 0 and 12 (Δ1.07 ± 2.20; p = 0.037). The SMM normalized by body weight (kg/kg, %) was higher, but not significantly, in the insufficient group (Δ0.38 ± 0.69; p = 0.050). For people with insufficient (serum 25[OH]D), supplemental intake of protein and vitamin D, calcium, and leucine and adequate energy intake increases muscle mass in middle-aged and older adults and would be likely to exert a beneficial effect on muscle health. TRIAL REGISTRATION Clinical Research Information Service Identifier: KCT0005111.
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The Mediterranean Diet in Osteoporosis Prevention: An Insight in a Peri- and Post-Menopausal Population.
Quattrini, S, Pampaloni, B, Gronchi, G, Giusti, F, Brandi, ML
Nutrients. 2021;13(2)
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Osteoporosis (OP) is a public health problem in western countries and steadily increasing worldwide. Management and prevention of osteoporosis starts with lifestyle, and diet is of critical interest because it is one of the few safely modifiable risk factors. Several different nutrients, especially calcium are essential for bone and mineral metabolism. It has been observed that the incidence of OP is lower in the Mediterranean area. This prospective observational study looks at the relationship between Mediterranean diet (MD), calcium intake and bone health. Two hundred peri- and post-menopausal women aged 30-80 years, took part. Their adherence to the MD and dietary calcium intake were evaluated by a first visit and a follow-up visit, through questionnaires. Although not statistically significant, in both visits a slight increase in calcium intake was observed for high adherence to MD diet. However, it did highlight the importance of preventive action such as a 15–20 min nutritional conversation to improve lifestyle habits. A cause-effect relationship between MD adherence and calcium intake could not be established by this study, a randomized controlled trial would be useful to gather more data.
Abstract
Osteoporosis represent a widespread public health problem. The management and prevention of osteoporosis and related low energy fractures start with a correct lifestyle and proper nutrition. Several different nutrients are essential for bone and mineral metabolism, especially calcium. Nevertheless, a well-balanced nutrition, such as Mediterranean diet (MD), proved to be beneficial for several chronic diseases and also fragility fractures resulted lower in the Mediterranean area. A prospective observational study in a population of two hundred peri- and post-menopausal women (aged 30-80 years) was developed at Careggi hospital, Florence. Both MD adherence and dietary calcium intake were evaluated in occasion of a "first visit" and a "follow-up" visit, through validated questionnaires. From a descriptive point of view, although not statistically significant, in both visits a slight increase in calcium intake was observed for high adherence to MD diet. Moreover, a short nutritional interview (20 min) was applied in our population and demonstrated to be sufficient to significantly improve MD adherence level (mean score at T0 = 6.98 ± 1.74 and T1 = 7.53 ± 1.68), opening promising paths in osteoporosis prevention.
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Safety and tolerability of 6-month supplementation with a vitamin D, calcium and leucine-enriched whey protein medical nutrition drink in sarcopenic older adults.
Bauer, JM, Mikušová, L, Verlaan, S, Bautmans, I, Brandt, K, Donini, LM, Maggio, M, Mets, T, Wijers, SLJ, Garthoff, JA, et al
Aging clinical and experimental research. 2020;32(8):1501-1514
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Older adults who have sarcopenia and osteoporosis are at risk of falls, fractures and hospitalisation. Sufficient dietary protein intake and an adequate vitamin D and calcium status has been proposed as a way to attenuate age-related loss of muscle and bone. This however may cause safety concerns with regard to kidney function and potential vitamin D or calcium toxicity. The aim of this randomised placebo-controlled trial was to determine the effect of 6 months supplementation with a vitamin D, calcium and leucine-enriched whey protein medical nutrition drink (WP-MND) on kidney function and on vitamin D, parathyroid hormone (PTH) and calcium levels in sarcopenic older adults. In conclusion, a 6-month intake of a vitamin D, calcium and leucine-enriched whey protein medical nutrition drink in addition to a regular diet does not impair kidney function or disturb vitamin D and calcium metabolism in sarcopenic older adults.
Abstract
AIMS: Safety and tolerability of prolonged supplementation with a vitamin D, calcium and leucine-enriched whey protein medical nutrition drink (WP-MND) was evaluated in sarcopenic older adults. METHODS A 13-week double-blinded, randomized, isocaloric placebo-controlled trial (PROVIDE study; n = 380) was extended with a voluntary 13-week open-label extension (OLE). OLE participants were randomized to receive daily 1 or 2 servings of WP-MND (21 g protein, 3 g leucine, 10 µg vitD and 500 mg calcium per serving). Gastro-intestinal tolerability, kidney function and serum levels of calcidiol, parathyroid hormone (PTH) and calcium were evaluated at week 0, 13 and 26. RESULTS AND DISCUSSION In response to the high daily protein intake (median1.5; IQR: 1.3, 1.7 g/kg BW/day), the estimated glomerular filtration rate (eGFR) increased in the test group during the RCT (p = 0.013). The same trend was observed for those participants with moderate chronic kidney disease. During OLE no eGFR change was observed in any of the groups. Serum calcidiol and calcium reached a plateau after 13-week WP-MND supplementation. As expected, PTH significantly changed in the opposite direction, decreasing during RCT in the test group (T vs C: p < 0.001) and during OLE in former control groups. During RCT, 20/366 participants with normal baseline calcidiol reached levels ≥ 100 nmol/L (T: n = 18; C: n = 2) and 6 developed albumin-corrected calcium levels > 2.55 mmol/L (T: n = 3; C: n = 3), without associated adverse events. CONCLUSION A 6 months intervention with up to 2 servings of WP-MND did neither result in kidney function deterioration nor symptoms of vitamin D or calcium toxicity. The product was overall well tolerated.
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Role of Calcium and Low-Fat Dairy Foods in Weight-Loss Outcomes Revisited: Results from the Randomized Trial of Effects on Bone and Body Composition in Overweight/Obese Postmenopausal Women.
Ilich, JZ, Kelly, OJ, Liu, PY, Shin, H, Kim, Y, Chi, Y, Wickrama, KKAS, Colic-Baric, I
Nutrients. 2019;11(5)
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A woman’s menopausal years are believed to bring about weight gain due to various biological mechanisms, such as depletion of oestrogen. Many women undertake weight loss diets, in an attempt to control the weight gain, and although weight loss can reduce the risk factors for metabolic and cardiovascular disease etc, it can also lead to accelerated loss bone density and muscle mass. The objective of this study was to investigate whether by complementing a low-calorie diet with 4 to 5 servings of low-fat dairy foods per day and/or supplementing with calcium and vitamin D supplements would aid weight loss and preserve either/both bone and muscle mass. The study was conducted on 189 early postmenopausal, obese women. It was a randomized, placebo-controlled clinical trial conducted over 6 months. Researchers found that results were better for the participants on the low-fat dairy foods and those supplementing with calcium and vitamin D when compared to the placebo group (who only had placebo pills). They suggest that when embarking on a weight loss program it is beneficial to include 4 to 5 servings of low-fat dairy foods each day and take calcium and vitamin D supplements will have a positive impact on weight loss, bone density and muscle mass in post-menopausal women.
Abstract
Several studies have investigated the possibility of dairy foods and calcium (Ca) mediating weight and body composition, but a consensus has not been reached. We aimed to investigate weight-loss-related outcomes during intervention with low-fat dairy foods or Ca + vitamin D supplements, both as complements to hypocaloric diets. Overweight/obese Caucasian, early-postmenopausal women (n = 135) were recruited for a 6 month energy-restricted weight loss study complemented with either low-fat dairy foods (D; 4-5 servings/day), or Ca + vitamin D supplements (S); both to amount a total of ~1500 mg/day and 600 IU/day of Ca and vitamin D, respectively, or placebo pills (C). Bone mineral density (BMD) and lean and fat tissue were measured by Lunar iDXA. Serum and urinary markers of bone turnover were analyzed. Diet and physical activity were assessed with 3-day records. Participants on average lost ~4%, ~3%, and ~2% of body weight, fat, and lean tissue, respectively. The significantly better outcomes were noticed in participants in the D group regarding body composition (fat loss/lean tissue preservation) and in participants in the S group regarding the BMD outcomes, compared to those in the C group. Therefore, increasing low-fat dairy foods to 4-5 servings/day and/or increasing Ca & vitamin D intake by supplements (in those who are at the borderline dietary intake) may be beneficial for weight loss/maintenance and may lead to more favorable bone and body composition outcomes in postmenopausal women during moderate weight loss.
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Dairy product consumption and risk of hip fracture: a systematic review and meta-analysis.
Bian, S, Hu, J, Zhang, K, Wang, Y, Yu, M, Ma, J
BMC public health. 2018;18(1):165
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Dairy products contain calcium and Vitamin D, two elements that are known to support bone health. The consumption of dairy products therefore, may affect the risk of bone fracture, however the research remains inconclusive. This meta-analysis examined and quantified the potential association between dairy consumption and the risk of hip fracture. The final analysis included 10 cohort studies and 8 case-control studies. After pooling the data from these studies, the researchers concluded that: • Consumption of yoghurt and cheese was associated with a lower risk of hip fracture • Consumption of total dairy products and cream was not significantly associated with the risk of hip fracture • There was insufficient evidence to deduce an association between milk consumption and the risk of hip fracture. 200g of milk per day may be beneficial however the effects of higher volumes were unclear.
Abstract
BACKGROUND Dairy product consumption may affect the risk of hip fracture, but previous studies have reported inconsistent findings. The primary aim of our meta-analysis was to examine and quantify the potential association of dairy product consumption with risk of hip fracture. METHODS We searched the databases of PubMed and EMBASE for relevant articles from their inception through April 17, 2017. The final analysis included 10 cohort studies and 8 case-control studies. Random-effects models were used to estimate the pooled risk. Subgroup and dose-response analyses were conducted to explore the relationships between the consumption of milk and the risk of hip fracture. RESULTS After pooling the data from the included studies, the summary relative risk (RR) for hip fracture for highest versus lowest consumption were 0.91 (95% CI: 0.74-1.12), 0.75 (95% CI: 0.66-0.86), 0.68 (95% CI: 0.61-0. 77), 1.02 (95% CI: 0.93-1.12) for milk, yogurt, cheese, and total dairy products in cohort studies, respectively. Higher milk consumption [Odds ratio (OR), 0.71, 95% CI: 0.55-0. 91] was associated with lower risk of hip fracture for highest versus lowest consumption in case-control studies. After quantifying the specific dose of milk, the summary RR/OR for an increased milk consumption of 200 g/day was 1.00 (95% CI: 0.94-1.07), and 0.89 (95%CI: 0.64-1.24) with significant heterogeneity for cohort and case-control studies, respectively; There was a nonlinear association between milk consumption and hip fracture risk in cohort, and case-control studies. CONCLUSIONS Our findings indicate that consumption of yogurt and cheese was associated with lower risk of hip fracture in cohort studies. However, the consumption of total dairy products and cream was not significantly associated with the risk of hip fracture. There was insufficient evidence to deduce the association between milk consumption and risk of hip fracture. A lower threshold of 200 g/day milk intake may have beneficial effects, whereas the effects of a higher threshold of milk intake are unclear.
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Consumption of calcium-fortified cereal bars to improve dietary calcium intake of healthy women: randomized controlled feasibility study.
Lee, JT, Moore, CE, Radcliffe, JD
PloS one. 2015;10(5):e0125207
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Calcium intake is essential to maintain bone heath and reduce the risk of osteoporosis, however most adult women are not meeting the current daily recommendations. The aim of this trial was to examine the benefits of including a non-dairy source of calcium in the diet of women during a 9-week crossover study. 35 women aged 21-58 were assigned to consume two calcium-fortified cereal bars daily for three weeks, after which diets were switched for another three weeks. Diet diaries were used to monitor intake. This study found that dietary calcium was significantly higher during the intervention period when two calcium-fortified cereal bars were consumed than during the baseline period. This addition did not increase total energy intake or result in weight gain. Further research is warranted to determine the whether consumption of calcium-fortified bars improves calcium bioavailability, and should monitor changes of bone health markers and bone density.
Abstract
UNLABELLED Calcium is an important structural component of the skeletal system. Although an adequate intake of calcium helps to maintain bone health and reduce the risk of osteoporosis, many women do not meet recommended daily intakes of calcium. Previous interventions studies designed to increase dietary intake of women have utilized primarily dairy sources of calcium or supplements. However, lactose intolerance, milk protein allergies, or food preferences may lead many women to exclude important dairy sources of dietary calcium. Therefore, we undertook a 9 week randomized crossover design trial to examine the potential benefit of including a non-dairy source of calcium in the diet of women. Following a 3 week run-in baseline period, 35 healthy women > 18 years were randomized by crossover design into either Group I or Group II. Group I added 2 calcium-fortified cereal bars daily (total of 400 mg calcium/day) (intervention) to their usual diet and Group II continued their usual diet (control). At the end of 3 weeks, diets were switched for another 3 weeks. Intakes of calcium and energy were estimated from 3-day diet and supplemental diaries. Wilcoxon signed-rank tests were used for within group comparisons and Mann Whitney U tests were used for between group comparisons of calcium and energy intake. Dietary calcium was significantly higher during intervention (1071 mg/d) when participants consumed 2 calcium-fortified cereal bars daily than during the baseline (720 mg/d, P <0.0001) or control diets (775 mg/d, P = 0.0001) periods. Furthermore, the addition of 2 calcium-fortified cereal bars daily for the 3 week intervention did not significantly increase total energy intake or result in weight gain. In conclusion, consumption of calcium-fortified cereal bars significantly increased calcium intake of women. Further research examining the potential ability of fortified cereal bars to help maintain and improve bone health of women is warranted. TRIAL REGISTRATION ClinicalTrials.gov NCT01508689.
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Physiologic and behavioral indicators of energy deficiency in female adolescent runners with elevated bone turnover.
Barrack, MT, Van Loan, MD, Rauh, MJ, Nichols, JF
The American journal of clinical nutrition. 2010;92(3):652-9
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Young female runners are more likely to have a low bone mass for their age. It is thought that this might be partly due to them using more energy (calories) than they consume. This study looked at the relationship between nutrition intake and biomarkers of bone turnover in young female runners. Participants were competitive cross-country runners, aged 14-17. The girls ate their usual diet and kept a food diary for a week, to allow the researchers to analyse their nutritional intakes. Runners that had an elevated bone turnover consumed significantly less calories and calcium than the runners with a normal bone turnover. They were also more likely to have a lower body mass, fewer menstrual cycles, lower oestrogen and vitamin D levels, lower BMI and lower bone mass. The authors concluded that nutritional support to increase energy and calcium intake, and vitamin D levels may improve bone growth in young female runners.
Abstract
BACKGROUND Female adolescent runners have an elevated prevalence of low bone mass for agemdashan outcome that may be partially due to inadequate energy intake. OBJECTIVE The objective was to evaluate diet, menstrual history, serum hormone concentrations, and bone mass in female adolescent runners with normal or abnormal bone turnover. DESIGN Thirty-nine cross-country runners (age: 15.7 plusmn 0.2 y) participated in the study, which included a 7-d dietary assessment with the use of a food record and daily 24-h dietary recalls; serum measures of insulin-like growth factor I, estradiol, leptin, parathyroid hormone, progesterone, triiodothyronine, 25-hydroxycholecalciferol, bone-specific alkaline phosphatase (BAP), and cross-linked C-telopeptides of type I collagen (CTX); an evaluation of height, weight, bone mass, and body composition with the use of dual-energy X-ray absorptiometry; and a questionnaire to assess menses and sports participation. Age- and sex-specific BAP and CTX concentrations of at least the 97th percentile and no greater than the third percentile, respectively, were considered abnormal. RESULTS All abnormal BAP and CTX concentrations fell within the elevated ( ge 97%) range. Runners with an elevated bone turnover (EBT) (n = 13) had a lower body mass, fewer menstrual cycles in the past year, lower estradiol and 25-hydroxycholecalciferol concentrations, and a higher prevalence of body mass index lt 10% for age, vitamin D insufficiency, amenorrhea, and low bone mass. Girls with EBT consumed less than the recommended amounts of energy and had a higher prevalence of consuming lt 1300 mg Ca than did those with normal bone turnover. CONCLUSIONS Runners with EBT had a profile consistent with energy deficiency. Nutritional support to increase energy, calcium intake, and 25-hydroxycholecalciferol concentrations may improve bone mineral accrual in young runners with EBT. This trial was registered at clinicaltrials.gov as NCT01059968.