Category Archives: Supplements

Resveratrol and SIRT1 Reduces Sclerostin Expression In-Vitro

Abstract

Low sirtuin 1 levels in human osteoarthritis subchondral osteoblasts lead to abnormal sclerostin expression which decreases Wnt/β-catenin activity.

Wnt/β-catenin (cWnt) signaling plays a key role in osteogenesis by promoting the differentiation and mineralization of osteoblasts, activities altered in human osteoarthritic subchondral osteoblast (OA Ob). Sclerostin (SOST) has been shown to alter cWnt signaling. Sirtuin 1 (SIRT1) acts as a novel bone regulator and represses SOST levels in Ob. However the role of SIRT1 and SOST in OA Ob remains unknown. Herein, we explored the role played by SIRT1 and SOST on the abnormal mineralization and cWnt signaling in OA Ob.
Primary human normal and OA Ob were prepared from tibial plateaus. SOST levels were evaluated by immunohistochemistry, the expression and production of genes by qRT-PCR and WB analysis. Their inhibitions were performed using siRNA. cWnt signaling was measured by the TOPflash TCF/lef luciferase reporter assay. Mineralization was determined by alizarin red staining.
SOST levels were significantly increased in OA Ob compared to normal and were linked with elevated TGF-β1 levels in these cells. SIRT1 expression was significantly reduced in OA Ob compared to normal yet not modified by TGF-β1. Specific inhibition of SIRT1 increased TGF-β1 and SOST expressions in OA Ob, while stimulating SIRT1 activity with β-Nicotinamide mononucleotide reduced the expression of TGF-β1 and SOST, and increased mineralization in OA Ob. Resveratrol also reduced SOST expression in OA Ob. Reduced cWnt signaling, β-catenin levels, and mineralization in OA Ob were all corrected via reducing SOST expression.
These data indicate that high level of SOST is responsible, in part, for the reduced cWnt and mineralization of human OA Ob, which in turn is linked with abnormal SIRT1 levels in these pathological cells.

Abed É, Couchourel D, Delalandre A, Duval N…
Bone Feb 2014
PMID: 24184155

Bone Density and Arterial Stiffness Again

Abstract

Low bone mineral density is associated with increased arterial stiffness in participants of a health records based study.

Many epidemiological studies have shown that low bone mineral density (BMD) and atherosclerosis appear to be related. However, their precise correlation is not completely understood after full adjustment the shared confounders of atherosclerosis and bone metabolism. The aim of this cross-sectional study was to investigate the relationship between BMD and subclinical atherosclerosis in a healthy Chinese population and the difference in gender.
The study population consisted of 2,487 subjects (1,467 men, 1,020 women) who participated in health check-up programs and were selected to be free of major diseases which might affect atherosclerosis and bone metabolism. Bone status was assessed by BMD in lumbar spine. The brachial-ankle PWV (baPWV) was assessed as a functional marker of atherosclerosis. The ankle-brachial index (ABI), carotid artery intima-media thickness (CIMT), estimated glomerular filtration rate (eGRF) and microalbuminuria were evaluated as indexes of structural markers of atherosclerosis.
After adjustment for risk factors, significant association was shown between baPWV and BMD in both genders (male: r=-0.084, P=0.035; female: r=-0.088, P=0.014). The correlation was stronger in females than in males, and in females, the correlation was stronger after menopause. Similarly, mean baPWV differed significantly according to the decreased BMD (normal BMD, Osteopenia, Osteoporosis). In contrast, no significant differences were observed for ABI, CIMT, eGFR or microalbuminuria with BMD.
Independent of confounding factors, low BMD is associated with the functional marker of subclinical atherosclerosis (increased baPWV), but not with structural markers (ABI, CIMT, eGFR or microalbuminuria) among healthy females and males.

Wang YQ, Yang PT, Yuan H, Cao X…
J Thorac Dis May 2015
PMID: 26101634 | Free Full Text

From the full text discussion:

There are several potential mechanisms to explain this link. Both osteoporosis and atherosclerosis share similar or common risk factors. Bone-associated matrix proteins, homocysteine, high levels of OPG, inflammatory mediators, estrogen and vitamin D deficiency all play an important role both in bone metabolism and in the development of atherosclerosis (32).

Review: Dairy for Bones

Abstract

Invited review: Dairy intake and bone health: a viewpoint from the state of the art.

The aim of this review was to focus on the complex relationships between milk and dairy products intake and bone health, with particular emphasis on osteoporosis. The literature was extensively examined to provide an objective overview of the most significant achievements on the subject. Osteoporosis can be defined as a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. Although the major determinants of peak bone mass and strength are genetic, major factors during childhood and adolescence may affect the ability to achieve peak bone mass. These include nutrition, particularly calcium and protein intake, physical activity, endocrine status, as well as exposure to a wide variety of risk factors. The role of calcium intake in determining bone mineral mass is well recognized to be the most critical nutritional factor to achieve optimal peak bone mass. The greatest amount of dietary calcium is obtained from milk and dairy foods, which also provide the human diet with vitamin D (particularly for products fortified with vitamin D), potassium, and other macro- and micronutrients. Although studies supporting the beneficial effects of milk or calcium on bone health are predominant in the literature, perplexity or discordance on this subject was expressed by some authors. Discordant data, mainly on the risk of fractures, provided limited proof of the unfavorable effect of dairy intake. More often, discordant works indicate no effect of dairy consumption on bone safety. Some considerations can be drawn from this viewpoint. Milk and dairy products are an optimal source of calcium as well as of other limiting nutrients (e.g., potassium and magnesium), with important effects on bone health. Bioactive components occurring in milk and dairy products may play an essential role on bone metabolism, as shown by in vivo and in vitro studies on colostrum acidic proteins and milk basic proteins. Calcium intake positively affects bone mass and is crucial in childhood and youth for correct bone development. In elderly people, calcium intake as well as vitamin D availability should be carefully checked. As a general conclusion, calcium is essential for bone health, although it will not prevent bone loss due to other factors; in this context, milk and dairy foods are bioavailable, relatively inexpensive sources of calcium for the human diet.

Caroli A, Poli A, Ricotta D, Banfi G…
J. Dairy Sci. Nov 2011
PMID: 22032348 | Free Full Text

This article reviews some of the negative studies on dairy for bones. Including this study. The article concludes with:

In any case, some general conclusions can be drawn. First, milk and dairy products are an optimal source of calcium as well as other limiting nutrients (e.g., potassium and magnesium), with important effects on bone health. Bioactive components occurring in milk and dairy products may play an essential role in bone metabolism, as shown by colostrum acidic proteins and MBP. Calcium intake positively affects bone mass and is crucial in childhood and youth for correct bone development. In elderly people, calcium intake as well as vitamin D availability should be carefully checked. The literature reporting favorable effects of milk and dairy products on bone is highly predominant compared with contradictory papers, including discordant and perplexing works. Discordant data, mainly on the risk of fractures, provided limited proof of the unfavorable effects of dairy intake. The majority of the contradictory papers indicate that dairy consumption does not alter bone safety. The best conclusion comes from Lindsay and Nieves (1994):

“Calcium will not prevent the bone loss due to other factors . . . nonetheless, milk is a bioavailable, relatively inexpensive source of calcium for those who can ingest it.”

Milk Increases Risk of Fracture in Women

Abstract

Milk, dietary calcium, and bone fractures in women: a 12-year prospective study.

This study examined whether higher intakes of milk and other calcium-rich foods during adult years can reduce the risk of osteoporotic fractures.
This was a 12-year prospective study among 77761 women, aged 34 through 59 years in 1980, who had never used calcium supplements. Dietary intake was assessed with a food-frequency questionnaire in 1980, 1984, and 1986. Fractures of the proximal femur (n = 133) and distal radius (n = 1046) from low or moderate trauma were self-reported on biennial questionnaires.
We found no evidence that higher intakes of milk or calcium from food sources reduce fracture incidence. Women who drank two or more glasses of milk per day had relative risks of 1.45 for hip fracture (95% confidence interval [CI] = 0.87, 2.43) and 1.05 for forearm fracture (95% CI = 0.88, 1.25) when compared with women consuming one glass or less per week. Likewise, higher intakes of total dietary calcium or calcium from dairy foods were not associated with decreased risk of hip or forearm fracture.
These data do not support the hypothesis that higher consumption of milk or other food sources of calcium by adult women protects against hip or forearm fractures.

Feskanich D, Willett WC, Stampfer MJ, Colditz GA
Am J Public Health Jun 1997
PMID: 9224182 | Free Full Text

Calcium More or Less Than 800mg Increases Heart Risk, More or Less Than 900mg Increases All-Cause Mortality

Abstract

Dietary calcium intake and mortality risk from cardiovascular disease and all causes: a meta-analysis of prospective cohort studies.

Considerable controversy exists regarding the association between dietary calcium intake and risk of mortality from cardiovascular disease and all causes. Therefore, we performed a meta-analysis of prospective cohort studies to examine the controversy.
We identified relevant studies by searching MEDLINE, Embase, and the Cochrane Library databases between 1 September 2013 and 30 December 2013. Reference lists of relevant articles were also reviewed. Observational prospective studies that reported relative risks and 95% confidence intervals for the association of calcium intake with cardiovascular and all-cause mortality were eligible. Study-specific relative risks were pooled using a random-effects model.
In this meta-analysis, 11 prospective studies with 12 independent cohorts, involving 757,304 participants, were eligible. There was evidence of a non-linear association between dietary calcium intake and risk of mortality from cardiovascular disease (P for non-linearity <0.01) and all causes (P for non-linearity <0.01). A dose-response analysis showed a U-shaped relationship between dietary calcium intake and cardiovascular mortality. Intakes that were lower and higher than around 800 mg/day were gradually associated with a higher risk of cardiovascular mortality. For all-cause mortality, we also observed a threshold effect at intakes around 900 mg/day. The risk of all-cause mortality did not decrease further at intakes above 900 mg/day.
This meta-analysis of prospective cohort studies suggests that dietary calcium intake is associated with cardiovascular mortality in a U-shaped manner and that high dietary calcium intake (>900 mg/day) is not associated with a decreased risk of all-cause mortality.

Wang X, Chen H, Ouyang Y, Liu J…
BMC Med 2014
PMID: 25252963 | Free Full Text

From the full text:

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Calcium Supplements Associated with Increased Fracture Risk In Women

Abstract

Calcium intake and fracture risk: results from the study of osteoporotic fractures.

The relation between dietary calcium, calcium, and vitamin D supplements and the risk of fractures of the hip (n = 332), ankle (n = 210), proximal humerus (n = 241), wrist (n = 467), and vertebrae (n = 389) was investigated in a cohort study involving 9,704 US white women aged 65 years or older. Baseline assessments took place in 1986-1988 in four US metropolitan areas. Dietary calcium intake was assessed at baseline with a validated food frequency questionnaire. Data on new nonvertebral fractures were collected every 4 months during a mean of 6.6 years of follow-up; identification of new vertebral fractures was based on comparison of baseline and follow-up radiographs of the spine done a mean of 3.7 years apart. Results were adjusted for numerous potential confounders, including weight, physical activity, estrogen use, protein intake, and history of falls, osteoporosis, and fractures. There were no important associations between dietary calcium intake and the risk of any of the fractures studied. Current use of calcium supplements was associated with increased risk of hip (relative risk = 1.5, 95% confidence interval 1.1-2.0) and vertebral (relative risk = 1.4, 95% confidence interval 1.1-1.9) fractures; current use of Tums antacid tablets was associated with increased risk of fractures of the proximal humerus (relative risk = 1.7, 95% confidence interval 1.3-2.4). There was no evidence of a protective effect of vitamin D supplements. Although a true adverse effect of calcium supplements on fracture risk cannot be ruled out, it is more likely that our findings are due to inadequately controlled confounding by indications for use of supplements. In conclusion, this study did not find a substantial beneficial effect of calcium on fracture risk.

Cumming RG, Cummings SR, Nevitt MC, Scott J…
Am. J. Epidemiol. May 1997
PMID: 9149664 | Free Full Text

Calcium Intake of 903mg to 1025mg Associated with Lowest Fracture Risk, More and Less Increases Risk

Abstract

Dietary calcium intake and risk of fracture and osteoporosis: prospective longitudinal cohort study.

To investigate associations between long term dietary intake of calcium and risk of fracture of any type, hip fractures, and osteoporosis.
A longitudinal and prospective cohort study, based on the Swedish Mammography Cohort, including a subcohort, the Swedish Mammography Cohort Clinical.
A population based cohort in Sweden established in 1987.
61,433 women (born between 1914 and 1948) were followed up for 19 years. 5022 of these women participated in the subcohort.
Primary outcome measures were incident fractures of any type and hip fractures, which were identified from registry data. Secondary outcome was osteoporosis diagnosed by dual energy x ray absorptiometry in the subcohort. Diet was assessed by repeated food frequency questionnaires.
During follow-up, 14,738 women (24%) experienced a first fracture of any type and among them 3871 (6%) a first hip fracture. Of the 5022 women in the subcohort, 1012 (20%) were measured as osteoporotic. The risk patterns with dietary calcium were non-linear. The crude rate of a first fracture of any type was 17.2/1000 person years at risk in the lowest quintile of calcium intake, and 14.0/1000 person years at risk in the third quintile, corresponding to a multivariable adjusted hazard ratio of 1.18 (95% confidence interval 1.12 to 1.25). The hazard ratio for a first hip fracture was 1.29 (1.17 to 1.43) and the odds ratio for osteoporosis was 1.47 (1.09 to 2.00). With a low vitamin D intake, the rate of fracture in the first calcium quintile was more pronounced. The highest quintile of calcium intake did not further reduce the risk of fractures of any type, or of osteoporosis, but was associated with a higher rate of hip fracture, hazard ratio 1.19 (1.06 to 1.32).
Gradual increases in dietary calcium intake above the first quintile in our female population were not associated with further reductions in fracture risk or osteoporosis.

Warensjö E, Byberg L, Melhus H, Gedeborg R…
BMJ 2011
PMID: 21610048 | Free Full Text

From the full text:

• Dietary calcium intakes below approximately 700 mg per day in women were associated with an increased risk of hip fracture, any fracture, and of osteoporosis

• The highest reported calcium intake did not further reduce the risk of fractures of any type, or of osteoporosis, but was associated with a higher rate of hip fracture

fig2

Calcium Alone Increases Hip Fractures but Lowers Total Fractures

Abstract

Effect of calcium supplementation on hip fractures.

There have been numerous studies of the effects of calcium supplementation, with or without vitamin D, on fractures. Individually, they have not provided clarity regarding calcium’s anti-fracture efficacy, though they have established that calcium does have beneficial effects on bone density throughout the skeleton in women. Meta-analysis of these data suggests that total fracture numbers are diminished. However, the data from the 5,500 women involved in trials of calcium monotherapy show consistent adverse trends in numbers of hip fractures (relative risk 1.50, 95% CI 1.06-2.12). Observational data from the Study of Osteoporotic Fractures show a similar increase in risk of hip fracture associated with calcium use. We hypothesize that reduced periosteal expansion in women using calcium supplementation might account for the differences in anti-fracture efficacy of calcium at the hip, in comparison with other sites. Until there are further trial results to clarify this area, the present findings suggest that reliance on high calcium intakes to reduce the risk of hip fracture in older women is not appropriate. In addition, those at risk should be looking to other agents with a proven capacity to prevent hip fractures, such as bisphosphonates.

Reid IR, Bolland MJ, Grey A
Osteoporos Int Aug 2008
PMID: 18286218 | Free Full Text

Furthermore, our own recent trial of calcium monotherapy suggested that there might be heterogeneity between the responses of hip and other fractures to calcium supplementation [2], with downward trends in vertebral, forearm, and total osteoporotic fractures, but a significant increase in hip fractures.

[…]

Observational studies have also assessed the relationship between calcium use and fractures. While there is a potential problem of confounding by indication, it is noteworthy that the Study of Osteoporotic Fractures reported an increase in hip fracture risk in postmenopausal women taking calcium supplements of almost identical magnitude to that found in the present meta-analysis (relative risk 1.5; 95%CI, 1.1–2.0) [18]. This consistency across the available intervention studies and a large observational study raises doubts regarding the safety of calcium monotherapy in elderly postmenopausal women, though we cannot completely preclude the possibility that these results are a chance finding arising from the smaller numbers of this particular fracture type.

The adverse effect of calcium monotherapy on hip fractures poses the question of how this could occur when the same intervention has the opposite effect on total fracture numbers.

Resveratrol Stimulates Bone Formation or Mineralization in Obese Men

Abstract

Resveratrol Increases Bone Mineral Density and Bone Alkaline Phosphatase in Obese Men: A Randomized Placebo-Controlled Trial.

Context: Metabolic syndrome (MetS) is associated with low-grade inflammation, which may harmfully affect bone. Resveratrol (RSV) possesses anti-inflammatory properties, and rodent studies suggest bone protective effects. Objective: This study sought to evaluate effects of RSV treatment on bone in men with MetS. Setting and Design: The study was conducted at Aarhus University Hospital as a randomized, double-blinded, placebo-controlled trial assessing changes in bone turnover markers, bone mineral density (BMD), and geometry. Participants: The study population comprised 74 middle-aged obese men with MetS recruited from the general community, of which 66 completed all visits. Mean age of participants was 49.3 ± 6.3 years and mean body mass index was 33.7 ± 3.6 kg/m(2). Intervention: Oral treatment with 1.000 mg RSV (RSVhigh), 150mg RSV (RSVlow), or placebo daily for 16 weeks. Main Outcome Measure: Prespecified primary endpoint was change in bone alkaline phosphatase (BAP). Results: BAP increased dose dependently with RSV (R = 0.471, P < .001), resulting in a significantly greater increase in BAP in the RSVhigh group compared with placebo at all time-points (week 4, 16.4 ± 4.2%, P < .001; week 8, 16.5 ± 4.1%, P < .001; week 16, 15.2 ± 3.7%, P < .001). Lumbar spine trabecular volumetric bone mineral density (LS vBMDtrab) also increased dose dependently with RSV (R = 0.268, P = .036), with a significant increase of 2.6 ± 1.3% in the RSVhigh group compared with placebo (P = .043). In addition, changes in BAP and LS vBMDtrab were positively correlated (R = 0.281, P = .027). No consistent changes were detected in bone density at the hip. Conclusions: Our data suggest that high-dose RSV supplementation positively affects bone, primarily by stimulating formation or mineralization. Future studies of longer duration comprising populations at risk of osteoporosis are needed to confirm these results.

Ornstrup MJ, Harsløf T, Kjær TN, Langdahl BL…
J. Clin. Endocrinol. Metab. Oct 2014
PMID: 25322274

Review: Resveratrol, Inositol, Vitamin D and K for Bone and Cardiovascular Risk

Abstract

Resveratrol, inositol, vitamin D and K in the prevention of cardiovascular and osteoporotic risk: a novel approach in peri- and postmenopause.

The prevention of cardiovascular and osteoporotic risk is a topic of great importance in the peri- and postmenopausal periods. This paper reviews the role of resveratrol, inositol, vitamin D and K in the prevention of cardiovascular and osteoporotic risk in peri- and post-. The phytoestrogen-like activity of resveratrol has potential clinical implications in the gynecological practice. In particular transresveratrol inhibits low-density lipoprotein oxidation, which is a recognized risk factor for cardiovascular diseases. Resveratrol has also a documented antiplatelet effect and may prevent cardiovascular diseases inhibiting the cardiac fibroblasts proliferation. With regard to bone health, in in vitro studies resveratrol has shown activities in osteoblastic MC3T3-E1 cells. Resveratrol also interacts with vitamin D in promoting bone health. Resveratrol is considered a caloric restriction mimetic and potentially effects factors involved in the metabolic syndrome. Myo-inositol has documented in clinical studies its effectiveness in improving the metabolic syndrome in post menopausal women. Thus the supplementation with inositol and resveratrol may be useful in the prevention of insulin resistance and consequently metabolic syndrome and cardiovascular diseases risk. Finally vitamin K2 effects calcium metabolisms and subjects with higher levels of calcium in the bones tend to have a lower frequency of vascular calcifications and a lower cardiovascular risk. Vitamin K2 also has a key role in the bone homeostasis. A supplement including resveratrol, inositol, vitamin K and vitamin D offers a novel opportunity to the woman in peri- and postmenopause.

Parazzini F
Minerva Ginecol Oct 2014
PMID: 25245999