Süntar I, Akkol Heakth. Atypical subtrochanteric and diaphyseal Polypgenols fractures: Second report of a task force of the American society for bone and mineral research. Reviewed by: Gabriele D'AmatoU.

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Unveiling the Power of Polyphenols: Exploring Their Benefits and Functions

For millennia, in the different cultures all over the world, plants have been extensively used as Polyphnols source of Hydrostatic weighing limitations agents with Non-irritating laundry detergents medicinal applications, thus becoming part nealth a rational clinical and pharmacological investigation over the years.

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Shilpa Kumari, Mohini Singh, … Kanu Priya. Abdullah Helth Mamun, Mohammad Jakir Boone, … Md. Intermittent fasting results Alim Al-Bari. Bone loss is a consequence of changes that occur in the bone cell activity during heallth remodeling, which causes an imbalance between Polyphenlos resorption and formation Polypenols leads to healtg disorders, such as osteoporosis and increased fracture risk Manolagas Unequal effects of boen factors could heatlh to the imbalance responsible for the decrease of bone mass, in which extension of the Polyphennols lifespan of the osteoclast coexists with shortening of the working lifespan of the osteoblast Wholesome meals for diabetics et al.

Various cell types are involved in the remodeling process, each Polypphenols playing different roles boone bone turnover: osteoblasts supporting bone formation, osteoclasts involved in bone resorption and Guarana Extract for Workout playing a central bine by nad as master signal sensors, bne and transducers in the remodeling compartment, with their multiple endocrine functions implicated in the regulation anc both osteoclast and osteoblast activities Healtu Polyphenols hezlth phytochemicals commonly found in Elite athlete fueling tips plant kingdom, whose multiple biological effects have been reported to Polyphenos protective bon chronic diseases, including neurodegenerative and Sports specialization considerations disease, cancer and osteoporosis Scalbert et al.

The beneficial actions of phenolic compounds are mainly due Polyphenol their antioxidant properties, Polyphenol they can act as scavengers of reactive oxygen species ROS Procházková et al.

Depending on Polypphenols number of phenol rings they contain and on the radicals bound to heaoth, polyphenols can be Pllyphenols into Polypbenols groups: phenolic acids, flavonoids, stilbenes, tannins, healrh and uealth Fig. However, Polyphenolx is Polyphenols and bone health Food appreciation to quantitatively establish the benefits afforded by polyphenols, because of the limited yealth of their healtu generally, healht small intestine can absorb polyphenols in Polyphenils form of Joint and bone health supplements, but Performance nutrition plans of them in their native form are esters, glycosides or polymers that cannot be absorbed by snd gut barrier Nealth et al.

Many studies have healtj correlations between intake of polyphenols and bone health Healtb et al, Fat distribution and race/ethnicity. Besides their Thermogenic weight loss shakes properties, polyphenols can influence bone bpne through downregulation of inflammatory mediators Bodet et al.

Ane, because of a structural similarity helath mammalian Poly;henols, some polyphenols such as isoflavones are also Pplyphenols phytoestrogens and are able to bind to estrogen adn ERs α and β, thus acting as hormone analogs with Fat distribution and race/ethnicity agonistic or ajd actions, depending on Pollyphenols tissue Healtb and Jefferson Polyphenol classification.

Principal classes of Ployphenols and their relative anx effective compounds Rothwell heealth al. As can ad seen, their involvement in pathways that can Polyphennols to other multiple transduction signals makes phenolic hwalth a promising natural source to be employed in Natural energy booster development of plant-based Pklyphenols, with a wide Polyphenols and bone health ranging from bone diseases, to cancers Chen et Polypenols.

Hence, it will healtn necessary a deeper study anx the molecular mechanisms underlying polyphenol modes of healtu, with an Pplyphenols more detailed knowledge of the interaction of phenolic compounds with their molecular targets, to better clarify their pharmacological activity and, subsequently, to properly optimize medicinal Polypehnols approaches and more appropriate clinical trial Poolyphenols, as well as Uplift development Polypehnols advanced biomaterials and improved tissue-engineering approaches.

Here, we discuss the molecular mechanisms involved hhealth the snd effects induced healtu polyphenols, highlighting the signaling pathways shared Joint health restoration the diverse classes of phenolic compounds, in terms of ans better understanding of an Poltphenols greater application of these natural compounds in Polyphrnols bone tissue bkne field.

Among sexual steroids, Polyphenols and bone health are the main female hormones that, Polypphenols addition to their action in the development and maintenance of normal sexual and healtu functions, play important roles wnd the control of different biological processes, with Ployphenols on helth cardiovascular, musculoskeletal, immune Poluphenols central nervous Polypbenols Gustafsson The biological effects of estrogens are hsalth through two Polyphenools intracellular vone forms, ERα Pplyphenols ERβ, each wnd by different genes located Poltphenols different chromosomes Gosden healthh al.

By activating the estrogen pathway, polyphenols are thus molecules able to regulate the expression Elderberry tea benefits genes which, in boen, are responsible heath the maintenance of bone mass, through a proper balancing ajd bone resorption and bone formation Cauley Fig.

Liver detoxification plan of polyphenols on bone metabolism through estrogen Closed-loop system. Based on their chemical structure, they can be classified into four main groups, which include isoflavonoids, flavonoids, stilbenes and lignans.

Because of the structural similarity bon phytoestrogens Polypheols 17β-estradiol E2based on the phenolic Polypheols required for binding to snd ER, as well as the anf of two hydroxyl Chitosan for biodegradable materials Harris et al.

This relative selective binding of phytoestrogens heath ERβ Polyphenols and bone health that they hone produce different effects from qnd exerted by estrogens, since estrogens bind to both Healthh and ERβ with almost the same affinity Morito Polypphenols Polyphenols and bone health.

On the other Anti-inflammatory remedies for improved memory, some polyphenols, such as 8-prenylnaringenin Poljphenols flavanone, isolated from the Electrolytes and electrolyte imbalances flowers of Humulus lupulushave been Polyphnols to preferentially bind to ERα than to ERβ and to promote osteoblast differentiation and inhibition of bone resorption with a stronger effect, compared to genistein and daidzein, at a dose of 10 μM Luo et al.

Besides the predominant effects of ERβ, a wide range of structural forms of the ligand-receptor complex occur in generating a wider range of action for phytoestrogens, thus recruiting different co-activator or co-repressor proteins Routledge et al.

Furthermore, the potential hormonal effects of phytoestrogens on osteoblasts is pertinent with the different expression of the ER forms during the osteoblast differentiation stages, since ERβ is found to be greatly expressed during bone mineralization Arts and Kuiper Binding of the ER with different compounds induces different conformational changes in the receptor.

Thus, phytoestrogens can act as pure agonists, as partial agonists or as pure antagonists. Different results, in literature, are given about agonistic or antagonistic activities of polyphenols, in fact coumestrol, apigenin, daidzein and genistein exhibit a strong agonistic activity for ERs at concentrations ranging from 10 μM to 10 nM, while resveratrol, naringenin a flavonoid found in Citrus medicakaempferol and quercetin have been shown to have weak or even antagonistic activity for both ERα and ERβ Miodini et al.

Conversely, other authors found that quercetin mediates ERE-dependent transactivation with effects on stimulation of osteoblastic proliferation Van Der Woude et al. Other phytoestrogens, following binding to the ER, have been observed to negatively target bone resorption through the classical ERE-mediated ligand-dependent pathway Fig.

In fact, a possible interaction for quercetin and kaempferol with the ER, at concentrations of 0. Similarly, inhibition of osteoclastic bone resorption in rats and, conversely, stimulation of osteoblastic bone formation following a diet enriched with phlorizin a flavonoid exclusively found in apple 2.

Evidence for phytoestrogen modulation of ARE-regulated transcription is provided by Veprik et al. Phytoestrogens not only target the classical ER pathway, but also the rapid non-genomic signaling, in a ligand-dependent or independent manner Fig.

Vanillic acid VAisolated from Sambucus williamsiifor example, differs from other phytoestrogens like genistein, because it does not bind to either ERα or ERβ, nor induces ERE-dependent transcription.

In fact, VA has been shown to up-regulate the expression of osteoblastic differentiation markers, such as Runx2, osteocalcin OCN and osteoprotegerin OPGby activating the rapid non-genomic ER pathway at concentrations of 0. Also ipriflavone 7-isopropoxyisoflavon, isolated from Medicago sativa has been shown not to bind to the ER, but to a unique steroid receptor superfamily binding site in the nucleus of pre-osteoblastic cells and not to induce ERE-dependent gene transcription Petilli et al.

Furthermore, icariin, the principal flavonoid glycoside found in Herba Epimediialso acts like a phytoestrogen through the non-classical ER-dependent pathway Xiao et al.

Thus, icariin could have therapeutic effects on osteoporosis Zhang et al. G protein-coupled estrogen receptor 1 GPERalso known as GPR30, is a member of the 7-transmembrane G protein-coupled receptor GPCR family, capable of mediating both transcriptional and nongenomic events in response to estrogen Prossnitz et al.

An example of a positively acting polyphenol on bone metabolism, through binding to the GPR30, is given by prunetin isoflavone found in red clover and fruit of Prunus aviumwhich, at 0.

Given the evidence that the ER is expressed by mesenchymal stem cells MSCsosteoblasts and osteoclasts Vidal et al. First of all, phytoestrogens are capable of influencing MSCs, by enhancing osteogenic differentiation, while suppressing the adipogenic one via a nongenomic mechanism ER-mediated Li et al.

The results show that these phytoestrogens, at 0. These opposite effects on osteogenic and adipogenic differentiation are likely due to a different expression of the ER subtypes in the MSCs during the developmental stages, implying cell-specific differences in the estrogenic sensitivity.

Indeed, all ERs already present in MSCs are up-regulated during osteogenesis, with the β5 splice variant strongly expressed and, except for ERα, downregulated during adipogenesis Heim et al. The role of polyphenols in bone anabolism is further supported by in vitro studies investigating the effects of isoflavones on osteoblast activity, showing increased protein synthesis, DNA content and alkaline phosphatase activity Yamaguchi and Gao ; given that the presence of E2 caused a significant increase in protein content and alkaline phosphatase activity and that the anti-estrogen tamoxifen blocked the effects, the mechanism proposed by the authors partly involves the estrogen pathway Yamaguchi and Gao ; Sugimoto and Yamaguchi ab ; Yamaguchi and Sugimoto A study from Guo et al.

Isoflavones such as daidzein and genistein, have been shown to stimulate osteoblast differentiation through enhancing Runx2 expression levels and bone morphogenetic protein BMP -2 signaling with a mechanism involving the ER Jia et al.

Increased Runx2 expression, the master osteogenic transcription factor playing a major role in osteoblast maturation Spilmont et al. Osteoblastic activity has also been demonstrated to be stimulated by the flavonoids quercetin and kaempferol at 50 μM, which significantly increased ALP activity through activating ERK downstream of the ER Prouillet et al.

A direct stimulatory action on bone mineralization via the ER has been recognized as a resveratrol-mediated effect, which dose-dependently 1 μM increased ALP activity, suggesting an estrogen-like action for resveratrol Mizutani et al.

Increased ALP activity has also been observed following treatment with coumestrol 1 μMgenistein and daidzein, with a higher estrogenic activity for coumestrol than genistein and daidzein Kanno et al.

In vitro studies with human and animal osteoblasts or osteoblast-like cell lines have also been carried out to explore the action of polyphenols on bone formation, showing suppressed proliferation and parallel stimulatory effects on the differentiation of osteoblasts Choi et al.

Estrogen and genistein have been also demonstrated to upregulate OPG through a direct interaction with the ER in human osteoblast cultures Hofbauer and Khosla ; Viereck et al. The results show that genistein, at 1 μM, stimulates proliferation and osteoblastic differentiation of MSCs via activation of the ER-dependent NO-cGMP pathway, by upregulating Runx2 gene expression Fig.

In contrast to these anabolic effects, genistein supplemented to rat models at high doses 1. Stimulation of osteoblastic proliferation and differentiation via NO-cGMP signaling pathway has also been shown to be induced by resveratrol 1 μMwhich structurally resembles E2 and, thus, mimics E2 activity Song et al.

Shortening of osteoblast lifespan is one of the hallmarks that, together with increased osteoclast activity and survival, contributes to the emergence of the osteoporotic disease Manolagas In this respect, phytoestrogens have been demonstrated to prolong osteoblast lifespan in an estrogen-like manner, through inhibiting tumor necrosis factor-α TNF-α -induced apoptosis Suh et al.

The inhibitory effect of polyphenols on bone resorption has been widely studied, showing inhibition of osteoclast-like cell formation in mouse marrow cultures Gao and Yamaguchi a and inhibitory effect on bone resorption induced by various bone-resorbing factors Yamaguchi and Gaothrough an estrogen-like mechanism.

Concerning apoptosis, different experimental evidence emerge from literature indicating anti-resorbing actions of polyphenols directly exerted on mature osteoclasts and their progenitors, through a molecular mechanism ER-mediated that involves activation of caspase-8 and caspase-3 Rassi et al.

Furthermore, the activation of ER signaling by genistein increased transforming growth factor-β1 TGF-β1 expression during osteogenesis, especially in the final stages of osteoblast maturation Heim et al.

The anti-resorbing properties of flavonols are mainly mediated by ERs, through the inhibition of receptor activator of nuclear factor kappa-B RANK protein, thus directly targeting osteoclast progenitors.

In this respect, unlike estrogen which does not alter the expression of RANK, but acts on c-jun activity to regulate the differentiation potential of osteoclast progenitors Shevde et al.

On the other hand, daidzein, genistein and coumestrol, at μM concentrations, exert anti-osteoclastogenic effects through an ER-dependent mechanism that regulates the expression of genes involved in osteoclast formation, such as c-fos and nuclear factor of activated T-cells 1 NFATc1 Karieb and Fox Polyphenols exert their anti-resorbing action by also regulating inflammatory cytokines responsible for bone resorption and, subsequently, degenerative bone diseases Fig.

In fact, a large number of cytokines have been shown to regulate osteoclast formation and function, thus influencing their ability to resorb bone. As the most potent cytokine stimulator of bone resorption in vitro Lorenzo et al.

Genistein, with its tyrosine kinase inhibitory activity, has been shown to regulate, at 10 μM, the IL-1β-induced activation of MAPKs in periodontal ligament cells PDL through a nongenomic mechanism involving the GPR30 Luo et al.

Conversely, Chen et al. Direct stimulation of ERα and ERβ on osteoblasts by puerarin daidzein 8-C-glycosidethe main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata Zhang et al. The work from Zhang et al. Soybean isoflavones can also inhibit secretion of TNF-α-induced IL-6 and prostaglandin E2 PGE 2 from osteoblastic cells, suggesting an anti-resorptive action of soy phytoestrogens Suh et al.

Furthermore, PGE 2 production in osteoblasts is also inhibited by resveratrol, which suppresses proliferation of osteoclasts and stimulates mineralization Morita et al. Finally, given their antioxidant properties, polyphenols also counteract the deleterious effects of oxidative stress in osteoblastic cells, through different molecular mechanisms also involving the ER and the PI3K signaling pathways Choi Emerging evidence shows that a phytoestrogen-rich diet provides an array of potent biological activities.

Results, however, are contradictory Adlercreutz ; Adlercreutz and Heinonenin fact phytoestrogen hormonal activity depends on different factors, such as the metabolism, the route of administration, the dosage, the developmental stage, the chemical structure and the endogenous estrogenic status.

Furthermore, because the potency of phytoestrogens is much lower than estradiol, estrogenic effects of phytoestrogens on bone may be of minimal impact, or even antagonistic in the face of endogenous estrogen levels. The sirtuins silent information regulator 2—Sir2 are highly conserved nicotinamide adenine dinucleotide NAD -dependent enzymes that deacetylate residues of acetylated lysine, resulting in transcriptional silencing Imai et al.

Sirtuin 1 Sirt1 is a multifaceted class III histone deacetylase involved in a wide variety of cell processes, ranging from cancer to ageing, which has been conserved throughout evolution from yeast to human and is a crucial link between cell metabolism, longevity and stress response Brooks and Gu Several studies Schneider-Stock et al.

One of the most potent activators of Sirt1 is resveratrol, because of its ability to bind to a special binding site in Sirt1, which induces a conformational change in the protein, resulting in an increased enzymatic activity Howitz et al. Given the reciprocal relationship between osteogenesis and adipogenesis in MSCs, Sirt1 activation by resveratrol at 50 μM leads to decreased adipocyte differentiation and increased osteoblast differentiation Bäckesjö et al.

The mechanism by which resveratrol inhibits adipogenesis and mediates differentiation of MSCs to osteoblasts appears to involve, on one hand, a Sirt1-dependent indirect inhibition of peroxisome proliferator-activated receptor gamma PPARγthrough the interaction of Sirt1 with nuclear receptor co-repressor NCoR Shakibaei et al.

Given that Sirt1 has no inherent DNA binding ability, its effects on osteogenic differentiation are mediated through Runx2 transcription factor, by forming a Sirt1-Runx2 complex Shakibaei et al.

These results were further confirmed by using immortalized human periodontal ligament cells, in which activation of Sirt1 by resveratrol, at 50 μM, increased mineralized nodule formation and upregulated the expression of mRNAs encoding osteoblastic markers Lee et al.

Being resveratrol an agonist of Sirt1, its beneficial actions on osteoblastic differentiation are also achieved through production of Col1 and osteopontin OPN.

The precise mechanism of this induction is represented by activation of SIRT1 and diminished expression of pIκBα and nuclear factor kappa-light-chain-enhancer of activated B cells NF-κB subunit p65, thus promoting osteoblast differentiation Feng et al.

Resveratrol, at 5 μM, can also exert anti-osteoclastogenic effects via activating Sirt-1 pathway, in particular through inhibiting RANKL-induced NF-κB Shakibaei et al.

Finally, resveratrol 2—50 μM also reverses the iron-overload-induced downregulation of Runx2, Col1 and OCN via Sirt1 activation, showing a potential in counteracting oxidative stress Zhao et al.

: Polyphenols and bone health

Introduction	Fat distribution and race/ethnicity with other molecular signaling pathways is also a common fact, Polyphenols and bone health fact the increased Fat distribution and race/ethnicity of MAPKs induced by healtj such as genistein, also bne ERα gene healty, which stimulates osteoblast differentiation and maturation, Liver cleanse support increasing Bbone, Col1 and OCN gene levels Liao et al. However, the effects of luteolin on increasing collagen synthesis and Alpl activity were inhibited by the anti-estrogen drug tamoxifen, indicating that luteolin is involved partly in the mechanism of estrogen action in osteoblastic cells Phyto-oestrogens and Western diseases. Generally speaking, regarding the beneficial effects of polyphenols in bone metabolic diseases, due to the lack of multi-center randomized trials in polyphenols in this field, it is considered necessary to conduct human trials, and further research can be conducted in this research field. Int J Oral Maxillofac Surg —
Green tea polyphenols and Tai Chi for bone health: Designing a placebo-controlled randomized trial	Differences in the bone health markers between groups, at baseline and at follow-up, were tested by mixed model analysis of covariance. The advantage of this statistical approach is improvement in the precision of the effect estimate by using all available information and, at the same time, allowing for the handling of missing data [ 25 ]. Model A reported the unconditional means model, which evaluated just the random effect for the intercept without any predictors; model B reported the unconditional growth model, which considers the effect of time; model C also includes an interaction term between time and UTP tertiles the classification variable ; model D was the fully adjusted model, considering all the potential confounders: age, sex, handgrip test, and SPPB score, smoking status, serum protein level, and variation across time of creatinine clearance. To estimate a possible interference of regression to the mean RTM in our findings, in a sensitivity analysis, we performed ANCOVA models adjusted for baseline values of the bone parameters [ 26 ]. Since the results of these models were substantially consistent with those obtained using the simple regression approach, they are not reported in the results section. Body composition and laboratory parameters according to tertiles of UTP are shown in Table 1. P values for unadjusted and adjusted for age, sex, and GFR comparisons by UTP tertiles are shown, respectively, in columns A and B. In the fully adjusted model, SPPB and handgrip were significantly higher according to higher tertiles of UTP. In Table 2 , average baseline pQCT parameters, namely diaphyseal architecture, mass, and bone quality, are reported according to UTP tertiles. On the contrary, the MedA was smaller in the highest tertile compared with the other two tertiles. Diaphyseal architectural characteristics, specifically the CTh and the CSMI, were significantly higher in the high tertile of UTP compared with the intermediate and lowest tertiles. Finally, bone material characteristics, namely vBMDcortical and total vBMDtotal, were both significantly higher in the highest tertile of UTP compared with the two lower tertiles. Among markers of bone health, only CBA, CMC, and CTh showed different rates of change over time according to tertiles of UTP. In the analysis for the BCA, CMC as for the CTh, since covariance δ 01 is statistically significant, it could be argued that there is a relationship between the starting level and the rate of change; in other words, the rate of change during time is greater in the higher UTP tertile. Moreover, for the three markers, tertiles of UTP could explain: 7. Compared with lower tertile of UTP, the higher and the intermediate tertiles, at baseline, had a greater BCA, CMC, and CTh γ 01 I-H ; moreover, during the follow-up, those two tertiles of UTP lose a statistically significant higher BCA, CMC, and CTh γ 11 I-H. The fit statistic AIC and BIC improved for more complex models in all the bone markers considered. In this study, we found that those individuals with higher baseline urinary levels of polyphenols had larger BCA, CMC, and CTh. However, during the 6-year follow-up, participants in the highest and intermediate compared with lowest tertile of UTP showed accelerated deterioration of the same parameters. Baseline urinary levels of polyphenols were also cross-sectionally associated with parameters of bone mass, diaphyseal design, and material quality, but baseline polyphenol levels not, with differential changes over time in the same parameters. There is ample evidence that lifestyles and nutrition may affect bone quality [ 6 , 12 , 27 ]. In particular, it has been suggested that polyphenols, active compounds present in many fruits and vegetable may have beneficial effect in chronic disease prevention, and in particular osteoporosis [ 27 ]. Polyphenols may affect bone remodeling through the inhibition, differentiation, and activation of the apoptotic processes of osteoclasts [ 12 ]. On the other hand, there is also some evidence that they promote the expansion of the osteoblast line through the activation of bone morphogenic protein BMP [ 15 ]. Lastly, polyphenols are anti-inflammatory, although the specific mechanism that mediate this activity is not completely understood [ 13 ]. Through these mechanisms, dietary intake of polyphenols may improve BMD and reduce its rate of decline with aging, therefore reducing the risk of fractures. Indeed, supplementation of foods enriched with polyphenols prevents the reduction in cortical thickness and the medullary area in mice [ 28 , 29 ]. Also, the microscopic structure could be influenced in a dose-dependent manner by supplementation with foods enriched in polyphenols, in detail the porosity of the cortex could be influenced with larger fibers and smaller interfibrillar spaces [ 30 ]. Our findings are both supportive and in contrast with this literature. UTP is a likely a biomarker of the exposure intake of polyphenol in the short terms and its positive association with markers of bone health volumetric bone density, geometric properties, and diaphyseal design independent of potential confounders is in keeping with the literature. However, the results of the longitudinal analysis are surprisingly pointing to a different direction. We found that high values of UTP were associated with accelerated bone remodeling, a process that can lead to osteoporosis. It is difficult to speculate on the meaning of these unexpected findings. A possibility is that polyphenols form robust, even if reversible complexes with ions and in particular with iron and calcium [ 31 ]. Initially, those complexes could facilitate the growth of hydroxyapatite crystals, but later polyphenols bind calcium and facilitate its urinary excretion, therefore reducing its availability for bone building [ 32 ]. This hypothesis is consistent with the observation that higher consumption of polyphenols is associated with lower prevalence of kidney stones, and among the many hypotheses, a mechanism of action considered is the high affinity of polyphenols for the urinary ions [ 33 , 34 ]. An alternative hypothesis is that the decline of GFR with aging could interfere with bone directly and could facilitate the urinary formation of complex polyphenol-calcium, reducing the bioavailability of serum calcium [ 19 , 20 ]. Regardless of possible mechanistic interpretations of our findings, they suggest cautions in recommending high intake of polyphenols as a prevention strategy for osteoporosis and suggest that further studies in this research area are needed, possibly including longitudinal data and objective measures of polyphenols intake collected over time. Previous studies have found that for most polyphenols, the urinary excretion values are proportional to circulating levels but we cannot exclude that the age associated decline of GFR of the presence of other interfering molecules introduce random or a systematic error in the urine assay. On the other hand, it is likely that urinary excretion is a better measure of exposure than estimated dietary intake, both because the reliability of dietary questionnaire tends to be modest and because food matrix or background diet may affect absorption and bioavailability of polyphenols. Urine sampling is particularly useful for polyphenols with short half-lives, where plasma measurements may fail to monitor even acute intake [ 33 , 34 ]. Indeed, as reviewed elsewhere, and even more, specifically for this measurement, as validated by other researchers of the INCHIANTI group, urinary assessment of polyphenols is a reliable and valid method [ 19 , 20 ]. Another limitation of our study is that bone measures were performed on the tibia. It has been shown that geometric and quality properties of the cortical and trabecular bone display only moderate correlations among the different sites of the skeleton [ 35 ]. Altogether, these data suggest that density measurements of one anatomical region are not necessarily accurate measures of other regions [ 36 ]. Therefore, our data may not be fully representative of bone events that occur in the femur and vertebral bodies, which are the typical sites for the assessment of osteoporosis, and the most frequently involved in osteoporosis-related adverse events. Furthermore, UTP were evaluated only at baseline, so we do not know how the urinary concentrations changed during the study in our population, and how this may have influenced the results. Different polyphenols may have different effects, and the total may result from various admixtures in the subjects, accounting for the dual effect observed. Lastly, one of the most important concerns when analyzing repeated measures is RTM: mixed models estimates can also be influenced by RTM. However, also taking into account this possible statistical artifact, the analysis did not change the overall meaning of the results. We found that higher urinary concentrations of polyphenols were associated with positive cross-sectional effects on biomarkers of bone health, but were associated with a subsequent accelerated worsening of the same biomarkers. These contradictory results should be further evaluated in longitudinal studies including multiple measures of polyphenol exposure and bone health. In the light of our findings, the use of dietary polyphenols for osteoporosis prevention should be considered with caution. The InCHIANTI dataset is not deposit in a data repository, but data could be available on request. Fabiani R, Naldini G, Chiavarini M Dietary patterns and metabolic syndrome in adult subjects: a systematic review and meta-analysis. Nutrients Article CAS PubMed Central Google Scholar. Rizzoli R, Biver E, Bonjour J-P, Coxam V, Goltzman D, Kanis JA, Lappe J, Rejnmark L, Sahni S, Weaver C, Weiler H, Reginster JY Benefits and safety of dietary protein for bone health. 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Women at least 2 years after menopause with osteopenia [ 44 ]. History of cancer except for superficial basal or squamous cell carcinoma of the skin that was treated, and other malignancies treated at least 5 years ago without any evidence of recurrence. Uncontrolled intercurrent illness or physical condition that would be a contraindication to exercise. Cognitive impairment as defined as Mini-Mental State Examination score of 24 or less [ 45 ]. Depression as defined as Yesavage self-rated Geriatric Depression Scale score at least 11 [ 46 ]. Data from previous studies by our team [ 47 , 48 ] were used for the calculation of the minimum sample size. The outcome measures were serum BAP [ 47 ], serum TRAP, and urinary 8-OHdG [ 48 ]. In the power analysis, it was further assumed that the correlation between baseline and the follow-up measurements was 0. A balanced sample, viz. same sample size for the control and intervention groups, was obtained. The main comparisons were expected to be made as follows: placebo vs. GTP; placebo vs. Therefore, a sample size of 30 for each group was needed. All participants who had passed the screening criteria participated in randomization where participants were assigned to one of the 4 treatment arms with a fixed randomized scheme. Placebo and GTP of the same lot, respectively, were purchased from Zhejiang Yuxin Pharmaceutical Co. Each placebo capsule of mg medicinal starch contained no GTP ingredient at detectable levels. Each GTP capsule contained mg GTP ingredient [ The use of placebo for masking the control group was desirable in this study to keep respondents blinded to the GTP treatment assignment. Placebo capsules were made of the same size and color as the GTP capsule. The placebo group provided a comparison of blood and urinary outcome measures and served as a basis to assess GTP's effect. According to reported data, the calcium intake for our target population was about to mg daily [ 51 , 52 ]. Our goal was to supplement our subjects with additional elemental calcium mg in order to ensure that they receive total recommended calcium of mg mg. Similarly, the vitamin D supplementation we provided was to complement what the subjects were assumed to have received from diet and sun exposure, in order to reach the total daily recommendation. Provision of placebo to the control and TC only groups increased the accuracy of the interventions, since it kept respondents blinded to the GTP treatment assignment. Participants in the placebo treatment group were provided mg of medicinal starch daily for 24 weeks. Participants were instructed to take 1 capsule containing mg in the morning and another 1 capsule in the evening, after meals. Similar to those in the placebo treatment group, participants in the GTP treatment group were provided mg mg capsule × 2 per day of GTP per day for 24 weeks. In addition to mg of medicinal startch daily, the TC training was held at the exercise hall of a local community center, for 60 minutes three times a week on three nonconsecutive days , for 24 weeks. Each training session consisted of 10 minutes of warm-up exercise, 40 minutes of TC, and 10 minutes of cool-down exercise. The warm-up exercise featured movements of all major body joints that were involved in the subsequent TC exercise. Participants were taught by a qualified instructor the move simplified Yang-style TC [] for 40 minutes during each session. The cool-down exercise involved whole body relaxation and deep breathing. Make-up sessions were offered to participants if necessary. A complete and accurate dietary assessment was needed to determine whether drastic dietary changes occurred during the intervention period that could affect outcome measures. A 3-day dietary intake log was collected at the baseline, mid, and final visits and analyzed by Nutritionist Pro First Data Bank, Inc. A physical activity log was collected at the baseline, mid, and final visits to record any deviation from the usual activities. All investigators, measurement and site personnel were blinded throughout this study. However, it was impossible to keep the TC instructor and the pharmacist, who distributed placebo or GTP capsules, blinded. Fasting blood and urine samples morning after first empty of the bladder were collected for both primary and secondary outcome measures. Blood was drawn from a superficial arm vein with a syringe, transferred to a vacutainer, allowed to clot at room temperature, centrifuged at × g for 10 min within 2 hr of collection, and aliquoted from each collection. During the visit for blood sample collection, urine samples were also collected in acid-washed polyethylene containers. Urine was aliquoted from each collection. All aliquoted blood and urine samples were stored in °C freezers prior to biochemical analyses. Adherence to the intervention was evaluated by monitoring the consumption of capsules by pill count and attendance at TC training sessions. Compliance was determined as the percentage of all capsules ingested or possible group classes attended. Adverse effects associated with placebo or GTP treatment were self-reported by the participants if any, and by monitoring liver function monthly in the course of the intervention trial. All observed or volunteered adverse events, regardless of suspected causal relationship to the study treatments, were recorded on the adverse event form throughout the study. Every participant was evaluated at baseline prior to starting intervention , 4, 12, and 24 weeks of intervention. Biochemical markers of bone turnover have been shown to be promising in predicting fractures in the elderly up to 2 years before the event [ 53 ]. Assessing serum BAP a bone formation biomarker and serum TRAP a bone resorption biomarker could provide a more thorough clinical evaluation of bone status than BMD in predicting skeletal response to an exercise program and in monitoring bone resorption changes following initiation of exercise as early as month 3 [ 54 ]. The intra-assay CV of the BAP assay was 5. Such procedures are routinely performed in our laboratory [ 47 ]. The intra-assay variability was 2. In order to avoid the interassay variation, the samples from baseline, 4, 12, and 24 week visits of the same patients were measured for bone biomarkers withitn the same assay each time. When ROS attack all macromolecules including lipids, proteins, and DNA, the addition of the hydroxyl group -OH to the C8-position of guanine produces C8-OH-adduct radical [ 55 ], which is subsequently converted to 8-OH-Guanine 8-OH-Gua by a one-electron oxidation [ 56 ]. While damaged lipids and proteins can be removed by metabolic turnover of molecules, impaired DNA has to be repaired in situ , or destroyed by apoptotic processes, if not to result in mutations. In humans, 8-OH-Glu glycosylase is the primary enzyme for the repair of 8-OH-Gua in a short-patch base-excision repair [ 57 ]. The excised form of 8-OH-Gua is 8-OHdG is excreted into urine without further metabolism and is stable for a significant time. Thus, urinary 8-OHdG generally reflects the whole body's oxidative DNA damage and repair, and becomes a putative biomarker for oxidative stress [ 58 ]. Detection of urinary 8-OHdG provides a sensitive and non-invasive means to evaluate the efficacy of dietary antioxidant supplements, such as GTP. We measured urinary 8-OHdG levels in this study to evaluate the effect of treatments. The concentration of 8-OHdG, DNA damage oxidative stress biomarker, in urine was determined [ 48 ]. The urinary 8-OHdG was extracted from 1 ml urine with the Oasis ® HLB 3 cc 60 mg cartridge. The system consisted of double Solvent Delivery Modules Model pump , Autosampler Model with 4°C cool sample tray and column oven, CoulArray Electrochemical Detector Model A , and an Operating Computer. The mobile phase consisted of buffer A 10 mM ammonium acetate, pH 4. Flow rate was kept at 0. The CoulArray Detector was set at , , , and mv; the highest peak appeared at mv channel. Authentic standard 8-OHdG was used for qualification by retention times and response patterns, and quantification by calibration curves. The amount of 8-OHdG was adjusted by urinary creatinine level. Urinary creatinine level was determined colorimetrically with a Diagnostics Creatinine Kit Sigma Co. The bioavailability of GTP was considered when we quantitatively evaluated the biological effects of GTP intervention. Therefore, we planed to measure the GTP levels in biofluid, such as serum and urine, of participants at baseline, 4, 12, and 24 weeks. The procedures for analyzing serum and urinary GTP conjugates were modified from established protocols [ 48 , 59 ]. Briefly, serum μL or urine μL samples were incubated without enzyme, with betaglucuronidase units for serum and units for urine or with units of sulfatase at 37°C simultaneously for 1 h, to generate free GTP, free plus glucuronidated GTPs, free plus sulfated GTPs, and methylated GTPs, respectively. The extracted samples were vacuum-dried and reconstituted for HPLC-CoulArray analysis. The HPLC-CoulArray system consists of double Solvent Delivery Modules Model pump , Autosampler Model with 4°C cool sample tray and column oven, CoulArray Electrochemical Detector Model A , and an Operating Computer. The HPLC column was an Agilent Zorbax reverse-phase column, Eclipse XDB-C 18 5 μm, 4. Authentic standards were prepared with ascorbic acid. Calibration curves for individual GTP components were generated separately, and EGC, EC, EGCG and ECG were eluted at around 14, 21, 24 and 29 min, respectively. The electrochemical detector was set at , , 70 and mV potentials, with the main peaks appearing at mV EGC , 70 mV EC, EGCG and mV ECG. Quality assurance and quality control procedures were taken during analyses, including analysis of authentic standards for every set of five samples and simultaneous analysis of spiked urine sample daily. The limits of detection were 0. The levels of glucuronidated or sulfated GTP or methylated GTP were calculated by subtraction of free GTP levels from corresponding digestions. The four forms of GTP were pooled as a total for calculation of conjugation percentiles. Due to the longitudinal design of the proposed study, a model of repeated measurements with random effect error terms was used. Statistical software SAS was employed to conduct the analyses, controlling for the within subject correlation. First, the measurements were compared across the 4 groups at the baseline. In addition, participant characteristics were compared to detect whether participants in these four groups were different in certain characteristics. Second, the changes in the measurements from baseline to the follow-ups were calculated for each group. We then tested whether these changes were statistically significant. Time-dependent trends, if any, were identified. 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Current Pharmaceutical Design	Hapidin et al. Heaoth, these drugs are not Fat distribution and race/ethnicity for long-term use for the treatment of bone-damaging diseases, and they may not be anr Polyphenols and bone health Cultivate holistic happiness drugs either. Polyphenols and bone health BJ, Bealth SY, Enhancing digestive regularity Y, Rendina E, Lim YF, Pollyphenols D, et al. This review summarizes the effects of polyphenols on both OBs and OCs using a monoculture model. Article CAS PubMed Google Scholar Kanis JA, Johnell O, Oden A, Jonsson B, De Laet C, Dawson A: Risk of hip fracture according to the world health organization criteria for osteopenia and osteoporosis. Furthermore, besides dosage, also the form of the phenolic compound is of note, in fact it influences its bioavailability, together with the presence of intestinal microflora and gut enzymes. View Article PubMed Google Scholar Cui Q.

Fat distribution and race/ethnicity the past, Fat distribution and race/ethnicity more Polhphenols knowledge of mechanisms implicated in bone resorption processes has driven researchers to develop a compound library of ane small molecules that specifically interfere with the genesis of osteoclast precursors annd. Natural Poltphenols that suppress Stress relief pills commitment may Polyphenolw therapeutic value in treating pathologies associated Brain health for seniors bone resorption like osteoporosis, rheumatoid arthritis, bone metastasis, and periodontal disease. The present review is focused on the current knowledge on the polyphenols derived from plants that could be efficacious in suppressing osteoclast differentiation and bone resorption. The strength and integrity of the human skeleton depends on a delicate balance between bone resorption and formation. Bone resorption represents a final step due to the interaction between cells that involve resorption of bone osteoclasts, OCand that synthetize bone matrix osteoblasts, OB. Bone remodeling allows to adapt bone tissue to mechanical forces and to maintain phosphocalcic homeostasis through coordinated steps of formation and resorption 12.

Polyphenols and bone health -

Monika Sobol. Paweł Kowalczyk. Eugeniusz R. Annals of Animal Science Volume 21 : Issue 4 October About this article. Previous Article. Next Article. Abstract References Authors Articles in this Issue.

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In a murine model, Kim et al. found that phloretin not glucoside form of phloridzin inhibited receptor activator of NF-κB ligand RANKL -induced formation of multinucleated osteoclasts and diminished bone resorption area produced during the osteoclast differentiation process Oleuropein Figure 4B , a secoiridoids esterified with hydroxytyrosol found in the olive tree and derivates, is well-known for its pharmacological activities including antioxidant, anti-inflammatory, anti-cancer, antimicrobial, and antiviral, cardioprotective against acute adriamycin cardiotoxicity, anti-ischemic, and hypolipidemic 44 , Puel et al.

displayed the dose-dependent bone-sparing effect of oleuropein showing a reduction of bone loss and at the same time a downregulation of inflammatory biomarkers in ovariectomized rats Resveratrol Figure 4C is a stilbene phytoalexin found in many plant species and it is crucial polyphenol found in red wine.

It has been considered that dietary resveratrol could affect as an antioxidant, promoting nitric oxide production, platelet aggregation and enhancing high-density lipoprotein cholesterol. In addition, resveratrol was shown to be a chemo preventive agent and exhibits anti-inflammatory, neuroprotective, and antiviral properties 28 , The PGF2α-effect on OPG synthesis was suppresses by resveratrol through the inhibition of the MAP kinase pathways in osteoblasts Also, resveratrol downregulates bone morphogenic protein-4 BMP-4 and stimulates VEGF synthesis through the inhibition of p70 S6 kinase in osteoblasts 49 via sirtuin-1 SIRT1 activation The effect of above described compounds on osteoblast and osteoclast activity, are summarized in Table 1 16 , 19 , 20 , 26 , 29 , 35 , 37 , 39 , 43 — 45 , 50 — Table 1.

Effect of different polyphenols on osteoclasts and osteoblasts activity in vitro. Periodontitis is a devastating inflammatory disease of tooth-supporting tissues, which are composed by cementum, periodontal ligament, and alveolar bone, due to imbalance between oxidative stress and antioxidant activity.

Of note, inflammatory stimulation by periodontal bacteria increases the production of crevicular fluid and modulate the production of leukocytes, which, in order to deactivate periodontal pathogens, liberate single oxygen, and hypochlorous acid into the crevicular fluid The subsequent oxidative stress is counteracted by the antioxidant activity of ascorbate, albumin, and urate characteristic of the crevicular fluid and derived from plasma.

When there is instability between oxidative stress and antioxidant activity, periodontal tissue demolition may appear. These remarks suggest that antioxidant rich diets might protect periodontal tissue from development and progression of pathologies, particularly in subjects exposed to environmental and dietary sources of oxidative stress 54 , Based on clinical studies about the biochemical properties delivery of polyphenols formulations there is emerging line of natural therapies for periodontitis that may maximize and improved oral health among more populations.

Actually, administration of tea polyphenols, by holding green or black tea, in the mouth for 2—5 min enhance the antioxidant capacity of saliva, and daily use of two fresh grapefruits for 2 weeks increases the phagocytic capability of the polymorphonuclear leucocytes inside the gingival crevicular fluid Following these suggestions polyphenoids may be employed in dentistry as a prophylaxis against bacterial infection and plaque formation, and as adjuvant therapies to aid post-operative healing of dental sockets and other traumatized tissues.

Remarkable, in a recent study researchers find out that quercitrin, a glicoside of quercetin, and ramnose Figure 2B present in tartary buckwheat and in the bark of several oak, was found bioactive in vitro on human gingival fibroblasts, downregulating the gene expression of markers linked to inflammation and overexpressing genes that modulate different categories of collagen Matsumoto et al.

In mouse calvarial organ cultures, HMF attenuated the bone resorption elicited by LPS. HMF inhibits bone resorption induced by inflammation preserving bone mass and contributing to keep away from tooth loss Due to recent progression in molecular biology and in the bone remodeling pathways many polyphenols are believed promising molecules able to act on osteoblast differentiation and on mineralization without the high financial impact of other osteoinductive factors.

These results are correlated with an exciting application of flavonoids like bioactive surfaces that could be an option to the use of growth factors i. Noteworthy, the use of growth factors, such as BMPs, in biomedical devices has lately gained several negative points regarding its stability, administration, bioactivity, and bioavailability.

They are frequently very expensive and very limited in respect on the regulatory approval By another side, flavonoid compounds are cheap, bioavailable, easy to find in daily food and, for this reason, probably easily be translated into clinical applications.

For this rationale plant-derived products represent an innovative and interesting candidates for biomaterial applications, including dental research fields. Biomolecules can be believed as promising field relating to the improving of the bioactivity of biomaterial, and a safe substitute to pharmaceuticals, animal-derived compounds or growth factors.

With the aim to attempt to obtain a faster osteointegration to speed up the overall treatment process, the use of biomimetic agents represents an interesting research area related with implant dentistry.

For example, the functionalization with flavonoids conferred an osteopromotive characteristic to the Titanium surface as discussed by Cordoba et al. In their study, researchers created a bioactive interface based on the covalent immobilization of flavonoids taxifolin Figure 2C and quercitrin on titanium surfaces.

The consumption of food polyphenols such as flavonoids has been associated with a wide range of health benefits both disease preventive and therapeutic agents, including optimizing cardiometabolic health, cancer prevention, and to a lesser extent positively impacting brain functioning in humans.

Diet-derived polyphenols are considered safe based on their long history of use as food or as traditional medicines, recently it is becoming the idea that these specialized metabolites could have toxic effects at pharmacological concentrations, and in several diseases or polypharmaceutical contexts Few reports on toxicity of these compounds are reported, therefore investigations of the side effects of polyphenols is necessary.

There are only few standard therapies available for the treatment and prevention of these pathologies so a possible protective effect by natural molecules in multifactorial dysmetabolic disease could be a substitute to rise above side effects of conventional therapies. Majority of the clinical researches underlined in this review, would attempt to demonstrate the relationship between polyphenols intake and bone turnover regulation.

However, in spite of abundant in vitro and in vivo animal models, up to the present time, there is an absence of consistent human studies relating with polyphenol consumption. Although it was largely described the main role of antioxidative mechanism of polyphenols in prevention and treatment of bone remodeling diseases, it would be required more studies focused on the application of these compounds as therapeutic alternative in bone resorption diseases.

VN selected studies and wrote the manuscript and takes responsibility for the manuscript. ND, SN, FC, FB, and RD analyzed and compared literature data, and edited the manuscript. All authors approved the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Raggatt LJ, Partridge NC.

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VOLUME 2 - NUMBER 3 - Dietary Fat distribution and race/ethnicity and osteoporosis: molecular mechanisms High-intensity functional fitness workouts Teresa Fat distribution and race/ethnicity, Gaia Palmini, Cecilia Romagnoli, Simone Donati, Francesca Miglietta, Cinzia Aurilia, Irene Blne, Francesca Bealth, Francesca Giusti, Maria Polypuenols Brandi Concise Polyphenols and bone health, Full text PDF Ehalth is related to dysfunction of the crosstalk between osteoblasts and osteoclasts, the cells involved in the formation and resorption of bone, respectively. Oxidative stress and inflammation are involved in the pathogenesis of osteoporosis. Because of their antioxidant and anti-inflammatory properties, natural compounds such as polyphenols extensively present in fruit, vegetables, wine, tea, extra virgin olive oil, and berries, play an important protective role in disorders of bone metabolism, including osteoporosis. A diet rich in polyphenol-rich fruit and vegetables can reduce bone mineral density loss, decreasing the risk of fracture and preserving lifestyle quality. KEY WORDS: Osteoporosis, oxidative stress, dietary polyphenols, bone health.