The search strategy included a combination of MeSH terms and free words, and the strategy was adjusted based on the characteristics of each database. Two researchers independently conducted literature screening and data extraction and cross-checked the results.

Disagreements were resolved by discussion or by consulting a third researcher. The following data were extracted: 1 basic information of the included study: author, title, year of publication, animal species, weight, age, and sample size, 2 specific details of intervention measures, including medication dosage and duration, 3 the various information elements of bias risk assessment, and 4 outcome indicators and outcome measurement data.

We used the risk of bias tool for animal studies provided by the Systematic Review Center for Laboratory Animal Experience SYRCLE to conduct a literature quality evaluation of the included studies 19 , This evaluation tool has a total of 9 items, including random group allocation, groups similar at baseline, blinded group allocation, random housing, blinded interventions, random outcome assessment, blinded outcome assessment, reporting of drop-outs, and other biases.

Each item can be judged as having low bias risk, high bias risk, and unclear bias risk 19 , This meta-analysis used the random-effects model for pooled data analysis. In each included study, if there were 2 or more sets of satisfactory measurement data within the same dose range the same study , the group with the lowest dose was selected for meta-analysis.

Considering that differences in race and age of rats may affect the reliability of the conclusion, we conducted subgroup analyses based on those two factors. In particular, the resveratrol group used in the subgroup analysis was the lowest-dose group in each included study. We also constructed funnel plots for each outcome indicator to evaluate potential publication bias.

After removing duplicate literature, we initially obtained articles. In the initial screening, we excluded literature that clearly did not meet the inclusion criteria based on the information provided by the title and abstract.

After applying the inclusion and exclusion criteria and screening full texts, a total of 15 studies on the treatment of OP animal models with resveratrol that met the requirements of this meta-analysis were ultimately included 21 — The search process and details are shown in Figure 1.

This meta-analysis included 15 experimental studies on the treatment of OP rats with resveratrol. A total of rats were included in this study, including in the resveratrol group and in the control group. There are three types of rat strains, namely, Albino rats, SD rats, and Wistar rats.

The modelling method for OP is OVX. The specific details and characteristics of each included study are shown in Table 1.

Most of the 15 studies included in this meta-analysis were evaluated for unclear risk bias. Only 2 studies used the random number table method 30 , 33 ; 2 studies did not use random assignment 21 , 27 ; and the remaining studies did not provide sufficient information to determine whether the experimental animals were randomly assigned.

One study used a blinding method for the evaluators of results One study did not provide a detailed explanation of missing data 29 , which may lead to potential data reporting bias. The quality evaluation results of the literature included in the study are shown in Figure 2. A total of 5 studies 22 , 25 , 27 , 30 , 33 reported total-body BMD Figure 3.

A total of 5 studies 26 — 29 , 35 reported FBMD Figure 4. Three studies 27 , 29 , 35 reported LBMD Figure 5. This meta-analysis analysed three parameters related to micro-CT, namely, Tb.

Th Supplementary material 1 , Tb. N Figure 6 , and Tb. Sp Supplementary material 2. Four studies 24 , 26 , 29 , 31 reported changes in serum calcium concentration Figure 7. Similarly, four studies 24 , 26 , 29 , 31 reported changes in serum phosphorus concentration Supplementary material 3.

A total of 6 studies 21 , 22 , 24 , 26 , 29 , 31 reported serum ALP levels Figure 8. A total of 4 studies 22 , 24 , 30 , 33 reported changes in serum osteocalcin levels Supplementary material 4.

A total of 3 studies were included in the subgroup analysis 22 , 25 , A total of 2 studies were included in the subgroup analysis 22 , We plotted corresponding funnel plots for all outcome indicators to evaluate publication bias.

The funnel plot results show that the funnel plots of BMD of the total body, Tb. Th, serum phosphorus, and serum osteocalcin are asymmetric, indicating that there may be publication bias in these outcome indicators.

The funnel plot of all outcome indicators is shown in Supplementary material 5. OP is known as the silent killer, and osteoporotic fractures are a serious complication of OP, which means that the prevention and treatment of OP are important aspects to which public health needs to pay attention.

Ethnic medicine or botanical medicine has always been the focus of drug conversion. In recent years, the therapeutic effect of resveratrol on OP has received considerable attention, but research on its anti-OP efficacy or mechanism is mostly limited to animal or cell experiments, which seriously limits the progress of resveratrol in clinical application.

To further clarify the anti-OP efficacy of resveratrol, this study summarizes preclinical evidence to provide support to proceed with clinical trials. In terms of improving the parameters related to micro-CT, resveratrol can increase Tb. Th and Tb. N and reduce Tb. In addition, resveratrol can reduce the concentration of calcium and phosphorus in serum but has no significant effect on serum ALP and osteocalcin, which was also verified in this meta-analysis.

Based on preclinical animal research data, we found that resveratrol may have enormous clinical application potential in the treatment of OP, which means that resveratrol may become a candidate drug for OP treatment, but this still needs to be verified through large-scale clinical studies in the future.

Resveratrol has the characteristics of multiple targets, low cost, and low toxicity 36 , and its therapeutic effect in OP is receiving increasing attention. The dynamic balance between osteoblasts and osteoclasts has always been considered the core content of OP research.

An experimental study found that resveratrol can activate the osteogenic transcription factor CBFA-1 37 and enhance the transcription of bone-specific type I collagen in a CBFAdependent manner, stimulate the proliferation and differentiation of osteoblasts, and activate Sirt-1 to transform osteoblasts into osteoblasts.

Research shows that resveratrol can upregulate the expression level of Sirt-1 and then upregulate the expression of FoxO1 protein to inhibit the differentiation of osteoclasts The occurrence of oxidative stress can cause damage to bone cells and osteoblasts 39 , 40 and lead to bone resorption activity exceeding bone formation.

Resveratrol is a natural antioxidant and can effectively prevent bone loss caused by oxidative stress in the body 15 , which may be the potential mechanism of its anti-OP effect.

In addition, resveratrol can bind to oestrogen receptors and exert oestrogenic effects 32 , thus compensating for bone loss caused by oestrogen deficiency. In addition, this meta-analysis showed that resveratrol achieved better efficacy in improving biochemical markers.

Serum biochemical indicators reflect the essence of bone metabolism and the direct reflection of bone formation and bone resorption.

This meta-analysis found that resveratrol has a better effect than the control treatment in reducing serum calcium concentration, which may be because resveratrol inhibits oxidative stress and reduces bone loss, thereby reducing the content of calcium entering the serum.

Oxidative stress may lead to oxidative damage to bone cells and osteoblasts in the bone microenvironment, leading to imbalanced bone remodelling.

The antioxidant effect of resveratrol can maintain bone homeostasis, thus stabilizing bone microstructure. Based on the undeniable regulatory role of resveratrol in bone metabolism, its clinical application in OP deserves in-depth attention.

This study has limitations that should be considered when interpreting the results. First, the animal models included in the study may exhibit significant differences in factors such as species of rats, drug dosage, and sample size, which may lead to heterogeneity in the experiment and compromise the reliability of the conclusions of this study.

Second, the included animal experiment reports focus on the construction of animal models and outcome evaluation, but the report on experimental design, implementation, and measurement methods is relatively brief, which may lead to poor methodological quality in literature reports, difficulty in estimating potential bias risks, and reduced data credibility.

Third, there may be differences in the BMD measurement tools and serum markers used in all 15 included studies, which may lead to measurement errors between studies. Given the limitations of animal experimental design, future clinical studies targeting the treatment of OP with resveratrol should avoid these situations, which would be beneficial for improving the reliability of evidence-based data on this research topic.

This study found that resveratrol can increase BMD in OP rat models, and its mechanism of action may be closely related to improving bone microstructure and regulating calcium and phosphorus metabolism. Given that this study focuses on an OP rat model, the efficacy of resveratrol in treating OP still needs to be further validated through clinical studies in the future.

JZ: conceptualization, validation, data curation, writing — original draft, writing — review and editing, visualization, supervision, and project administration. GZ and JY: writing — original draft, and writing — review and editing.

JP: investigation, data curation, and formal analysis. BS and ML: investigation and data curation. WY: conceptualization, methodology, software, validation, formal analysis, and data curation.

JL: conceptualization, supervision, validation, and funding acquisition. LZ: conceptualization, methodology, software, validation, formal analysis, data curation, writing — original draft, writing — review and editing, visualization, supervision, and funding acquisition. JZ and GZ: contributed equally to this work.

All authors contributed to the article and approved the submitted version. This work was supported by the National Natural Science Foundation of China No. BJKY01 , Project of Philosophy and Social Science Planning of Guangzhou No. 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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

OP, osteoporosis; CNKI, China National Knowledge Infrastructure; MD, mean difference; CI, confidence interval; BMD, bone mineral density; PMOP, postmenopausal osteoporosis; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta analyses; NR, not reported; Tb.

Th, trabecular thickness; Tb. N, trabecular number; Tb. SP, trabecular spacing; ALP, alkaline phosphatase; SYRCLE, Systematic Review Center for Laboratory Animal Experience; OVX, ovariectomy; SD, Sprague—Dawley.

Sabri, SA, Chavarria, JC, Ackert-Bicknell, C, Swanson, C, and Burger, E. Osteoporosis: an update on screening, diagnosis, evaluation, and treatment. doi: PubMed Abstract CrossRef Full Text Google Scholar. Li, N, Cornelissen, D, Silverman, S, Pinto, D, Si, L, Kremer, I, et al.

An updated systematic review of cost-effectiveness analyses of drugs for osteoporosis. According to these results, FoxO1 transcriptional activity was suppressed by H 2 O 2. In brief, our results revealed that RES upregulated FoxO1 transcriptional activity to achieve attenuation of oxidative stress damage and inhibition of osteoclastogenesis.

Forkhead box O1 FoxO1 protein level is elevated by resveratrol RES. A The protein levels of p-AKT, AKT, p-FoxO1 and FoxO1 were determined by western blot analysis. After this treatment, apoptosis was determined. Treatment of RAW At the end of the incubation period, the cells were harvested, and apoptosis analysis was performed.

Cell apoptosis A—C was statistically analyzed D. RES, a natural polyphenolic component, is known to exert numerous beneficial pharmacological effects including antitumor, scavenging free radical and anti-inflammatory activities 22 — Clinical and experimental investigations suggest that RES prevents bone loss by attenuating the damage of oxidative stress 25 , Furthermore, a previous study of our group demonstrated that OPG production was boosted, whereas RANKL synthesis was decreased in RES-treated OVX rats, and hence consequently osteoclast formation and differentiation were prevented However, the underlying molecular mechanisms of how RES, a natural antioxidant, plays a major role in preventing bone loss, has not yet been fully elucidated.

In the present study, we explored the potential molecular mechanisms of RES against osteoporosis. RANKL decrease , suppressed osteoclastogenesis, and thus eventually attenuated bone resorption and prevented bone loss in vivo. Apart from the above findings, RES was able to induce apoptosis of RAW Oxygen-derived free radicals are produced as by-products of aerobic metabolism.

This process occurs primarily in mitochondria due to electron escape passing through the electron transport chain 35 , 36 , and generates highly reactive and short-lived superoxide that is rapidly converted to the more stable and less reactive H 2 O 2 37 — H 2 O 2 , as the most abundant form of ROS, diffuses freely through the mitochondrial membranes into the cytosol 37 — Oxidative stress is the result of elevated ROS, which damages protein, lipids, and DNA and eventually triggers cell death.

H 2 O 2 additionally serves usually as both an extracellular and intercellular signal molecule RANKL and its receptor, pivotal factors required for osteoclast differentiation, are fundamental and necessary to promote osteoclastogenesis RANKL plays a dominant role in activation of the osteoclast differentiation program, including the necessary genes required for bone resorption and for fusion of monocyte progenitor cells When it binds to RANK, it triggers several intracellular signaling pathways in osteoclast precursor cells, ultimately inducing the expression of osteoclast-specific genes.

OPG, as an inhibitor of RANKL, also binds to RANK to antagonize the effect of RANKL and thereby regulates osteoclast activity and function in the bone. We here employed the mouse macrophage cell line, namely, RAW There have been several previous studies providing key evidence that ROS take part in bone regulation.

ROS, especially H 2 O 2 , may be involved in the regulation of osteoclast formation 43 , and has been observed both in vitro and in vivo to be produced by osteoclasts 44 — On the other hand, H 2 O 2 production in differentiated osteoclasts can also be stimulated by RANKL Bartell et al found that RANKL promotes the accumulation of H 2 O 2 in osteoclasts and in their progenitors.

In turn, H 2 O 2 improves osteoclast progenitor proliferation Furthermore, Kim et al provided evidence that ROS play an important role in osteoclast differentiation through NF-κB regulation, while the antioxidant α-lipoic acid inhibits osteoclast differentiation by reducing NF-κB DNA binding and has a potential therapeutic effect against bone erosive diseases Additionally, ROS enhanced the expression of RANKL in mouse and human MG63 cells 9.

Our findings showed that OVX induced oxidative stress ROS and MDA increased, yet SOD and GSH-PX decreased in the OVX group, compared with the Sham group , and simultaneously promoted a decrease in the OPG level, an increase in the RANKL level, increased production of TRAP-5b and damaged bone microstructure.

TRAP-5b in the serum, as a bone resorption marker enzyme, released by osteoclasts, well reflects the osteoclast activity directly along with bone resorption status in vivo.

In contrast, the treatment of the OVX rats with RES significantly reversed these changes in vivo. RES, conferring antioxidant power, effectively decreased RANKL together with the TRAP-5b level, but elevated the OPG level and attenuated bone microarchitecture damage.

Notably, the results demonstrated that RES, due to its antioxidant effect, suppressed the RANKL production in the OVX rats. In other words, the increased ROS level promoted the production of RANKL and then stimulated osteoclast differentiation and bone resorption.

This conclusion is consistent with previous studies 9 , 11 , 47 , These data indicate that RES has a significant bone protective effect via antagonizing oxidative stress to suppress osteoclast formation together with bone resorption activity both in vitro and in vivo.

Therefore, the reduction of ROS production may be a rational approach for the treatment of diseases associated with high bone resorption, including, for example, osteoporosis and arthritis.

FoxO1 activation in osteoclasts could be one valid approach to achieve this goal. Notably, an important finding of this study is that the redox regulator FoxO1 is a target of RES resisting oxidative stress and inhibiting osteoclastogenesis.

As important protein resistance to oxidative stress, FoxOs regulate the expression of antioxidant enzymes, where FoxO1 is a major member of the FoxO family.

Through cell-specific deletion and molecular analyses, among the 4 FoxO proteins, FoxO1 is the only factor required for proliferation and redox balance in osteoblasts, and as a result FoxO1 controls bone formation AKT has been shown to directly phosphorylate and inactivate FoxO1, which results in cytoplasmic retention, inactivation and inhibition of the expression levels of FoxO1-regulated genes that control various processes such as metabolism, cell cycle, cell death and oxidative stress In hematopoietic stem cells, FoxO1 has been demonstrated to reduce ROS by upregulating the expression of antioxidant enzymes including peroxiredoxins, GSH-PX and catalase 19 , After the deletion of FoxO1 in cells of the hematopoietic lineage, the number of osteoclast progenitors is increased in the bone marrow Particularly, Bartell et al showed that RANKL promotes the accumulation of H 2 O 2 in osteoclasts and their progenitors via an AKT-mediated repression of FoxO1 transcription that lowers catalase protein level.

They also demonstrated that as a consequence of the loss of FoxO1 function, the osteoclast number and bone resorption are prevented by the systemic administration of catalase This chain of events identify that FoxO1 is a major control node of osteoclastogenesis and bone resorption, both in physiologic or pathologic conditions.

Furthermore, other studies elucidated that FoxO1 also plays a crucial role in bone metabolism by influencing osteoblast physiology and function, due to its ability to maintain redox balance via ROS-dependent or -independent mechanisms 12 , 51 , This enhancement was confirmed by the higher mRNA levels of osteoclast-specific enzymes.

Taken together based on the findings in vivo , oxidative stress provokes RANKL production and RANKL promotes the accumulation of H 2 O 2 in osteoclasts via AKT-mediated repression of FoxO1 transcription that lowers catalase protein level Thus, we concluded that an antioxidant can upregulate the FoxO1 transcriptional activity by lowering the RANKL level.

In addition, FoxO1 transcription activation can elevate the antioxidant enzyme levels, then lower H 2 O 2 in osteoclasts, finally restraining osteoclastogenesis.

This notion is consistent with previously studies showing that FoxO1 reduces ROS by boosting the antioxidant enzyme expression 19 , N -acetylcysteine, a radical scavenger, induces FoxO1 nuclear translocation and replenishes the FoxO1 level in homocysteine-treated osteoblasts In contrast, in the presence of RES, the antioxidant power of cells was enhanced, and RAW It was confirmed that RES enhanced the FoxO1 protein level and transcriptional activity to prevent oxidative damage, induction of apoptosis and inhibition of osteoclastogenesis.

Accordingly, FoxO1 may be a novel and effective target of RES to play the role of resistance to osteoporosis.

RANKL binding to RANK on osteoclast precursors causes the recruitment of TNF receptor associated factor 6 TRAF6. As mentioned above, RANKL-induced AKT activation downregulates FoxO1 transcription Moreover, our in vivo results demonstrated that RES inhibited RANKL production in OVX rats.

This study was supported by the National Natural Science Foundation of China under grant no. Ozgocmen S, Kaya H, Fadillioglu E and Yilmaz Z: Effects of calcitonin, risedronate, and raloxifene on erythrocyte antioxidant enzyme activity, lipid peroxidation, and nitric oxide in postmenopausal osteoporosis.

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Am J Physiol Heart Circ Physiol. Since that time, interest in resveratrol has continued to expand due to human research demonstrating its effectiveness for joint health, immune health, prevention, muscle health, cognitive health, weight loss, and more.

Now, research suggests that resveratrol may also be beneficial for bone health. Preclinical research on resveratrol for bone health. Animal studies have shown that resveratrol prevents bone loss, reduces mineral density due to immobilization, older age, and ovariectomy, and causes bone healing and repair after surgical procedures or trauma.

A human clinical trial on resveratrol for bone health. Given these positive preclinical results, a double-blind randomized placebo-controlled trial was conducted to investigate the effects of resveratrol on bone mineral density BMD and on calcium metabolism biomarkers in type 2 diabetic T2D patients.

BMD, bone mineral content BMC , and other markers of bone health including serum levels of vitamin D were measured at baseline and after 6 months. The results were that, at follow-up, calcium concentrations increased in all patients, while other markers of bone health, including vitamin D, were higher in both resveratrol arms, and hydroxy vitamin D increased in the Resv arm only, without between-group differences.

Whole-body BMD significantly decreased in the placebo group, while whole-body BMC decreased in both the placebo and Resv40 arms. No significant changes in BMD and BMC values occurred in the Resv arm.

The differences of change from baseline were significantly different in the Resv arm vs placebo for whole-body BMD 0. In subgroup analyses, in Resv treated-patients BMD values increased to higher levels in those with lower calcium and hydroxy vitamin D values, and in alcohol drinkers.

Vascular dysfunction in aging: potential.