Possible alternative explanations for the absence of an MDA increase in our osteoporotic subjects compared with controls are 1 the decrease in antioxidants in osteoporotic women reflects an increased production of reactive oxygen intermediates ROI , i. free radicals, to such an extent that they are unable to generate high levels of MDA; 2 the decrease in antioxidants in osteoporotic women reflects an increased production of ROI, leading to the formation of oxidized biological molecules different from MDA e.

Although the first mechanism is purely speculative and is not substantiated by any evidence, the second one is at least in part supported by the results of a recent study that found a negative relationship between urinary levels of 8 iso-prostaglandin 2α and BMD MDA measurement, although performed by means of a reliable HPLC method, suffers from a number of limitations that might prevent its use as a marker of oxidative damage in osteoporotic subjects The third mechanism, i.

low dietary intake of antioxidants and metals, such as selenium, zinc, and copper, necessary for the activity of antioxidant enzymes, might also be supported by our data, because controls had higher BMI than osteoporotic subjects.

Although all subjects were receiving a free diet, it is possible that the diet of osteoporotic women included a lower number of fruit and vegetable servings than that of controls and hence did not provide an adequate amount of antioxidants.

Whatever the cause of the low antioxidant levels, the results of this and previous studies suggest that antioxidant deficiency has a negative impact on bone mass. Several potential mechanisms might underlie this relationship. For instance, nuclear factor-κB, which is known to mediate some of the important actions of TNFα, a cytokine synthesized in the bone microenvironment, on osteoclastogenesis, is activated in osteoblast-like cells by mitogens and cytokines through the generation of ROI 37 — In other words, intracellular free radical production might represent the final common mechanism of nuclear factor-κB activation by a variety of factors If this mechanism of action of osteoclastogenic cytokines satisfactorily fits most models of bone loss, it is conceivable that low intracellular and probably interstitial levels of antioxidants are a signal, i.

a consequence, of increased osteoclastogenic activity and bone turnover. Alternatively, it is also tenable that low levels of intracellular antioxidants may amplify osteoclastogenesis through uncontrolled availability of excess ROI.

Not only might osteoclastic differentiation of bone precursors be modulated by ROI, but osteoblastic differentiation as well. Mody et al. Quite recently, other evidence linking osteoporosis to increased oxidative stress has been produced, particularly for a severe osteoporotic syndrome in relatively young males A small 3.

Some important limitations of our study should be acknowledged. First, we did not measure dietary calcium. Different intakes in the two groups could have at least in part influenced BMD results, even because some of the positive effects of vitamin C on bone might not be realized in the absence of adequate calcium intake.

Secondly, we did not directly measure dietary whole caloric or single antioxidant intake. Although this potential bias was mitigated by the fact that all subjects were well nourished, there is a possibility that minor or selective nutritional deficits might be more represented in the osteoporotic group.

Thirdly, the results of our study may not apply to the general elderly population, because the frailest and oldest elders were not included. Finally, our study is limited by the fact that we did not verify any of the relationships between low levels of antioxidants and reduced BMD.

We conclude by suggesting that elderly osteoporotic women have lower antioxidant defenses compared with a normal age-matched reference population. is European Union Marie-Curie Fellow for the program Quality of Life and Management of Living Resources, project entitled Nutritional Health-Sustaining Factors and Determinants of Healthy Aging: Oxidative Stress-Related Biomarkers of Successful Aging and Age-Related Diseases.

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Download references. This work was supported by the Elderly Health Research Project of Jiangsu Commission of Health LKZ , the Natural Science Foundation of Nanjing University Of Chinese Medicine XZR , and the Foundation of The Second Affiliated Hospital of Nanjing University of Chinese Medicine SEZ Department of Orthopedics, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, No.

Department of Gynecology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China. You can also search for this author in PubMed Google Scholar. SC and JJ collected data. XW and XL organized the study and performed the statistical analysis.

HH and ZL drafted the manuscript, to which all authors contributed, and approved the final version for publication. Correspondence to Xianghui Li or Zhiwei Li.

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 analyses were based on data of the National Health and Nutrition Examination Survey NHANES.

The study was approved by the ethics review board of the National Center for Health Statistics. The detailed information is located on the NHANES website. Written informed consent was obtained from each participant before their inclusion in the NHANES database.

Detailed information on the ethics application and written informed consent are provided on the NHANES website. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Han, H. et al. Association of the composite dietary antioxidant index with bone mineral density in the United States general population: data from NHANES — J Bone Miner Metab 41 , — Download citation.

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Lycopene consumption decreases oxidative stress and bone resorption markers in postmenopausal women. Osteoporos Int. Mackinnon ES, Rao AV, Josse RG, Rao LG. Supplementation with the antioxidant lycopene significantly decreases oxidative stress parameters and the bone resorption marker N-telop eptide of type I collagen in postmenopausal women.

Mackinnon ES, Rao AV, Rao LG. Dietary restriction of lycopene for a period of one month resulted in significantly increased biomarkers of oxidative stress and bone resorption in postmenopausal women.

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At present, there are many clinical studies using melatonin as an auxiliary drug for the treatment of osteoporosis. Ferritin is closely related to the development of postmenopausal osteoporosis.

A serum test of 4, women found that serum ferritin is more closely related to bone density than iron intake and serum iron, which indicates that ferritin is a more reliable variable linking iron and osteoporosis Lu et al.

Spanner demonstrated that ferritin was widely expressed in osteoblastic lineage cells to maintain the intracellular metal balance through the uptake and storage of iron Spanner et al. The positive effect of ferritin on osteoporosis is mainly to inhibit iron ions.

Iron and iron-induced ROS accumulation was indicated to mediate osteoblast apoptosis and osteoclast differentiation via the NF-κB signaling pathway Wang et al.

Increasing the combination of ferritin and iron ions is an effective means to relieve iron damage and ferritin to treat osteoporosis. Ceruloplasmin CER , also called copper oxidase, is an important antioxidant in the body. CER can reduce free radicals produced in xanthine metabolism by inhibiting xanthine oxidase Krsek-Staples and Webster, Similar to ferritin, the effect of inducing lipid peroxidation by copper ions has also been weakened when combined with CER Burkitt, Current research indicates that CER relieves osteoporosis by inhibiting iron overload Zarjou et al.

However, the direct effect of CER on osteoporosis is unclear. A previous study indicated that the total SOD level decreased in menopausal mice, as measured by ELISA Cao et al.

Hidetoshi Nojiri found that bone mass decreased significantly in SOD-deficient mice Nojiri et al. Increasing mitochondrial SOD activity prevented osteoblast apoptosis induced by ROS Yang et al.

Moreover, SOD has a significant regulatory effect on the differentiation trend of bone marrow mesenchymal stem cells BM-MSCs. Catalase CAT is the marker enzyme of peroxisomes and is widely present in various tissues of the body Shin et al.

As the second defense system of antioxidant enzymes, the antioxidant mechanism of CAT mainly acts on the dismutation reaction on H 2 O 2 produced in SOD-mediated processes Ray and Husain, A large number of studies have reported that H 2 O 2 increased lipid peroxidation following the decrease of CAT in a postmenopausal osteoporosis model Ozgocmen et al.

In addition, CAT can have a positive effect on bone mass by inhibiting H 2 O 2 -induced osteoclastic resorption Fraser et al. However, the physiological role of CAT is mainly dependent on the regulation of forkhead box O1 FOXO1 Venkatesan et al.

FOXO1 increased the expression of SIRT1 participating in the mitochondrial biosynthesis to maintain the level of CAT Alcendor et al. Estrogen deficiency decreases the expression of FOXO1 protein, leading to the inhibition of BM-MSCs into osteoblasts Liao et al. Glutathione peroxidase GSH-Px is an important peroxidase enzyme characterized by each subunit containing a selenium Se atom in the form of selenocysteine Liu et al.

The antioxidant effect of GSH-Px is determined by the Se cysteine in its active center Zachara, The Se of the GSH-Px enzyme system catalyzes GSH to GSSG and reduces toxic peroxides to non-toxic hydroxyl compounds.

GSH-Px can intervene in the development of osteoporosis through the abovementioned GSH-dependent pathways and endoplasmic reticulum-mediated osteogenic differentiation of BM-MSCs via the mTOR pathway Wiswedel et al. Additionally, GSH-Px can relieve inflammation-induced osteolytic bone destruction by breaking down LPS Islam et al.

Upregulating GSH-PX activity can inhibit pro-inflammatory factors associated with osteoclast maturation genes, such as iNOS, IL-1β, and tumor necrosis factor-alpha TNF-α Kruger et al.

GSH-Px may be the key link in the oxidative stress-inflammation reaction in postmenopausal osteoporosis with great potential research value. However, the content of peroxidase in the fracture site was increased to compensate for fracture-induced stress damage when fractures occurred in patients with osteoporosis Föger-Samwald et al.

The metabolism of free purine bases after DNA damage aggravates oxidative stress damage. In contrast, a growing number of studies have shown that high uric acid levels can lead to decreased bone density and osteoporosis Sharaf El Din et al.

The ROS produced by the oxidation of purine inhibits osteoblast differentiation from BM-MSCs and bone mineralization through the ERK and NF-KB pathways Chang et al. ROS can stimulate the proliferation and differentiation of osteoclast progenitor cells through the RANKL pathway Garrett et al.

In addition to direct effects, purine metabolism also regulates bone homeostasis through the indirect activation of inflammatory cytokines Martinon, At high uric acid levels, mononuclear cell-derived inflammasomes phagocytose monosodium urate MSU and release IL-1, TNF-α, IL-6, and IL-8 Chhana et al.

They further activate RANK and macrophage colony-stimulating factor M-CSF , resulting in a large number of osteoclasts Ritchlin et al. Therefore, the damaged DNA must be repaired to ensure genomic integrity Radak and Boldogh, DNA repair enzymes reduce the production of purine bases to prevent further damage to the skeletal system, as well as the occurrence of osteoporosis Yao et al.

Lipid peroxide, a peroxidation product of unsaturated fatty acids with ROS, is the core of lipofuscin Adibhatla and Hatcher, ; Zadlo et al. Previous studies indicated that a large amount of lipid peroxide is deposited in the bone tissue of ovariectomized mice Al et al. It triggers oxidative damage and inflammation in the bone microenvironment, destroying bone homeostasis Wu et al.

Oxidized lipids cannot be repaired and need to be broken down into non-toxic products by specific enzymes. Phospholipase A2 PLA2 and acyltransferase AT are the important metabolic enzymes of lipid peroxide.

AT directly participates in lipid mobilization and β-oxidation Wang et al. PLA2 catalyzes the hydrolysis of the ester bond formed by the C2 hydroxyl group on the glycerol backbone in the phospholipid Prunonosa Cervera et al.

Compared with AT, the effect of PLA2 on the skeletal system is not limited to accelerate the metabolism of lipid peroxide. PLA2 can increase the expression of PGE2 to promote osteogenesis through the cyclooxygenase 2 COX2 pathway Yoshida et al.

At present, osteoporosis affects approximately one-third of postmenopausal women worldwide Gosset et al. In the past, scientific researchers and clinicians focused on the skeletal system, especially the inhibition of osteoclasts, to treat postmenopausal osteoporosis Ukon et al.

Although the deterioration has been improved to a certain extent, the pathogenesis of the disease has not been clarified, and effective control has not been achieved.

Oxidative stress damage, as a mediator linking estrogen, aging, and bone, is regarded as a breakthrough in exploring the development of postmenopausal osteoporosis.

Overloaded ROS break the balance between osteogenesis and osteoclastogenesis, leading to bone mass loss and bone quality decline Lee et al. The ROS accumulation is due to excessive production and inefficient removal.

The DNA damage caused by ROS and the metabolism of DNA purine bases form a closed loop, which continuously increases the production of free radicals Calkins et al. DNA repair enzymes are essential to break this vicious cycle Figure 4. The endogenous hormone melatonin maintains these antioxidant processes by protecting mitochondrial function Yang et al.

The ROS activation of the NF-κB pathway involved in osteoclast maturation is also inhibited by antioxidant systems. Inflammation is also an important connection between oxidative stress and postmenopausal osteoporosis.

Oxidative stress causes biomolecular damage and releases cytokines and chemokines to recruit and activate inflammatory cells, resulting in chronic inflammation in the body Sindhu et al.

ROS can induce the hyperactivation of NF-κB by modulating the activity of AP-1 Arcambal et al. Activated NF-κB also induces the expression of inflammatory factors, such as IL-1β, IL-6, and TNF-α to exacerbate inflammation Ma et al.

These inflammatory factors also stimulate ROS production to exacerbate oxidative damage Zhu et al. A vicious cycle exists between oxidative stress and inflammation. Osteoporosis is also regarded as a chronic inflammatory disease Montalcini et al. Estrogen deficiency could induce an inflammatory storm and decrease antioxidant capacity Mohamad et al.

The secretion of inflammatory factors activates osteoclasts to worsen osteoporosis Wu et al. Therefore, anti-inflammatory drugs have been applied to treat osteoporosis and have the ability to improve bone mass Tao et al.

Due to the unclear pathogenesis of postmenopausal osteoporosis, past studies have obvious limitations. Our review clarified the nature of postmenopausal osteoporosis from the perspective of oxidative stress damage induced by aging and described the potential ability of antioxidants to treat it in detail.

Antioxidants not only systematically improve the oxidation state of the body, but also locally regulate the imbalance of the skeletal system. At present, antioxidant substances have been verified to improve bone mass in animal models, such as vitamin C, vitamin E, and GSH Deng et al.

However, there is no special drug designed based on the antioxidant ability that is being applied for osteoporosis treatment. Three classes of antioxidant systems are very important for the prevention and treatment of postmenopausal osteoporosis. Our review contributes to antioxidant drug designs for postmenopausal osteoporosis.

KY contributed to data curation, formal analysis, data curation, methodology, and writing — original draft. FC contributed to investigation, methodology, software, and writing — original draft. YX contributed to software and validation. LT contributed to conceptualization, software, validation, writing, review, and editing.

YZ contributed to funding acquisition, project administration, resources, writing, reviewing, and editing. All authors read and approved the manuscript. This study was supported by the Shenyang Young and Middle-aged Innovative Talent Project RC 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.

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