Omega-3 polyunsaturated fatty acids (
Hence, it has been suggested that
To date few studies have examined the role of these essential fatty acids, particularly
Bone remodeling is regulated by controlling osteoblast (bone-forming cells) and osteoclast (bone-resorption cells) cell number and activity. Osteoclastogenesis is in large part regulated by a triad of proteins consisting of a ligand, receptor-activated nuclear kappa-
Bone remodeling occurs within the skeleton and is activated in response to mechanical strain. Osteocytes are “mechanosensing” specialized cells that reside in bone matrix. They detect mechanical strain and initiate signaling pathways, promoting both osteoclastogenesis and osteoblastogenesis [
Although the importance of AA and PGE2 in regulating bone remodeling is well established, the involvement of LCPUFA in the control of bone metabolism may be much more extensive than being currently known.
Reactive oxygen species (ROS) are oxygen-containing molecules, which are produced during normal metabolism. Overproduction of ROS induces an imbalance between antioxidants and prooxidants in cells and tissues causing oxidative stress, which has been related to ageing, tissue inflammation, and degeneration [
According to evidence, there is a link between bone metabolism and redox balance regulation, indicating that ROS may play a major role in osteoporosis in part by inhibiting osteoblast generation. ROS are also involved in cartilage homeostasis and degradation, in particular with respect to the development of osteoarthritis (OA). Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation which causes joint destruction. Although, RA is not generally recognized as a disease of oxidative stress, it has been suggested that the level of ROS in patients with RA is higher than in healthy subjects. Researches have also reported that ROS could be a key modulator of bone cell function and play a role mediating intracellular signaling [
Physical activity plays role in bone health; in this way, it is recommended as a treatment for the prevention of bone loss. Exercise influences the cellular homeostasis, and some
During normal physiological conditions ROS are produced at low levels and removed by endogenous antioxidant systems. Their “steady-state” concentrations are determined by the balance between their rates of production and removal by various antioxidants [
Enzymatic antioxidant defenses include superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). These can be modified by exercise, nutrition, and aging. Nonenzymatic antioxidants include a variety of quenchers such as ascorbic acid,
At the molecular level, cellular stress response pathways are controlled by four categories of molecules and transcriptional regulators: insulin/IGF-1 signalling, sirtuins, target of rapamycin, and AMP-activated protein kinase-dependent pathways. All these pathways have one molecular target in common, named forkhead box O (FoxO) transcription factors, a family of transcription factors that comprises four members: FoxO1/FKHR, FoxO3/FKHRL1, FoxO4/AFX, and FoxO6. FoxOs play an important role in bone biology by enabling the maintenance of a physiologically appropriate lifespan of mature osteoblasts through their defense activities or via modulating the activity of other transcription factors such as
Bone remodeling is performed by osteoblasts and osteoclasts. Tipping this balance in favour of the osteoclasts leads to pathological bone resorption, as seen in bone diseases. ROS are involved in apoptosis of osteoblasts and osteocytes and osteoclastogenesis and in this way in bone resorption [
ROS-activated signalling pathways affecting the genesis of osteoblasts and osteoclasts. In osteoclast precursors, RANKL-induced activation of RANK stimulates ROS production, which is important for osteoclastogenesis. ROS-induced bone resorption occurs through the modulation of kinases and transcription factor activities in both osteoclasts and osteoblasts.
Mitochondria and ROS, particularly H2O2, play a crucial role in osteoclast function and differentiation. ROS increases osteoclast number and resorption by stimulating RANKL and TNF-
RANKL activates mature osteoclasts and mediates osteoclastogenesis. It binds to its receptor, RANK, promoting their differentiation into mature osteoclasts. OPG acts as a decoy receptor for RANKL, avoiding it from binding to and activating RANK. Abnormalities of the RANK-RANKL-OPG system with an unbalanced increase in RANKL activity have been implicated in the pathogenesis of various skeletal diseases, including osteoporosis and bone disease secondary inflammation. The increased osteoclastic activity may increase the superoxide anion (
Osteoblasts can produce antioxidants to protect against ROS, such as GPx, as well as transforming growth factor-
In response to stress, DNA-damage repair genes that counteract the adverse effects of ROS and FoxOs upregulate enzymatic scavengers, therefore representing an indispensable homeostatic mechanism for skeletal health. This response involves upregulation of the expression of the mitochondrial enzyme SOD2, that converts hydroxyl radicals into H2O2, the peroxidase catalase, which converts H2O2 into water, and the growth arrest and DNA-damage-inducible GADD45 [
Human studies have reported wide evidence to implicate the crucial role of osteoclasts in the pathogenesis of bone erosions in patients with rheumatoid arthritis (RA). The role of osteoclasts in bone resorption has been found to be also crucial in other inflammatory arthritis.
Ritchlin et al. (2003) [
RANKL plays a role in controlling osteoclastogenesis. Inflamed synovial tissue produces a variety of other cytokines and hormones that can also influence osteoclastogenic activity. These factors include interleukin-1
The role of these cytokines in bone erosions and in inflammation reports further evidence to a link between immune system activation and bone resorption. When the function of OPG/RANK/RANKL in bone remodeling was perceived, it was hypothesized that RANKL may be of major pathophysiological importance in the bone and joint destruction observed in inflammatory RA [
According to some studies, activated T cells from the RA synovium and synovial fibroblasts produce RANKL [
The OPG/RANK/RANKL system and osteoclastogenesis.
In bone destruction associated with RA, IL-17-producing helper T cells (TH17) play a major role by inducing receptor activator of nuclear factor-
The relationship between obesity and bone is complex and continues being an active research area. Current data from epidemiological and animal studies have shown that fat accumulation may interfere with bone mass. Obesity possibly affects bone metabolism through several mechanisms. Both adipocytes and osteoblasts are derived from a common multipotential mesenchymal stem cell, thereby obesity may increase adipocyte differentiation and fat accumulation while decreasing osteoblast differentiation and bone formation. Obesity is also in relation to chronic inflammation. The increased circulating and tissue proinflammatory cytokines in obesity may stimulate osteoclast activity and bone resorption through modifying the receptor activator of NF-
A growing evidence supports that obesity and bone metabolism are linked. Firstly, both osteoblasts (bone forming cells) and adipocytes (energy storage cells) are derived from a common mesenchymal stem cell and agents inhibiting adipogenesis stimulated osteoblast differentiation [
Obesity is traditionally thought to be beneficial to bone and, hence protecting against osteoporosis. Mechanical loading stimulates bone formation by decreasing apoptosis and increasing proliferation and differentiation of osteoblasts and osteocytes through the Wnt/
According to available literature to date, obesity seems to affect bone metabolism through several mechanisms. Obesity may decrease bone formation (osteoblastogenesis) while increasing adipogenesis because adipocyte and osteoblasts are derived from a common multipotential mesenchymal stem cell. While research with obese animal model has established the negative effects of adiposity on bone metabolism, studies with human subjects continue to be controversial [
Obesity may increase bone resorption through upregulating proinflammatory cytokines such as IL-6 and TNF-
Obesity appears to affect bone metabolism directly or indirectly through adipocyte-derived cytokines such as leptin and adiponectin. Obesity is linked with significant increase in serum leptin and decrease in adiponectin. The action of leptin on bone may be complex and both positive and negative effects have been reported [
Based on current data obesity is detrimental to bone health. The decreased bone mass with obesity may be due to increased marrow adipogenesis at the expense of osteoblastogenesis, increased osteoclastogenesis due to the upregulation of proinflammatory cytokines, excessive leptin secretion or reduced adiponectin production [
In fact, a high-fat diet, a common cause of obesity, has been reported to interfere with intestinal calcium absorption. Free fatty acids can form unabsorbable calcium soaps and contribute to low calcium absorption. Increased body weight associated with obesity may counteract the detrimental effects of obesity on bone metabolism. It is well known that body weight or body mass index (BMI) is positively correlated with bone mineral density or bone mass [
Diet can be modified for the maintenance and development of bone mass. The most relevant nutrients to bone health are calcium and phosphorus because they compose roughly 80% to 90% of the mineral content of bone hydroxyapatite; protein is essential because it is incorporated into the organic matrix of bone for collagen structure upon which mineralization occurs; and other minerals, trace elements, and vitamins (e.g., vitamins D and K) are also crucial in carrying out metabolic processes and reactions in bone [
Data from the Framingham study [
An adherence to a Mediterranean diet pattern is not associated with indices of bone mass (in a sample of adult women), whereas adherence to a dietary pattern close to the Mediterranean diet, that is, high consumption in plant foods and olive oil, low in meat and dairy products, and with moderate intake of alcohol, is positively related to bone mass and total body bone mineral content, suggesting potential bone-preserving properties of this pattern throughout adult life [
It is known that the intake of fruit and vegetables is positively associated with bone health by provision of essential micronutrients for bone formation, buffer precursors which reduce acid load, and phytochemicals affecting inflammation and oxidative stress.
The beneficial effect is because of the provision of micronutrients magnesium, potassium, calcium, vitamins A, C, E, and K, and potentially a lower dietary acid load conferred by the fruit and vegetables food group [
The low grade metabolic acidosis induced by the modern diet is exacerbated during ageing when renal function begins to decline requiring the body’s skeletal reserves to be called upon to relinquish bicarbonate to produce alkaline buffers needed to continuously balance the acid load. Therefore bone mass is gradually and indefinitely reduced after the age of 30 years, accelerating at menopause to lower bone strength and mineral density. Fruit/vegetables influence on acid-base balance is crucial, being the unique dietary source of alkaline precursor constituents, so it is important reason to increase consumption to avoid bone loss during ageing [
An increase in vegetable and fruit consumption to ≥9 servings/day will reduce the estimated net endogenous acid production by approximately 20 mEq/day and result in reduction in bone markers of resorption C telopeptide of type 1 collagen (CTx) and bone formation marker Procollagen 1 N-terminal peptide (P1NP) in postmenopausal women. Those women who include 4-5 servings of vegetables, herbs, and fruit featured bone resorption inhibitory properties (BRIPs) and half of the 9 servings/day will reduce resorption marker CTx by a greater amount. It is also hypothesised that this increase in fruit and vegetable intake will significantly affect inflammatory and metabolic markers including C-reactive protein (CRP) adiponectin, interleukin 6 (IL-6), interleukin 10 (IL10), tumour necrosis factor (TNF-
Furthermore, selenium is an essential nutrient that plays an important role in bone status. That role is likely to involve the functions of selenoproteins. Many selenoproteins are antioxidant enzymes that participate in maintaining cell redox balance, which is important in the regulation of inflammation and bone cell proliferation/differentiation. Selenium (Se) may play additional cellular roles, particularly at supranutritional doses, that is, doses greater than those required for maximal selenoprotein expression. These include the induction of cell cycle arrest, apoptosis, immune function, and the prevention of the bone resorption through the inactivation of osteoclasts. These cellular activities of Se at both nutritional and supranutritional doses may partially account for the potential protection against rheumatoid arthritis, osteoarthritis, osteoporosis, and ROS produced by osteoclasts during bone remodeling [
In a recent study [
Dietary fat may influence bone health. Long-chain polyunsaturated fatty acids (LCPUFAs), specially the omega-3 (
However, the cellular mechanisms of action of the LCPUFAs are complex and involve modulation of fatty acid metabolites such as prostaglandins, resolvins and protectins, cytokines, growth factors, and some other molecular signaling pathways. There are several mechanisms by which
The prostaglandins (PGs), produced from essential fatty acid precursors (20:4
In this sense, dietary intake of essential fatty acids plays a crucial role in the cell membrane and the production of various cytokines by inflammatory cells. The
The relationship between cytokines and osteoclastogenesis. IL-1: interleukine-1; IL-6: interleukine-6; TNF-
According to Casado-Díaz et al. [
The healthy recommended ratio of omega-6/omega-3 fatty acids is approximately 1 : 1; however actual estimations indicate that it is in fact much higher between 15 : 1 and 16.7 : 1. According to the evidence, a reduction in the omega-6/omega-3 proportion decreases the risk of suffering cardiovascular pathologies, tumors, and other chronic diseases, including osteoporosis [
Various
A diet rich in omega-6 fatty acids which rises omega-6/omega-3 ratio seems to cause not only cardiovascular problems but also an increase in the adiposity of the bone marrow, by enhancing the adipogenic differentiation of MSC, inhibiting their differentiation into osteoblasts. Consequently, this could have a negative impact on bone metabolism. Furthermore, a diet with a suitable proportion of omega-6/omega-3 fatty acids appears to avoid pathologies in the bone health associated with aging, such as osteoporosis [
The NHANES III data has established the correlation between dietary fat and hip BMD (bone mineral density) in 14,850 men and women. There was no significant association between total fat intake and BMD at any sites of the analysis. On the other hand, saturated fat intake was negatively associated with BMD in the femoral neck across all subjects, and the greatest effect was observed in men younger than 50 years of age. This indicates the probability of more vulnerability of men to the undesirable effects of saturated fat on bone density [
In other research, it was investigated the role of fatty acids on bone accumulation and attainment of peak bone mass in young men. In this cohort study 78 healthy young men were enrolled. BMD of the total body, hip, and spine was measured at baseline and at 22 and 24 years of age. Fatty-acid concentration was measured at 22 years of age. The results showed that
It is well known that reactive oxygen species (ROS) and oxidative stress are one of the main factors in the regulation of bone status [
Although enhanced osteoclastic activity and increased production of ROS are linked in many skeletal pathologies, it remains to be unclear whether increased ROS production overwhelms the antioxidant defenses, in subjects with oxidative stress.
Osteoclasts chisel away at older bone, opening tiny holes that will be refilled by osteoblasts. The chisel molecule is a superoxide radical, which is one of the highest reactive oxygen species (ROS). ROS also play a specific role in sculpting or remodeling of bone. The role of antioxidants in controlling ROS formation is also well established. In this way, decreased activity of the antioxidant enzymes, SOD, and GSH-PX showed a defense mechanism that appears to have been overtaken in reducing the increased superoxide production by the osteoclasts [
A long-term study reported that
The influence of
The susceptibility of fatty acids to oxidation is known to be directly dependent on their degree of unsaturation. Nevertheless, some
Based on evidence, the higher number of unsaturations present in
From a mechanistic viewpoint, NAD(P)H oxidase is one of the major contributors to endothelial free radical production: its inhibition by DHA and (presumably) other PUFAs might greatly explain the observed effects on ROS production. Massaro et al. (2006) [
In conclusion, based on evidence showing reduced excretion of lipid peroxidation products, that is, isoprostanes, after polyunsaturated fatty acid intake and data on ROS production and direct superoxide removal by LCPUFAs, mainly those of the omega-3 series, this series of fatty acid might indirectly act as anti- rather than prooxidant in vascular endothelial cells, thereby decreasing inflammation and, in turn, the risk of atherosclerosis [
The inflammatory response clears and fights against infection, repairing damaged tissue and organ systems, and removing harmful chemical. Though the net process is protective, the failure to resolve the inflammation and return the target tissue to homeostasis can result in disease. Evidence has provided that dietary
Dietary intake of
The metabolites of PUFAs actively participate in cell signal transduction pathways and to some degree regulate gene expression. Generally,
The fact that selective COX-2 inhibitors gave satisfactory relief of symptoms in both osteoarthritis and rheumatoid patients suggests that eicosanoids participate in the inflammatory process of these severe bone/joint diseases. COX-2 and its product PGE2 appear to be a common link between the two disease states, and since it is possible to regulate the activity and expression of COX-2, this enzyme is a potential target for dietary intervention in optimizing bone formation and controlling bone disease [
Inflammatory cytokines (e.g., IL-1, a major player in rheumatoid arthritis (RA) and osteoarthritis (OA)) are known to inhibit chondrocyte proliferation and induce cartilage degradation, therefore part of the response may be mediated by PGE2. Excessive production of PGE2 is linked to joint pathology (rheumatoid arthritis), known to exacerbate inflammatory responses, and results in a net loss of proteoglycan from articular cartilage [
The mode of
It has been suggested that dietary supplementation with LC
It has also been reported that DHA has more potent anti-inflammatory effects than EPA, and that DHA is a key controller of hepatic lipid metabolism and is ultimately involved in the suppression of lipogenesis which could impact on weight management. In this way, there are gender difference in the metabolism of LC
There is conflicting evidence on the effect of LC
Madsen et al. (2008) [
Conflicting findings have also been reported from studies investigating the effect of diet and/or weight on C-reactive protein (CRP) levels. One study reported that LC
Obesity is regulated by cytokines and endocrine factors that have effects on bone and calcium absorption; obesity also increases bone fracture risk. Long-chain omega-3 polyunsaturated fatty acids (LC
There is controversy about the beneficial effects of supplementation with LC
A growing evidence supports that there are gender differences in the metabolism of
The mechanisms by which LC
It is possible that an extended period of
It is also possible that incorporation of
While there is evidence from a considerable number of animal studies that LC
In human studies it is becoming apparent that an increased intake of LC
An observational study of 124 adults found that obese individuals had significantly lower plasma
Studies in youth report significantly decreased plasma
Randomized controlled trials in humans examining the relationship between
Published literature supports evidence for a role of
Moreover, different organ systems in the body and various pathways are involved in appetite, food intake, and energy homeostasis, and the disruption of these systems leads to obesity. These include brain structures such as the brain stem, hypothalamus, and reward pathways, as well as the gastrointestinal tract, adipose tissue, and the pancreas. Increasing evidence suggests that the
While the effects of EPA/DHA on the endocannabinoid system and on dopaminergic reward systems in the brain have been described, no animal or human studies have examined the role of DHA and EPA in modulating these systems to affect appetite and food intake. As the endocannabinoid and mesocorticolimbic pathways play a role in appetite, energy intake, and obesity, we hypothesize that, in addition to beneficial effects on metabolism, EPA and DHA regulate the endocannabinoid and mesocorticolimbic dopamine systems in humans to decrease appetite, increase satiety, reduce food intake, and ultimately contribute to prevent or reduce overweight and obesity [
Further studies are necessary to elucidate the effects of EPA/DHA supplementation on the reward associated with food intake and appetite, food consumption, weight loss, and, at the same time, the molecular effects on the function of the endocannabinoid system and the mesocorticolimbic system. Studies in humans are especially noteworthy, because molecular and behavioral changes in animal models may not correspond to the same effects in humans. In addition, the interplay between diets of differing composition of essential fatty acids and effects of EPA/DHA must be further examined because the effects of
Animal and human studies indicate that EPA and DHA supplementation may be protective against obesity and might reduce weight gain in already obese animals and humans. There is evidence in animal studies that
The best way to avoid osteoporosis in women is to build strong bones in early life by consuming a well-balanced diet (vitamin D, calcium,
Although osteoporosis occurs in both women and men, postmenopausal women have the greatest risk of developing this disease. Extensive research has been conducted to find a cure for the disease; however, optimizing bone development in the young and reducing bone resorption to maintain bone mass and restore skeletal integrity in the older are still the best means to control the disease. Direct evidence of any beneficial effect of dietary
Some studies suggest that using
Högström et al. (2007) [
There is an available study that demonstrates that tissue levels of
Epidemiologic studies have shown a positive association between BMD and the intake of n-3 PUFA in older adults or the intake of fish in postmenopausal women and the elderly [
Although the mechanism is not known,
In the female population, postmenopausal individuals are regarded as more vulnerable to oxidative stress (OS) than those in reproductive age, because their oxidative balance is deranged not only by the generally older age but also by a lower level of 17
OS is not itself a characteristic condition of subjects affected by PO, but that it might influence BMD loss in women who have already experienced the menopausal transition, thus increasing the risk of this severe bone degenerative disease. In other terms it can, therefore, be assumed that the association between altered hydroperoxide levels and the selective decline in BMD in postmenopausal women might reflect an interplay between OS and the menopausal endocrine changes [
Although relevant progress has been achieved in the understanding of how estrogen deficiency induces bone loss, the underlying pathogenic mechanisms have proven to be remarkably complex. One of the mechanisms suggested takes into account the ability of E2 to regulate receptor activator of nuclear factor-kappa
Pansini et al. (2008) [
The involvement of oxidative status in the relationship between estrogen PO is further supported by the finding that in osteoclast cell lines estrogen upregulate glutathione peroxidase responsible for the intracellular degradation of hydrogen peroxide and major antioxidant enzymes of these cells [
Sharif et al. (2010) [
A cohort study that evaluated the effects of omega-3 fatty acids on bone health has investigated the associations between dietary polyunsaturated fatty acid and fish intakes and hip bone mineral density (BMD) at baseline (
According to the physiological mechanisms of
There is growing evidence that LC
In conclusion, strong evidences featured in the scientific literature available to date support the benefits of
The authors declare that there is no conflict of interests regarding the publication of this paper.