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Role of iron in the collagen synthesis. 

Role of iron in the collagen synthesis. 

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Iron is essential in oxygen transport and participates in many enzymatic systems in the body, with important roles in collagen synthesis and vitamin D metabolism. The relationship between iron and bone health comes from clinical observations in iron overload patients who suffered bone loss. The opposite scenario—whether iron deficiency, with or wit...

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... and they form flattened lining cells on the bone surface until a new remodeling cycle is triggered or become osteocyte cells (as reviewed previously, osteocytes are cells derived from osteoblasts embedded in bone) [31]. Biochemical bone turnover markers are released during bone remodeling and provide a measure of the rate of bone metabolism. They comprise enzymes secreted by osteoblasts and osteoclasts during remodeling, degradation products formed during resorption, and precursors released during new bone formation. They reflect metabolic abnormalities such as accelerated bone turnover (Table 2) [46]. Iron participates in a variety of enzymatic systems in the body, including the enzymes involved in collagen synthesis. Collagen is the most abundant protein in animals, and the major component of connective tissue [47]. Regarding bone tissue, about 90% of total bone protein is composed of type I collagen [31]. For collagen synthesis, first, a three-dimensional stranded structure is assembled, with the amino acids glycine and proline as its principal components. This is not yet collagen but its precursor, procollagen. Procollagen is then modified by the addition of hydroxyl groups to the amino acids proline and lysine. This step is important for later glycosylation and the formation of the triple helix structure of collag en. This reaction requires α -ketoglutarate, molecular oxygen, ferrous iron, and a reducing agent [48,49]. In this regard, ascorbate reduces the inactive Fe 3+ state to the active Fe 2+ state [50]. During the reaction, α -ketoglutarate is decarboxylated oxidatively to produce succinate and CO 2 [48] (Figure 3). These hydroxylation reactions are catalyzed by two different enzymes: prolyl-4-hydroxylase [48] and lysyl-hydroxylase [49]. Another mechanism in which iron participates in bone metabolism is through vitamin D activation and deactivation. In this pathway, the cytochrome P450 superfamily, a large number of heme-containing monooxygenases, plays an important role [51]. Vitamin D undergoes two steps of hydroxylation for its activation. The first step occurs in the liver and as a result 25-hydroxyvitamin D (25OHD) is produced. This is the first and bounden step in the production of the active form of this vitamin [51,52]. This step occurs in the liver and is catalyzed by the cythocrome P-450 25-hydroxylase (CYP2R1) [51]. Mutations in CYP2R1 gene lead to low serum levels of 25OHD and are associated with rickets (softening and weakening of bones in children, ...
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... performed specific interventions in these women. Anemic women were treated with ferrous sulfate, and it was found that those who recovered normal hemoglobin levels exhibited a decrease in bone remodeling, as both P1NP and NTx were lower at the end of treatment compared to baseline [95]. Two nutritional interventions were carried out in iron-deficient women using functional foods. One of them studied the effects of consuming an iron-fortified fruit juice compared to placebo. This functional food was very efficacious in improving iron status [96]; however, iron formation and resorption markers did not change during the 16-week intervention period [90]. The other nutritional intervention investigated the effects of an iron- or iron and vitamin D-fortified dairy product on iron and bone metabolism. This product did not provide bioavailable iron and iron status did not improve [11]; the vitamin D fortification reduced both bone formation and resorption in these women, as expected, but the possible effect of iron on bone could not be seen [91]. It is difficult to explain why the bones of anemic women responded to the iron recovery, but no variation in bone remodeling was observed in the iron-deficient women who consumed the iron-fortified fruit juice, or why bones from iron-deficient women treated with vitamin D clearly improved. Therefore, further studies in this line are needed. Different mechanisms by which iron deficiency affects bone have been suggested. On the one hand, there is the role of iron as an essential cofactor for hydroxylation of prolyl and lysil residues of procollagen, as detailed before (Figure 2). On the other hand, there is its participation in vitamin D metabolism through the cytochromes P450 (Figure 3). A third mechanism to be considered is hypoxia. A state of hypoxia occurs when oxygen supply to tissues is reduced, as occurs in anemia. Hypoxia is a major stimulator of bone resorption, inducing osteoclastogenesis, which is later followed by osteoblastogenesis [97,98]. Interestingly, during normoxia, α -ketoglutarate and both molecular oxygen and iron are needed for the activity of a prolyl hydroxylase domain protein that acts on the hypoxia inducible factor α (HIF - 1α) for its degradation , preventing its action. The role of iron in HIF- 1α is similar to that involved in the collagen synthesis, as indicated previously (Figure 3). Under hypoxia conditions, HIF- 1α is not degraded and translocates to the nucleus where transcription of >100 genes is regulated [48]. Among these genes, erythropoietin (EPO), PDGF, and transferrin are of particular interest in exploring the link between iron deficiency anemia and bone health. In this regard, apart from the erythropoiesis function, several pleiotropic effects of EPO have been recognized. EPO acts ...
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... performed specific interventions in these women. Anemic women were treated with ferrous sulfate, and it was found that those who recovered normal hemoglobin levels exhibited a decrease in bone remodeling, as both P1NP and NTx were lower at the end of treatment compared to baseline [95]. Two nutritional interventions were carried out in iron-deficient women using functional foods. One of them studied the effects of consuming an iron-fortified fruit juice compared to placebo. This functional food was very efficacious in improving iron status [96]; however, iron formation and resorption markers did not change during the 16-week intervention period [90]. The other nutritional intervention investigated the effects of an iron- or iron and vitamin D-fortified dairy product on iron and bone metabolism. This product did not provide bioavailable iron and iron status did not improve [11]; the vitamin D fortification reduced both bone formation and resorption in these women, as expected, but the possible effect of iron on bone could not be seen [91]. It is difficult to explain why the bones of anemic women responded to the iron recovery, but no variation in bone remodeling was observed in the iron-deficient women who consumed the iron-fortified fruit juice, or why bones from iron-deficient women treated with vitamin D clearly improved. Therefore, further studies in this line are needed. Different mechanisms by which iron deficiency affects bone have been suggested. On the one hand, there is the role of iron as an essential cofactor for hydroxylation of prolyl and lysil residues of procollagen, as detailed before (Figure 2). On the other hand, there is its participation in vitamin D metabolism through the cytochromes P450 (Figure 3). A third mechanism to be considered is hypoxia. A state of hypoxia occurs when oxygen supply to tissues is reduced, as occurs in anemia. Hypoxia is a major stimulator of bone resorption, inducing osteoclastogenesis, which is later followed by osteoblastogenesis [97,98]. Interestingly, during normoxia, α -ketoglutarate and both molecular oxygen and iron are needed for the activity of a prolyl hydroxylase domain protein that acts on the hypoxia inducible factor α (HIF - 1α) for its degradation , preventing its action. The role of iron in HIF- 1α is similar to that involved in the collagen synthesis, as indicated previously (Figure 3). Under hypoxia conditions, HIF- 1α is not degraded and translocates to the nucleus where transcription of >100 genes is regulated [48]. Among these genes, erythropoietin (EPO), PDGF, and transferrin are of particular interest in exploring the link between iron deficiency anemia and bone health. In this regard, apart from the erythropoiesis function, several pleiotropic effects of EPO have been recognized. EPO acts ...

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... Bone is a natural composite material consisting of an organic phase (collagen) and inorganic phase (calcium phosphate) [34]. Fe participates in diverse enzymatic systems, such as the catalysis of prolyl-4-hydroxylase and lysyl-hydroxylase, as well as activation of the cytochrome P450 family in the body [35,36]. Collagen synthesis involves hydroxylation of pro-collagen on proline, and the hydroxylation reaction is catalyzed by prolyl-4-hydroxylase and lysyl-hydroxylase [37,38]. ...
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Background & aims Previous experimental studies demonstrated that either deficient or excessive trace elements, such as manganese (Mn), iron (Fe), copper (Cu) and selenium (Se), are detrimental to bone health. Epidemiologic evidence for the effect of the four trace elements on osteoporosis (OP) risk remains inadequate. This cross-sectional study aimed to examine their associations with the OP risk among Chinese adults. Methods Concentrations of Mn, Fe, Cu, and Se were measured in plasma using an inductively coupled plasma mass spectrometer among 627 Chinese adults aged ≥ 50 years. Individual effect of the four elements on OP risk was analyzed by logistic regression and Bayesian Kernel Machine Regression (BKMR) models. The latter model was also adopted to examine the exposure-response relationships and joint effects of the four elements on OP risk. Results The median Mn, Fe, Cu, and Se levels were 4.78, 1026.63, 904.55, and 105.39 μg/L, respectively, in all participants. Inverse associations of Fe and Se levels with OP risk were observed in the logistic regression model. BKMR analysis revealed a U-shape pattern for the Fe-OP association, and a reduced OP risk in response to co-exposure of the four elements above the 50th percentiles but an elevated one in response to that below the 50th percentiles. Sex discrepancy existed in the findings. No interactions were found for the four elements affecting OP risk. Conclusions Co-exposure to Mn, Fe, Cu, and Se was associated with improved bone density, where Fe contributed most to the beneficial effect. Further studies are needed to verify these findings and explore the underlying biological mechanism.
... Anemia can lead to bone resorption and increases bone fragility [364,365]. Iron deficiency may negatively impact cytochromes' P450 activity, which is essential for vitamin D metabolism and bone health [366]. β thalassemia causes ineffective erythropoiesis and bone marrow expansion that leads to medullary destruction and cortical thinning [367]. ...
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Fragility fracture is a worldwide problem and a main cause of disability and impaired quality of life. It is primarily caused by osteoporosis, characterized by impaired bone quantity and or quality. Proper diagnosis of osteoporosis is essential for prevention of fragility fractures. Osteoporosis can be primary in postmenopausal women because of estrogen deficiency. Secondary forms of osteoporosis are not uncommon in both men and women. Most systemic illnesses and organ dysfunction can lead to osteoporosis. The kidney plays a crucial role in maintaining physiological bone homeostasis by controlling minerals, electrolytes, acid-base, vitamin D and parathyroid function. Chronic kidney disease with its uremic milieu disturbs this balance, leading to renal osteodystrophy. Diabetes mellitus represents the most common secondary cause of osteoporosis. Thyroid and parathyroid disorders can dysregulate the osteoblast/osteoclast functions. Gastrointestinal disorders, malnutrition and malabsorption can result in mineral and vitamin D deficiencies and bone loss. Patients with chronic liver disease have a higher risk of fracture due to hepatic osteodystrophy. Proinflammatory cytokines in infectious, autoimmune, and hematological disorders can stimulate osteoclastogenesis, leading to osteoporosis. Moreover, drug-induced osteoporosis is not uncommon. In this review, we focus on causes, pathogenesis, and management of secondary osteoporosis.
... Our study identified IDA as a risk factor nonunion and can be potentially explained by the relationship of IDA with osteoporosis. Toxqui et al. discusses how chronic IDA can lead to osteoporosis through its roles in collagen synthesis, vitamin D activation, and hypoxia [14]. Iron plays is a key cofactor in several enzymes including collagen hydroxylases and the CYP450 superfamily of heme-containing monooxygenases. ...
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Purpose The incidence of proximal humerus fractures (PHF) is rising and surgical intervention carries risk for fracture nonunion. The purpose was (1) to compare patient demographics of those that developed nonunion and (2) identify patient risk factors that predispose to nonunion following open reduction and internal fixation (ORIF) for PHF. Methods A retrospective review of the Medicare Claims Database from 2005 to 2014 for patients who underwent primary ORIF for PHFs. Patients who developed nonunion were identified as the study group (n = 1020) and compared to a control group (n = 51,209). Primary endpoints were to compare demographics of the study group and the comparison cohorts and to identify patient-related risk factors associated with nonunion within 6-months following the index procedure. A logistic regression model was constructed to determine the association of comorbid conditions on developing a nonunion. A p value of 0.001 was the significance threshold. Results Patients who developed nonunion were younger, more likely to be male, and had higher Elixhauser-Comorbidity Index scores (7 vs. 5; p < 0.0001) when compared with controls. Iron deficiency anemia (OR: 1.32; p = 0.0001), tobacco use (OR: 1.32; p = 0.0004), rheumatoid arthritis (OR: 1.29; p = 0.0001), depression (OR: 1.28; p = 0.0002), and BMI range from 30–39 kg/m² (OR: 1.21; p = 0.001) were significant risk factors for nonunion. Conclusions Certain patient risk factors including tobacco use, iron deficiency anemia, rheumatoid arthritis, depression, and a BMI in the range of 30–39 were associated with nonunion within 6 months of ORIF for PHF. This study may help in the risk stratification of these patients.
... Interestingly, our study shows that specifically, posthemorrhagic anemia is a main cause for these complications in patients with osteoporosis. This could potentially be due to the fact that osteoporosis patients are at higher risk of anemia, associated with deficient levels in iron [37,38]. ...
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Objective To identify the impact of osteoporosis (OS) on postoperative outcomes in Medicare patients undergoing ASD surgery.Background Patients with OP and advanced age experience higher than average rates of ASD. However, poor bone density could undermine the durability of a deformity correction. Methods We queried the MarketScan Medicare Supplemental database to identify patients Medicare patients who underwent ASD surgery from 2007 to 2016. ResultsA total of 2564 patients met the inclusion criteria of this study, of whom n = 971 (61.0%) were diagnosed with osteoporosis. Patients with OP had a similar 90-day postoperative complication rates (OP: 54.6% vs. non-OP: 49.2%, p = 0.0076, not significant after multivariate regression correction). This was primarily driven by posthemorrhagic anemia (37.6% in OP, vs. 33.1% in non-OP). Rates of revision surgery were similar at 90 days (non-OP 15.0%, OP 16.8%), but by 2 years, OP patients had a significantly higher reoperation rate (30.4% vs. 22.9%, p < 0.0001). In multivariate regression analysis, OP increased odds for revision surgery at 1 year (OR 1.4) and 2 years (OR 1.5) following surgery (all p < 0.05). OP was also an independent predictor of readmission at all time points (90 days, OR 1.3, p < 0.005).Conclusion Medicare patients with OP had elevated rates of complications, reoperations, and outpatient costs after undergoing primary ASD surgery.
... Furthermore, this protocol enabled examination of possible crosstalk between bone and iron metabolism. Both iron overload and deficiency have been shown to impair bone homeostasis in animal models and clinical populations (Toxqui & Vaquero, 2015), and IL-6 has been implicated in increased bone resorption in the presence of PTH (Sims, 2021). Thus, the primary aim of this study was to examine the response of IL-6 and hepcidin to twice daily training in elite endurance athletes, with an opportunistic aim of determining whether pre-exercise calcium intake would interact with these effects via its downstream effects on bone turnover (Haakonssen et al., 2015). ...
... Furthermore, in relation to bone, it has been shown that hepcidin increases intracellular calcium in in vitro osteoblasts (Li et al., 2012;Xu et al., 2011), with hepcidin knockout mice exhibiting bone loss (Li et al., 2020). Iron is also necessary for collagen synthesis and vitamin D activation (Toxqui & Vaquero, 2015). Therefore, it appears possible that calcium ingestion may influence hepcidin concentrations, with potential downstream effects for both bone and iron status. ...
Article
Previous research investigating single bouts of exercise have identified baseline iron status and circulating concentrations of interleukin-6 (IL-6) as contributors to the magnitude of postexercise hepcidin increase. The current study examined the effects of repeated training bouts in close succession on IL-6 and hepcidin responses. In a randomized, crossover design, 16 elite male rowers completed two trials, a week apart, with either high (1,000 mg) or low (<50 mg) calcium pre-exercise meals. Each trial involved two, submaximal 90-min rowing ergometer sessions, 2.5 hr apart, with venous blood sampled at baseline; pre-exercise; and 0, 1, 2, and 2.5 hr after each session. Peak elevations in IL-6 (approximately 7.5-fold, p < .0001) and hepcidin (approximately threefold, p < .0001) concentrations relative to baseline were seen at 2 and 3 hr after the first session, respectively. Following the second session, concentrations of both IL-6 and hepcidin remained elevated above baseline, exhibiting a plateau rather than an additive increase (2 hr post first session vs. 2 hr post second session, p = 1.00). Pre-exercise calcium resulted in a slightly greater elevation in hepcidin across all time points compared with control ( p = .0005); however, no effect on IL-6 was evident ( p = .27). Performing multiple submaximal training sessions in close succession with adequate nutritional support does not result in an amplified increase in IL-6 or hepcidin concentrations following the second session in male elite rowers. Although effects of calcium intake require further investigation, athletes should continue to prioritize iron consumption around morning exercise prior to exercise-induced hepcidin elevations to maximize absorption.
... Growing evidence shows that iron plays an important role in the regulation of bone metabolism. Iron deficiency negatively affects collagen synthesis and vitamin D metabolism (Toxqui and Vaquero, 2015). However, iron overload, a state of excessive iron storage seen especially in patients with thalassemia, hemochromatosis, or sickle cell disease, is closely related to osteoporosis by promoting osteoclast differentiation and suppressing the proliferation and differentiation of osteoblasts (Jeney, 2017). ...
Article
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Osteoporosis is a prevalent bone disorder characterized by bone mass reduction and deterioration of bone microarchitecture leading to bone fragility and fracture risk. In recent decades, knowledge regarding the etiological mechanisms emphasizes that inflammation, oxidative stress and senescence of bone cells contribute to the development of osteoporosis. Studies have demonstrated that heme oxygenase 1 (HO-1), an inducible enzyme catalyzing heme degradation, exhibits anti-inflammatory, anti-oxidative stress and anti-apoptosis properties. Emerging evidence has revealed that HO-1 is critical in the maintenance of bone homeostasis, making HO-1 a potential target for osteoporosis treatment. In this Review, we aim to provide an introduction to current knowledge of HO-1 biology and its regulation, focusing specifically on its roles in bone homeostasis and osteoporosis. We also examine the potential of HO-1-based pharmacological therapeutics for osteoporosis and issues faced during clinical translation.
... Iron deficiency represents the stage between optimum and iron deficiency anemia. Iron deficiency is characterized by the depletion of stored iron and increase in transport proteins, while iron deficiency anemia is a considered a decrease in the concentrations of hemoglobin and hematocrit (7) . The prevalence of iron deficiency in women increases by ~20% during training (8,9) . ...
Article
In the US, as many as 20% of recruits sustain stress fractures during basic training. In addition, approximately one-third of female recruits develop iron deficiency upon completion of training. Iron is a cofactor in bone collagen formation and vitamin D activation, thus we hypothesized iron deficiency may be contributing to altered bone microarchitecture and mechanics during 12-weeks of increased mechanical loading. Three-week old female Sprague Dawley rats were assigned to one of four groups: iron adequate sedentary, iron deficient sedentary, iron adequate exercise, and iron deficient exercise. Exercise consisted of high-intensity treadmill running (54 min 3×/week). After 12-weeks, serum bone turnover markers, femoral geometry and microarchitecture, mechanical properties and fracture toughness, and tibiae mineral composition and morphometry were measured. Iron deficiency increased the bone resorption markers C-terminal telopeptide type I collagen and tartate-resistant acid phosphatase 5b (TRAcP 5b). In exercised rats, iron deficiency further increased bone TRAcP 5b, while in iron adequate rats, exercise increased the bone formation marker procollagen type I N-terminal propeptide. In the femur, exercise increased cortical thickness and maximum load. In the tibia, iron deficiency increased the rate of bone formation, mineral apposition, and zinc content. These data show that the femur and tibia structure and mechanical properties are not negatively impacted by iron deficiency despite a decrease in tibiae iron content and increase in serum bone resorption markers during 12-weeks of high-intensity running in young growing female rats.
... Among the possible reasons for this relationship is the notion that hypoxia may be essentially responsible, as it is a powerful controller of erythropoietin generation that activates osteoclast differentiation and causes bone loss [49]. Iron scarcity may also alter the bone structure, as it is an indispensable component of the hydroxylation of prolyl and lysil residues of procollagen and contributes to VD metabolism via the cytochrome P450 [50]. Numerous hematological neoplasms seem to be characterized by VD deficiency, which could be involved in both bone alterations and in the onset and progression of neoplasms. ...
Article
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Vitamin D (VD) is essential for bone homeostasis, but it is also involved in pleiotropic effects on various organs and tissues. In adults, VD deficiency can cause or exacerbate osteoporosis and induce osteomalacia. However, every tissue and cell in the body has a VD receptor, including the brain, heart, stomach, pancreas, skin, gonads, and immune cells, and a deficiency may modify the function of these organs. Thus, the wide-ranging actions of VD help to explain why a reduction in VD amount has been correlated with numerous chronic diseases. In fact, VD deficiency increases the risk of osteoporosis and several other diseases and complications characterized by impaired bone metabolisms, such as autoimmune diseases, inflammatory bowel diseases, allergy, endocrinological diseases, hematological malignancies, and bone marrow transplantation. This review aims to investigate the link between VD deficiency, osteoporosis, and its concomitant diseases. Further epidemiological and mechanistic studies are necessary in order to ascertain the real role of hypovitaminosis in causing the reported diseases; however, adequate vitamin supplementation and restoration of metabolic normality could be useful for better management of these pathologies.
... Low BMD has been reported to be associated with aging, low body weight, physical inactivity, smoking, excessive alcohol consumption, diabetes, dyslipidemia, and pernicious anemia [5][6][7]. In addition, chronic iron-deficiency anemia has been suggested to induce bone resorption and increase the risk of osteoporosis [8]. ...
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An association between anemia and an increased risk of osteoporosis has been suggested. The goal of this study was to estimate the association of hemoglobin (Hb) level with osteoporosis. A total of 69,760 osteoporosis patients aged ≥ 40 years old from the Korean National Health Insurance Service Health Screening Cohort were enrolled. From an identical cohort database, 69,760 comparison participants were randomly selected. Hb levels before the onset of osteoporosis were evaluated. The association of Hb level with osteoporosis was analyzed using a conditional logistic regression model adjusted for obesity, smoking status, alcohol consumption, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, and the Charlson comorbidity index score. Fifteen percent of the osteoporosis group and 14.17% of the comparison group had anemia. The Hb level was associated with 0.98-fold lower odds for osteoporosis (95% confidence intervals = 0.97–0.99, p < 0.001). A low Hb level was associated with a high risk of osteoporosis in the adult population. There was a consistent association between a low Hb level and osteoporosis in patients with comorbidities.
... Iron participates in enzyme systems such as those involved in neurotransmitter metabolism, vitamin D activation, collagen metabolism, and cholesterol catabolism. Therefore, iron is essential for oxygen transport and storage and many other metabolic functions related to growth, muscular activity, immunity, bone strength, and the nervous system (Toxqui and Vaquero 2015;Blanco-Rojo and Vaquero 2019). ...
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Iron deficiency anemia (IDA) is a global health concern that is affecting all age groups significantly. Among many of the existing methods, the fortification of foods with iron salts is the best and most cost-effective strategy for targeting large-scale populations to provide nutritional security. The fortification of foods with iron salts is a challenging task because most iron complexes (ferrous sulfate, ferrous chloride) used in fortification are highly water-soluble, which impart unacceptable organoleptic changes in food vehicles and also causes gastrointestinal problems. However, insoluble iron salts (ferric pyrophosphate) do not cause unacceptable taste or color in food vehicles but low bioavailable. Nanosized iron salts can overcome these concerns. The particle size of iron salts has been reported to play an important role in the absorption of iron. Reduction in the particle size of iron compounds increases its surface area, which in turn improves its solubility in the gastric juice leading to higher absorption. Nanosized iron compound produces minimal organoleptic changes in food vehicles compared to watersoluble iron complexes. Thus nanosized iron salts find potential applications in food fortification to reduce IDA. This paper focuses on providing a complete review of the various iron salts used in IDA, including their bioavailability, the challenges to food fortification, the effects of nanosized iron salts on IDA, and their applications in food fortification.