Role of Iron Accumulation in Osteoporosis and the Underlying Mechanisms.

Osteoporosis is prevalent in postmenopausal women. The underlying reason is mainly estrogen deficiency, but recent studies have indicated that osteoporosis is also associated with iron accumulation after menopause. It has been confirmed that some methods of decreasing iron accumulation can improve the abnormal bone metabolism associated with postmenopausal osteoporosis. However, the mechanism of iron accumulation-induced osteoporosis is still unclear. Iron accumulation may inhibit the canonical Wnt/ß-catenin pathway via oxidative stress, leading to osteoporosis by decreasing bone formation and increasing bone resorption via the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-B ligand (RANKL)/receptor activator of nuclear factor kappa-B (RANK) system. In addition to oxidative stress, iron accumulation also has been reported to inhibit either osteoblastogenesis or osteoblastic function as well as to stimulate either osteoclastogenesis or osteoclastic function directly. Furthermore, serum ferritin has been widely used for the prediction of bone status, and nontraumatic measurement of iron content by magnetic resonance imaging may be a promising early indicator of postmenopausal osteoporosis.

Can iron be teratogenic?

Several kinds of evidence indicate that elevated iron during the 3-8 week embryonic (organogenesis) period of human gestation may be teratogenic. (1) In the embryonic period, the natural maternal absorption of food iron is 30% below the estimated daily iron loss. (2) As compared with maternal serum, embryonic fetal coelomic fluid contains only one-fourth as much iron but nearly six times the quantity of the iron withholding protein, ferritin. (3) In the embryonic period, intraplacental oxygen pressure is 2-3 times lower than in the subsequent fetal growth period. (4) Iron is a strong inducer of emesis which peaks in the embryonic period. (5) In a murine gestation model, iron was neurotoxic at a sharp peak of 8-9 days. Thus it would be prudent, in human pregnancy, to delay any needed iron supplementation until the embryonic period has been completed.

First trimester curtailment of iron absorption: innate suppression of a teratogen?

In human pregnancies, maternal absorption of iron is markedly curtailed in the first trimester. In a murine model, iron was teratogenic in the analogous embryonic period. Although iron is a weak mutagen, it is a powerful oxidant and a catalyst of formation of hydroxyl radicals. Studies are needed to determine if there might be an association of first trimester iron supplementation with miscarriage/fetal abnormalities.

Is addition of iron to processed foods safe for iron replete consumers?

The great majority of US adults are iron replete; indeed, some are burdened with an excessive amount of the metal. Nevertheless, iron continues to be added by food processors to such items as flour, other grains and ready-to-eat cereals. In some cases, actual added quantities exceed the labeled amounts. Iron is a dangerous pro-oxidant as well as a mutagen and carcinogen. The metal is a serious risk factor for a variety of cardiovascular, endocrine, infectious, neoplasmic, neurodegenerative, orthopedic and respiratory diseases. For many of the conditions, iron can be a sole initiator or a cofactor in promoting the disease. For others, iron deposits are found in relevant tissue sites. For numerous additional diseases, iron is associated with elevated disease incidence. Accordingly, critical evaluation of the indiscriminate practice of adding the metal to processed foods is overdue.

Are iron supplements appropriate for iron replete pregnant women?

Iron replete pregnant women often are routinely advised to take a daily supplement of 30-40mg iron. An extensive review of controlled trials has failed to demonstrate that this practice improves clinical outcome of mother or newborn. However, this iron loading has long been assumed to be harmless. Recently, two hazardous complications of pregnancy, gestational diabetes and pre-eclampsia, have been recognized to be associated with iron loading. Accordingly, it may be appropriate to consider performing, at the patient's initial prenatal medical visit, a serum ferritin test to ascertain iron status. This simple procedure would enable evidence-based medical practice to replace mass medication with iron, a potentially toxic element.

Tobacco smoke iron: an initiator/promoter of multiple diseases.

Tobacco smoking enhances risk for a diversity of acute and chronic diseases. Iron is a constant prominent component of mainstream tobacco smoke. The manifold toxic activities of inhaled iron could be responsible for a notable portion of the spectrum of smoking-related diseases.

Iron loading: a risk factor for osteoporosis.

Iron loaded persons are at increased risk for infection, neoplasia, arthropathy, cardiomyopathy and an array of endocrine and neurodegenerative diseases. This report summarizes evidence of increased risk of iron loading for osteoporosis. Iron suppresses bone remodeling apparently by decreasing osteoblast formation and new bone synthesis. Low molecular mass iron chelators as well as a natural protein iron chelator, lactoferrin, may be useful in prevention of osteoporosis.

Suppression of bacterial biofilm formation by iron limitation.

The concentration of iron that permits bacterial differentiation generally differs from that needed for vegetative cell growth. An undesirable manifestation of differentiation is biofilm formation. The process in some, but not all, bacterial systems requires a higher level of iron than is needed for growth and it is suppressed by specific iron chelators. Human transferrin and lactoferrin, as well as at least six low molecular mass iron chelators, are now available for possible screening and clinical development as inhibitors of bacterial biofilm formation.

Do some carriers of hemochromatosis gene mutations have higher than normal rates of disease and death?

Some heterozygote carriers of hemochromatosis HFE gene mutations become iron loaded with ensuing increased risk of disease and premature death. Contributing nutritional, behavioral and genetic factors are beginning to be identified. Carriers of HFE gene mutations should be advised to minimize contributing factors, if possible, and to have their iron values tested periodically. If values begin to rise, a schedule of phlebotomies should be considered.

Human lactoferrin: a novel therapeutic with broad spectrum potential.

Lactoferrin (Lf), a natural defence iron-binding protein, has been found to possess antibacterial, antimycotic, antiviral, antineoplastic and anti-inflammatory activity. The protein is present in exocrine secretions that are commonly exposed to normal flora: milk, tears, nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervico-vaginal mucus and seminal fluid. Additionally, Lf is a major constituent of the secondary specific granules of circulating polymorphonuclear neutrophils (PMNs). The apoprotein is released on degranulation of the PMNs in septic areas. A principal function of Lf is that of scavenging free iron in fluids and inflamed areas so as to suppress free radical-mediated damage and decrease the availability of the metal to invading microbial and neoplastic cells. Mechanisms of action of Lf in addition to iron deprivation are also described. Administration of exogenous human or bovine Lf to hosts with various infected or inflamed sites has resulted in some prophylactic or therapeutic effects. However, an adverse response to the protein might occur if it were to stimulate antibody production or if it were to provide iron to the invading pathogen. The recombinant form of human Lf has become available and development of the product for use in a wide range of medical conditions can now be anticipated.

Iron, infection and sudden infant death.

Three risk factors for sudden infant death syndrome are well established: maternal smoking, prone sleeping position and non-breast feeding. Two additional risk factors have been proposed: microbial infection in the gastrointestinal or respiratory tracts and iron loading. This review endeavors to integrate these five disparate factors into a unifying concept.

Iron loading: a risk factor for Whipple's disease?

Because of impairment of microbial iron acquisition ability, some potential pathogens can cause disease only in iron loaded hosts. Tropheryma whippelii, the etiologic agent of Whipple's disease, is a possible example. Whipple's disease is non-contagious, occurs mainly in middle-aged white males, and displays many, but not all, of the complications of hereditary haemochromatosis. Tropheryma whippelii is a gastrointestinal commensal that causes disease in persons who have a Th1-Th2 imbalance. Host susceptibility may be exacerbated by iron loading. Consideration should be given to have patients evaluated for levels of interferon-gamma and interleukin-4 as well as for serum ferritin and transferrin iron saturation.

Microbial pathogens with impaired ability to acquire host iron.

Successful microbial pathogens must be adept in obtaining growth-essential iron from healthy hosts. Some potential pathogens, however, are sufficiently impaired in iron acquisition ability so as to be dangerous mainly in hosts with such iron loading conditions as alcoholism, asplenia, hemochromatosis, beta-thalassemia major, or tobacco smoking. The association of six impaired pathogens (Capnocytophaga canimorsis, Yersinia enterocolitica and Y. pseudotuberculosis, Vibrio vulnificus, Tropheryma whippelii, and Legionella pneumophila) with iron loaded humans is described.

Modulation of intramacrophage iron metabolism during microbial cell invasion.

The mechanisms whereby vertebrate hosts withhold iron from microbial invaders, as well as the methods used in attempts by invaders to capture the growth-essential metal, differ between host extracellular and intracellular environments. This review focuses on procedures employed by host cells and by invaders, respectively, that alter intramacrophage iron metabolism.

Iron-enriched rice: the case for labeling.

ABSTRACT Genetically modified rice that incorporates twofold to threefold increased amounts of iron is being developed. The product could provide improved nutrition to iron-deficient persons but may be a health hazard to large numbers of humans who are prone to iron overload. Clinical disorders such as African siderosis, beta-thalassemia, hemochromatosis, and alcoholic siderosis are of special concern. Conditions associated with iron loading include fatigue and depression; arthritis; endocrine disorders such as stunted growth, impotence, and diabetes; gastrointestinal maladies; infections and malignancies; several neurological diseases; and, not least, cardiovascular system decay. Therefore, it would be prudent to label sacks of iron-enriched rice to indicate that "this product may be dangerous to persons with iron loading conditions".