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This chapter reviews what is known about calcium metabolism and nutrition, inasmuch as calcium is the major mineral component of bone, and relates this to the epidemiology of osteoporosis. Over 99% of the calcium content of the human body, typically 1 to 1.5 kg, is found in the skeleton. In women, at the menopause, the loss of bone calcium is sudden and rapid and does not begin to slow until the seventh decade of life. Intestinal absorption of calcium proceeds by two routes: a saturable, transcellular pathway, regulated almost exclusively by vitamin D, and a nonsaturable, paracellular pathway that is not subject to acute regulation. Attempts to overcome osteoporosis, or at least to slow the course of bone mineral decrease, have, for many years, utilized vitamin D, either by itself or together with calcium supplementation. Typically vitamin D supplementation of women with osteoporosis will increase calcium absorption and urinary calcium output, with no effect on the overall retention of calcium.

Objective: Lanthanum carbonate (Fosrenol®) is a non-calcium phosphate binder that controls hyperphosphataemia without increasing calcium intake above guideline targets. The biological fate and bone load of lanthanum were modelled with the aid of a four-compartment kinetic model, analogous to that of calcium. Methods: The model used data from healthy subjects who received intravenous lanthanum chloride or oral lanthanum carbonate, and bone lanthanum concentration data collected from dialysis patients during three long-term trials (up to 5 years). Results: Infusion of lanthanum chloride or ingestion of lanthanum carbonate led to a rapid rise in plasma lanthanum concentrations, followed by an exponential decrease. Comparison of oral and intravenous exposure confirmed that lanthanum is very poorly absorbed. On a typical intake of lanthanum (3000 mg/day as lanthanum carbonate), the rate of absorption was calculated as 2.2 μg/h, with a urinary excretion rate constant of 0.004—0.01 h−1. The faecal content of endogenous lanthanum was estimated to be 8- to 20-fold greater than that of urine, compared with a ratio of only about 1 for calcium. The model predicts that upon multiple dosing, plasma lanthanum concentrations rise rapidly to a near plateau and then increase by about 3% per year. However, this small change is obscured by the variability of the study data, which show that a plateau is rapidly attained by 2 weeks and is thereafter maintained for at least 2 years. The initial deposition rate of lanthanum in bone was 1 μg/g/year and, after 10 years of lanthanum carbonate treatment, the model predicts a 7-fold increase in total bone lanthanum (from 10 mg to 69 mg [from 1 μg/g wet weight to 6.6 μg/g wet weight]), with lanthanum cleared after cessation of treatment at 13% per year. The model indicates that lanthanum flow from bone surface to bone interior is much lower than that of calcium. Conclusion: Bone is the major reservoir for metals, but bone lanthanum concentrations are predicted to remain low after long-term treatment because of very poor intestinal absorption.

Calcium is absorbed in the mammalian small intestine by two general mechanisms: a transcellular active transport process, located largely in the duodenum and upper jejunum; and a paracellular, passive process that functions throughout the length of the intestine. The transcellular process involves three major steps: entry across the brush border, mediated by a molecular structure termed CaT1, intracellular diffusion, mediated largely by the cytosolic calcium-binding protein (calbindinD(9k) or CaBP); and extrusion, mediated largely by the CaATPase. Chyme travels down the intestinal lumen in approximately 3 h, spending only minutes in the duodenum, but over 2 h in the distal half of the small intestine. When calcium intake is low, transcellular calcium transport accounts for a substantial fraction of the absorbed calcium. When calcium intake is high, transcellular transport accounts for only a minor portion of the absorbed calcium, because of the short sojourn time and because CaT1 and CaBP, both rate-limiting, are downregulated when calcium intake is high. Biosynthesis of CaBP is fully and CaT1 function is approximately 90% vitamin D-dependent. At high calcium intakes CaT1 and CaBP are downregulated because 1,25(OH)(2)D(3), the active vitamin D metabolite, is downregulated.

The amount of calcium absorbed in the intestine depends on habitual calcium intake. When intake is low, active transcellular calcium transport in the duodenum is upregulated and a larger proportion of calcium is absorbed by the active process than by the passive paracellular process that prevails in the jejunum and ileum. Bioavailability of the calcium source-digestibility and solubilization-plays a role under conditions of low calcium intake but is relatively unimportant when calcium intakes are high (e.g. >800 mg/d in people). Vitamin D intake is a second factor, as active calcium transport is directly and proportionally dependent on the presence in the intestinal cell of calbindin D9k, the biosynthesis of which is totally vitamin D dependent. Passive absorption in jejunum and ileum is the major absorptive process when calcium intake is adequate or high. Passive calcium absorption is a complicated function of solubility in the distal small intestine, the length of sojourn of the chyme in a given intestinal segment, and the rate of paracellular diffusion from lumen to lymph and blood. Calcium that reaches the large intestine undergoes absorption there by both active and passive processes. Probably no more than 10% of total calcium absorption takes place in the large intestine, whether calcium intake is low or high. Calcium absorption by the large bowel can assume nutritional importance under conditions of significant small bowel resection.

Calcium and vitamin D deficiency impairs bone health and may cause rickets in children and osteomalacia in adults. Large animal models are useful to study experimental osteopathies and associated metabolic changes. We intended to modulate vitamin D status and induce nutritional osteomalacia in minipigs. The control group (n = 9) was fed a semisynthetic reference diet with 6 g calcium and 6,500 IU vitamin D3/kg and the experimental group (n = 10) the same diet but with only 2 g calcium/kg and without vitamin D. After 15 months, the deficient animals were in negative calcium balance, having lost bone mineral density significantly (means ± SEM) with −51.2 ± 14.7 mg/cm3 in contrast to controls (−2.3 ± 11.8 mg/cm3), whose calcium balance remained positive. Their osteoid surface was significantly higher, typical of osteomalacia. Their plasma 25(OH)D dropped significantly from 60.1 ± 11.4 nmol/L to 15.3 ± 3.4 nmol/L within 10 months, whereas that of the control group on the reference diet rose. Urinary phosphorus excretion and plasma 1,25-dihydroxyvitamin D concentrations were significantly higher and final plasma calcium significantly lower than in controls. We conclude that the minipig is a promising large animal model to induce nutritional osteomalacia and to study the time course of hypovitaminosis D and associated functional effects.

The experimentally determined rate of transcellular calcium transport in the duodenum of vitamin D-replete rats is nearly two orders of magnitude greater than expected from the rate of self-diffusion of the calcium ion in the cytosol. No transcellular calcium transport occurs in vitamin D-deficient animals. The excess diffusional flux can be explained by the presence in the duodenal mucosal cells of calbindin D 9k , a vitamin D-dependent cytosolic protein that binds two calcium ions per molecule, thereby increasing the cytosolic concentration of diffusible calcium. The relationship between the V max of transport and calbindin D 9k concentration is positive and linear, both in the steady state and after vitamin D administration, and is abolished on vitamin D deficiency. Transport and calbindin content are upregulated by a low calcium diet and downregulated by a high calcium diet. In contrast, the paracellular pathway is non-saturable and directly proportional to the luminal calcium ion concentration. Thus, the rate of calcium transport across the intestinal cell is essentially determined by the rate of calcium movement through the cytosol, catalyzed by the cytosolic calcium binding protein, calbindin D 9k , rather than by membrane transport. An intracellular binding protein is likely to be the molecular mechanism when the transcellular movement of an ion exceeds its self-diffusion rate.

To determine whether calbindin D9k (CaBP) is subject to posttranscriptional control, 6-wk-old Sprague Dawley-derived rats were fed one of three purified diets, 1.5% Ca and 3.0% Ca, mostly as carbonate, and 2.9% Ca, mostly as gluconate. Two weeks later, 5-cm segments of duodenum, jejunum, ileum, cecum and colon were obtained and analyzed for CaBP and CaBP-mRNA. Analysis of the steady-state distribution of CaBP-mRNA and of CaBP revealed a statistically significant (r = 0.95; P < 0.01) linear relationship between CaBP-mRNA and CaBP. When, however, animals that had been fed the 1.5% Ca diet received by intrajugular injection 1.2 nmol 1,25-dihydroxycholecalciferol [1.25-(OH)2-D3] and their CaBP-mRNA and CaBP were analyzed as a function of time after 1,25-(OH)2-D3 administration, the kinetic response of the two molecules differed. The CaBP-mRNA increased linearly by approximately 68% for 4 h after administration and then declined over the next 6 h to a concentration below the preinjection value. Thus, appearance and disappearance of CaBP-mRNA approximated 17% x h(-1). The CaBP, however, increased steeply to 80% above preinjection concentration until 2 h postinjection, i.e., at a rate of 40% x h(-1). Thereafter, CaBP decreased to 35% above the preinjection value between 5 and 10 h postinjection (2.5% x h(-1)). These findings are consistent with a 1,25-(OH)2-D3-mediated posttranscriptional regulation of CaBP concentrations, because the 1,25-(OH)2-D3-mediated increase in CaBP-mRNA is not reflected in an immediately changed CaBP level.

Parathyroid Hormone and Parathyroid Hormone-Related Protein: Normal Function, Diseases, and Emerging Therapeutics.- Vitamin D: Normal Function, Metabolism, Diseases, and Emerging Therapeutics.- Gonadal Hormones, Diseases, and Emerging Therapeutics.- Thyroid and Thyroid Hormone: Normal Function, Diseases, Disorders, Emerging Therapeutics.- Pituitary Hormones and the Pathophysiology of Osteoporosis.- Calcitonin: Its Physiological Role and Emerging Therapeutics.- Glucocorticoids, Inflammation and Bone.- Diseases of Energy and Lipid Metabolism and Bone: Emerging Therapeutics.- Diseases of Mineral Metabolism and Bone: Emerging Therapeutics for Postmenopausal Osteoporosis.- Renal Diseases and Bone: Emerging Therapeutics.- Wasting Diseases and Metabolic Impact on Bone: Emerging Therapeutics and Treatment Options.- Paget's Disease of Bone: Pathogenesis and Treatment.- Bone Loss in Space Flight and Countermeasures.- Osteoimmunology: Relation to Disease and Therapy.- Bone and the Ear.- Bone and the cAMP Signaling Pathway: Emerging Therapeutics.- Nervous System Diseases, Disorders and Bone: Emerging Therapeutics and Treatment Options.

Skeletal size and mass are genetically programmed. Optimum skeletal size can be attained if the nutrient supply, ie, calcium, is ample, but the age-dependent decrease in skeletal mass that begins in the third decade cannot be arrested by adequate calcium intake alone. The decrease in skeletal mass is primarily caused by the age-dependent decrease in gonadal hormones. The dramatic drop in hormones in menopause is associated with a sharp decrease in trabecular bone and a slower decrease in cortical bone. In men this decrease is gradual. Replacement therapy with gonadal hormones can markedly slow this decrease in bone mass, provided calcium intake is adequate. Soluble forms of calcium are preferred to ensure adequate calcium absorption. Vitamin D supplementation beyond the recommended dietary allowance does not appear beneficial in osteoporosis, but may be so in cases of senile hyperparathyroidism. Calculations based on bone calcium turnover indicate that the recommended dietary allowance for calcium is adequate for boys and men, but is insufficient for adolescent girls. Calcium intake by women is probably too low to slow bone calcium turnover to its programmed minimum. Adequate calcium intake in childhood and adolescence is essential to attain the optimal bone mass and size.

The calcium metabolism of 13 very-low-birth-weight infants fed a high-calcium diet was evaluated by means of stable isotope kinetic and balance studies. The studies used orally and i.v. administered stable isotopes, and the kinetic data were evaluated with the aid of a sequential, three-compartment model. The infants (postmenstrual age 33 ± 1 wk, weight 1.34 ± 0.03 kg) had higher bone calcium deposition rates (160 ± 7 mg·kg−1.d−1 or 4.00 ± 0.18 mmol·kg−1·d−1) than those previously reported for either older children or adults. Furthermore, when analyzed as a function of net calcium absorption, bone calcium deposition rates increased markedly and significantly as net calcium absorption increased (r = 0.70, p < 0.01), whereas in older individuals, bone calcium deposition is a relatively invariant function of absorption. A relatively smaller response of bone calcium removal to calcium absorption was found for the very-low-birth-weight infants in this study (r = −0.39, p = 0.18), whereas in adults, bone calcium removal constitutes the major regulatory response. It is suggested that the calcium kinetic results in the very-low-birth-weight infants reflect the high rate of bone growth typical of the third trimester of gestation.

Epigenetic aspects of chronic diseases , Epigenetic aspects of chronic diseases , کتابخانه دیجیتال جندی شاپور اهواز

The term "bioavailability" attempts to include in a single concept the effect of a sequence of metabolic events, i.e., digestibility, solubilization, absorption, organ uptake and release, enzymatic transformation, secretion and excretion. Each of these events is difficult to measure experimentally, and, with the possible exception of digestibility and solubilization, all are age-dependent and subject to nutritional and hormonal controls. In the case of calcium, the body's demand increases and then decreases with age; it also increases with pregnancy and lactation. Age, pregnancy and lactation each affect the regulatable component of the intestinal absorption of calcium. The passive component of calcium absorption is a function of the amount of calcium solubilized and of intestinal transit time. Inasmuch as digestibility and solubilization of calcium are very difficult to determine separately, even a reliable measure of calcium absorption includes a measure of uncertainty. If one wishes to include in the term "calcium bioavailability" rates of net deposition in bone, as well as rates of excretion from the body, quantitative information on calcium pool size, turnover and the effects thereon of age, sex, endocrine and nutritional status are needed. In the case of other nutrients, rates of enzymatic transformation and organ utilization need also to be taken into account. It will therefore require major research programs before the term "bioavailability" of a nutrient can become a quantitative concept useful for clinical, nutritional or managerial evaluation and counseling.

Genetic and Epigenetic Aspects of Bone Development.- Tissue Interactions in Long Bone Development.- The Epiphyseal Growth Plate.- Hedgehog Signaling in Growth Plate and Bone Development.- Role of microRNA in Skeleton Development.- FGF/FGFR Signaling in Skeletal Dysplasias.- The Role of Hypoxia-Induced Factors.- BMP Signaling in Skeletogenesis.- Wnt Signaling in Bone Development.- Development of the Craniofacial Complex.- Dentin and Bone: Similar Collagenous Mineralized Tissues.- Evolution of Bone Proteins.- Osteogenesis Imperfecta.- Fibrodysplasia Ossificans Progressiva: Developmental Implications of a Novel Metamorphogene.- Bone-Mineral Homeostasis and Associated Pathologies.- Interrelationship Between Bone and Other Tissues: Brain-Bone Axis and Bone-Adipo Axis.- Mechanobiology of Bone Development and Computational Simulations.

Net calcium absorption was evaluated in 103 low-birth-weight preterm infants by a 72-h balance technique. At birth the infants had a mean (+/- SE) gestational age of 30.9 +/- 0.2 wk and weighed 1.43 +/- 0.03 kg. When tested 3 wk later, their net calcium absorption averaged 58 +/- 1% with an intake of 80 +/- 2 mg Ca.kg body wt-1.d-1. Of the 103 infants, 58 had been fed low-birth-weight formulas supplemented with vitamin D. The remainder received banked human milk, of whom 34 were supplemented with vitamin D and calcium; 11 infants received no supplementation. Calcium absorption in the four subgroups did not differ significantly, with neither vitamin D supplementation nor supplementation with vitamin D and calcium affecting percent absorption significantly. Net calcium absorption was a linear function of intake (40-130 mg Ca.kg body wt-1.d-1) with a zero intercept. Because vitamin D supplementation did not increase net calcium absorption, it is concluded that in preterm low-birth-weight infants calcium absorption proceeds by a nonsaturable route, with the transcellular, vitamin D-regulated mechanism not yet expressed.

Calcium absorption proceeds by transcellular and paracellular flux, with the latter accounting for most absorbed calcium when calcium intake is adequate. Vitamin D helps regulate transcellular calcium transport by increasing calcium uptake via a luminal calcium channel and by inducing the cytosolic calcium transporting protein, calbindinD(9k). Recent studies utilizing knockout mice have challenged the functional importance of the channel and calbindin. To integrate the new findings with many previous studies, the function of the two molecules must be evaluated in the calcium transport and economy of mice. When calcium intake is high, transcellular calcium transport contributes little to total calcium absorption. Therefore, increasing calcium intake seems the most effective nutritional approach to ensure adequate absorption and prevent bone loss.

The Pathogenesis of Osteoarthritis.- The Role of Bone in the Development of Osteoarthritis.- Cytokines, Growth Factors, and Bone-Derived Factors in Cartilage.- The Synovium and Its Role in Osteoarthritis.- Cartilage Matrix Destruction.- Anabolic Mediators of Cartilage Healing.- Chondrocyte Hypertrophy and Apoptosis at the Cartilage-Bone Interface.- Genetic and Epigenetic Aspects of Osteoarthritis.- Animal Models.- Biomechanical Aspects: Joint Injury and Osteoarthritis.- Novel Osteoarthritis Therapeutics.

Objective To investigate whether the abnormal expression of matrix metalloproteinases (MMPs) 3, 9, and 13 and ADAMTS-4 by human osteoarthritic (OA) chondrocytes is associated with epigenetic “unsilencing.” Methods Cartilage was obtained from the femoral heads of 16 patients with OA and 10 control patients with femoral neck fracture. Chondrocytes with abnormal enzyme expression were immunolocalized. DNA was extracted, and the methylation status of the promoter regions of MMPs 3, 9, and 13 and ADAMTS-4 was analyzed with methylation-sensitive restriction enzymes, followed by polymerase chain reaction amplification. Results Very few chondrocytes from control cartilage expressed the degrading enzymes, whereas all clonal chondrocytes from late-stage OA cartilage were immunopositive. The overall percentage of nonmethylated sites was increased in OA patients (48.6%) compared with controls (20.1%): 20% versus 4% for MMP-13, 81% versus 47% for MMP-9, 57% versus 30% for MMP-3, and 48% versus 0% for ADAMTS-4. Not all CpG sites were equally susceptible to loss of methylation. Some sites were uniformly methylated, whereas in others, methylation was generally absent. For each enzyme, there was 1 specific CpG site where the demethylation in OA patients was significantly higher than that in controls: at −110 for MMP-13, −36 for MMP-9, −635 for MMP-3, and −753 for ADAMTS-4. Conclusion This study provides the first evidence that altered synthesis of cartilage-degrading enzymes by late-stage OA chondrocytes may have resulted from epigenetic changes in the methylation status of CpG sites in the promoter regions of these enzymes. These changes, which are clonally transmitted to daughter cells, may contribute to the development of OA.

CHRONIC CONDITIONS: CHILDHOOD OBESITY, Rebecka Peebles and Lawrence D. Hammer MEDICAL WEIGHT CONTROL IN THE ADULT PATIENT, Jeanette Newton Keith and Lori Rowell ADULT OBESITY, WITH SPECIAL REFERENCE TO BARIATRIC SURGERY, Nitya Srinivasan Sharma, Annamaria Calleo-Cross, and Louis J. Aronne NUTRITIONAL MANAGEMENT OF THE ELDERLY, Lorraine S. Young and Caroline M. Apovian FOOD ALLERGY, Abba I. Terr NUTRITIONAL CONSIDERATIONS IN THE MANAGEMENT OF PREGNANCY AND LACTATION, Michelle G. Brenner and Jatinder Bhatia FACILITATING PATIENT BEHAVIOR CHANGE IN CLINICAL NUTRITIONAL MANAGEMENT, Richard K. Fleming, Carol Curtin, and Linda Bandini SPECIFIC DISEASE CONDITONS: GENETIC DISEASES AND ERRORS OF METABOLISM, Kimberlee Michals Matalon and Reuben Matalon MALNUTRITION AND THE IMMUNE SYSTEM, R. K. Chandra NUTRITIONAL AND DIETARY CONSIDERATIONS IN MANAGEMENT OF CHRONIC ORAL DISEASES, Jason M. Tanzer and Jill Livingston DERMATOLOGY AND NUTRITION, Meagen M. McCusker, Constance J. Marcy, Marti J. Rothe, and Jane M. Grant-Kels NUTRITIONAL MANAGEMENT IN THE PATIENT AND WITH AN UPPER GASTROINTESTINAL CANCER, Marcus Ferrone and James S. Scolapio NUTRITIONAL MANAGEMENT OF CACHEXIA OF CHRONIC ILLNESS, David Frankenfield and J. Stanley Smith INDEX

Calcium absorption, in terms of mechanisms and function, is well adapted to meet the calcium needs of mammals. When calcium levels in the food are low, the active, mediated transcellular calcium transport assumes primary importance. This process is vitamin D-dependent, largely localized in the duodenum, and involves three steps: entry across the brush border, mediated by a molecular structure, CaT1, with two components; a facilitated transport that saturates at low luminal calcium concentration; and a channel component through which most calcium enters the cell at the higher luminal concentrations. Intracellular diffusion is assured by a small, cytosolic calcium binding molecule, calbindinD(9k), which carries more than 90% of the calcium that traverses the duodenal cell, thus also serving as a buffer. Extrusion is by the CaATPase and is not a limiting step. Calcium entry is reduced by more than 90% in the absence of vitamin D, with biosynthesis of calbindinD(9k) totally vitamin D-dependent. Active transport is upregulated on low calcium intake and downregulated at high calcium intake, when paracellular calcium transport through the tight junctions of the intestine becomes the dominant process. The amount of calcium absorbed paracellularly is a function of the calcium gradient between lumen and plasma and of the time the chyme spends at a given intestinal site. The coexistence of mediated and nonmediated transport processes assures the organism of an adequate calcium supply, yet prevents excessive calcium absorption.

An adequate calcium intake throughout life is essential for maintenance of the skeleton, by far the largest body reservoir of calcium. Appropriately high calcium intake is particularly important in the first two decades, when the body calcium mass increases to near maximum. In subsequent decades, because calcium absorption is relatively modest, typically 25% or less, calcium intake must be kept near 1000 mg per day in order to minimize the possibility that the skeleton will be mined for its mineral content. The amount of calcium needed for signaling and to maintain the extracellular calcium constant is relatively small; however, skeletal turnover is enhanced in calcium deficiency, the increased turnover representing the body's attempt to preserve skeletal calcium.

Calcium is absorbed in the mammalian small intestine by two general mechanisms: a transcellular active transport process, located largely in the duodenum and upper jejunum; and a paracellular, passive process that functions throughout the length of the intestine. The transcellular process involves three major steps: entry across the brush border, mediated by a molecular structure termed CaT1, intracellular diffusion, mediated largely by the cytosolic calcium-binding protein (calbindinD(9k) or CaBP); and extrusion, mediated largely by the CaATPase. Chyme travels down the intestinal lumen in approximately 3 h, spending only minutes in the duodenum, but over 2 h in the distal half of the small intestine. When calcium intake is low, transcellular calcium transport accounts for a substantial fraction of the absorbed calcium. When calcium intake is high, transcellular transport accounts for only a minor portion of the absorbed calcium, because of the short sojourn time and because CaT1 and CaBP, both rate-limiting, are downregulated when calcium intake is high. Biosynthesis of CaBP is fully and CaT1 function is approximately 90% vitamin D-dependent. At high calcium intakes CaT1 and CaBP are downregulated because 1,25(OH)(2)D(3), the active vitamin D metabolite, is downregulated.

Nutritional Support in Children, C. J. Valentine, I. J. Griffin, and S. A. Abrams Nutrition and Cardiovascular Health, T. A. Kotchen, and J. Morley Kotchen Nutritional Support in Chronic Diseases of the Gastrointestinal Tract and the Liver, K. P. Navder and C. S. Lieber Nutritional Therapy of Impaired Glucose Tolerance and Diabetes Mellitus, H. G. Preuss and D. Bagchi Nutritional Management of Metabolic Disorders, V. Utermohlen Nutritional Support and Management of Skeletal Diseases, M.J. Favus, T. O. Utset, and C. Lee Nutritional Support and Management of Renal Disorders, T. A. Ikizler Nutrition and Vision, J. R. Trevithick and K. P. Mitton Nutritional Assessment and Management of the Cancer Patient, J. B. Mason and S.W. Choi Nutritional Aspects of Trauma and Postsurgical Care, J. S. Smith and W. W. Souba Nutritional Management of Immunocompromised Patients, with Emphasis on HIV and AIDS, S. B. Richter, S. S. Teuber, and M. E. Gershwin Food Intake Management in Patients with Psychiatric Disorders, A. R. Lucas, D. L. Olson, and F. K.Olson Nutrition and Alcoholism, Khursheed P. Navder, and C. S. Lieber Index

Publisher Summary This chapter focuses on the various metals present in the bones and discusses their possible effects. Aluminium accumulation in bone increases as the plasma concentration increases, whether due to increased intake, as in dialysis with liquids that contain Al, or under conditions of decreased capacity for excretion, as in renal osteodystrophy. Bone accumulation of Al can also increase when turnover is diminished, as in diabetes mellitus. As aluminum accumulates in the skeleton, it inhibits mineralization and acts on bone cells. Cadmium (Cd) intoxication, whether acute or chronic, is principally the result of heavy metal mining for lead, zinc, or copper, with Cd often not being the object of the mining process, but constituting a contaminant. Cd causes changes in cell morphology and causes a decrease in osteoblast and osteoclast number and in alkaline phosphatase activity, all of which are likely to contribute to diminished collagen production and impaired mineralization. A second indirect effect of Cd is the acceleration of bone turnover, particularly bone resorption, which can be a result of the induced calcium deficiency. The element chromium (Cr) belongs to the first series of the transition elements and occurs in several oxidation states and Cr deficiency or Cr excess may lead to bone changes. When Pb is ingested, it largely follows the routes of calcium. As it binds to calbindin in the duodenum, vitamin D enhances Pb absorption. High bone Pb levels are associated with attention deficit, aggression, and delinquency, which follows a developmental course.

Employing realistic parameters, we have demonstrated that a relatively simple mathematical model can reproduce key features of steady-state Ca2+transport with the assumption of two mechanisms of Ca2+entry: a channel-like flux and a carrier-mediated transport. At low luminal [Ca2+] (1–5 mM), facilitated entry dominates and saturates with Km= 0.4 mM. At luminal [Ca2+] of tens of millimolar, apical permeability is dominated by the channel flux that in turn is regulated by cytosolic Ca2+. The model reproduces the linear relationship between maximum Ca2+transport rate and intestinal calbindin D9K(CaBP) content. At luminal [Ca2+] > 50 mM, local sensitivity analysis shows transcellular transport to be most sensitive to variations in CaBP. At low luminal [Ca2+], transport becomes sensitive to apical entry regulation. The simulations have been run within the Virtual Cell modeling environment, yielding the time course of external Ca2+and spatiotemporal distributions of both intracellular Ca2+and CaBP. Coexistence of two apical entry mechanisms accords with the properties of the duodenal Ca2+transport protein CaT1 and the epithelial Ca2+channel ECaC.

The addition of 92 or 136 mM mannitol to a modified saline solution that contained 1.25 mM Ca 2+ led to a mannitol concentration-dependent increase in the amount of calcium absor- bed in 1 h from 8 cm long ileal loops prepared from fasted male Sprague-Dawley rats, with body weights of 190 ∠ 10 g. It is argued that this mannitol-enhanced movement of calcium out of the loop cannot have utilized the paracellular pathway, inasmuch as the luminal calcium concentration of the mannitol instillate decreased during the experiment, with a negative calcium gradient between lumi- nal and body fluids. Instead it is proposed that uncomplexed mannitol and the uncharged calcium com- plex of mannitol entered the ileal cells. The uncomplexed intracellular mannitol would bind additional calcium that had crossed the brush border down its gradient. The increase in total intracellular calcium will raise the effective intracellular gradient and thereby amplify intracellular calcium diffusion. This in turn increases calcium absorption. intestine / mannitol / paracellular calcium movement / transcellular calcium diffusion

The major components of calcium metabolism, as evaluated by a dual-tracer stable isotope method, were determined in 100 studies of 68 healthy girls, aged 5-18 y and analyzed from a developmental and regulatory viewpoint. Bone calcium deposition and removal rates were closely correlated with the size of the exchangeable bone calcium compartment. All three quantities, as well as intestinal calcium absorption, peaked at or near menarche. Both bone calcium deposition and removal rates were positively and linearly correlated with calcium absorption. However, in this correlation, because bone calcium deposition increased 70% faster than calcium absorption, most of the increase in the bone calcium compartment and its turnover must have occurred in response to something other than intestinal calcium input; presumably this occurred in response to developmental signals. Nevertheless, the constancy of the serum calcium in the face of a large intestinal calcium input and the modest way in which excretion overcame the calcium load in this population point to the importance of the exchangeable bone calcium compartment, in dynamic equilibrium with the bone mineral, as the site at which most of the load is taken up. In this population of girls, as in older women, this increase in the skeletal calcium balance resulted from a decrease in the bone calcium removal rate that was greater than the corresponding increase in the bone calcium deposition rate.

Intestinal calcium absorption proceeds by two mechanisms, an active transcellular process that takes place in the duodenum and a passive paracellular process throughout the small intestine. This article characterizes the three steps of transcellular calcium movement-entry, intracellular diffusion and extrusion-and identifies conditions that must be satisfied for other mineral ions to move transcellularly as part of a transepithelial transport process. Passive calcium movement is down a chemical gradient with the amount absorbed by this pathway determined in large measure by the sojourn time, most of which is spent in the ileum. Because transcellular movement of most mineral ions other than calcium, where measured, is either small or negligible, passive transport is likely to be the major route of intestinal absorption, the nature of which, however, has not been well established experimentally.

To investigate the nonsaturable, paracellular pathway of intestinal Ca absorption, the luminal contents of 12-cm segments of the intestine of 8-wk-old male Sprague-Dawley rats were analyzed for pH, sojourn time and soluble and insoluble Ca over a 24-h period. The rats had been fed one of two high Ca diets for 2 wk : 1.5% Ca (diet group 3a) and 3.1% (diet group 5a). The pH of the small intestine increased from 8.0 from duodenum to ileum ; transit time increased from 2.5 min in the duodenum to 58 min in the distal ileum, with the entire ileum accounting on the average for 74% of the transit time of 3 h. The amount of Ca solubilized throughout the intestine was 32 ± 3.3 μmol in diet group 3a and 53 ± 5.3 μmol in diet group 5a, i.e., 2.7% and 2.0% of the total luminal Ca. Because absorption by diet group 3a was 1.45 ± 0.23 mmol/d and that by diet group 5a was 2.50 ± 0.18 mmol/d, the amounts absorbed were 45.3 and 47.1 times greater than present in the lumen in soluble form at any one time. Thus, over a 24-h period, an average of 3.2% (46.2/1440) of the soluble Ca present in the lumen at any time was absorbed per min. Calculations involving the gradient between luminal and plasma Ca show that the rate of Ca diffusion from lumen to blood is

This article proposes a novel model of calcium homeostasis, based on the concept of a series of bone calcium-binding sites of varying calcium affinities. When an i.v. Ca load is administered to mammals, it is rapidly (t1/2 < 1 min) dispersed into a volume equivalent to the extracellular fluid. Thereafter the calcium concentration drops monoexponentially with a t1/2 of tens of minutes. When a negative Ca load is administered, as by EDTA injection, the return to the preinjection plasma Ca level, [Cas], occurs also mono-exponentially at the same rate as restoration after a positive load. The numerical value of the rate can be arrived at by taking into account the fraction of cardiac output (5%) that is directed to the skeleton. Acute regulation is brought about by controlling access to subpopulations of the Ca binding sites, whose average Km determines [Cas]. Osteoblasts, when active and extended, block low-affinity binding sites; osteoclasts, when active and extended, block high-affinity sites. Exposure of sites is brought about when bone cells respond by rapid shape changes, osteoblasts rounding up in response to parathyroid hormone (PTH) or vitamin D, osteoclasts rounding up in response to calcitonin. These shape changes are the first steps in the cascade of events that lead to bone formation and resorption, but acute regulation need not involve the latter steps of a cascade. The model accounts for the changes in the response times to Ca loads that have been observed in older animals or those deprived of PTH, calcitonin or vitamin D.

A new model of calcium (Ca) homeostasis is proposed. It is based on the kinetics of restoration of the plasma Ca level following positive or negative Ca loads in animals of different endocrine status. As others, we can account for the kinetics of plasma Ca restoration as being the result of a very rapid dilution of Ca into extracellular water (t1/2 less than 1 minute) and an uptake or release by bone (t1/2 = 14-80 minutes) that occurs as the fraction of cardiac output directed to bone is partially cleared of or repleted with Ca. In this model, bone surfaces have Ca-binding sites that demonstrate a range of affinities and whose average Km determines the plasma Ca level. Acute regulation is brought about by controlling access to subpopulations of Ca binding sites in bone, comprising the extremes of high and low affinity. Osteoblasts, when active and extended, block the low affinity sites, and osteoclasts, when active and extended, block the high affinity sites. Exposure of low- or high-affinity sites is brought about when these cells respond to hormonal signals by contraction, parathyroid hormone (PTH), and vitamin D leading to osteoblast, and calcitonin to osteoclast, contraction. These reciprocal cell shape changes are the first in a cascade of metabolic events that lead to bone formation and resorption, as well as changes in the number or affinity of the binding sites. The model also accounts for the prolongation of the response time to Ca loads in animals deprived of PTH, calcitonin, or vitamin D.

Publisher Summary This chapter discusses mechanisms by which cells transport calcium and modify calcium fluxes in the body. The major chemical functions that are dependent on calcium include: nerve excitation, muscle contraction, extrusion, and export processes. The level and regulation of the calcium content of body fluids involves millimolar concentrations. Food calcium may undergo solubilization and dilution with bile and intestinal fluids; calcium concentrations in the chyme can reach tens of millimoles. Thus, the body's calcium traffic—ingestion, digestion, absorption, plasma-calcium maintenance, cellular uptake and release, bone-calcium deposition and removal, i.e., resorption, urinary and fecal-calcium excretion—involves an unending manipulation of various calcium concentrations, as well as changes in state from liquid to solid and back to liquid. In the balance approach, the amount of calcium excreted in the stool is subtracted from the amount ingested during a comparable period. This is termed “net absorption.” The net amount of calcium absorbed represents the net load of calcium from the intestine. By using radioactive or stable isotopes of calcium, along with a balance procedure, one of the streams of calcium in the intestine can be labeled—either the endogenous or the food calcium—and thereby the true amount absorbed and the quantity of endogenous calcium lost in the stool can be quantitated.