Calcium

Calcium, a trace mineral plays an important role in build and maintain strong bones and teeth, found abundantly in meat, poultry, fish,  nut, seeds, bean, etc. As we age, calcium is absorbed less effectively.

1.  Osteoporosis: vitamin D and calcium
Osteoporosis is a bone disease that predisposes to fractures. Sufficient intake of calcium and vitamin D is recommended for prevention and treatment. According to the study of 28,406 respondents aged 50 or older to the 2009 Canadian Community Health Survey (CCHS)--Healthy Aging, found that
In 2009, 19.2% of women and 3.4% of men aged 50 or older reported having been diagnosed with osteoporosis; the 2004 rates were similar. Age, sex and household income were associated with the probability of reporting osteoporosis. In 2004, based on dietary and supplement intake, 45% to 69% of the population aged 50 or older had inadequate intake of calcium, and 54% to 66% had inadequate intake of vitamin D(1).

2. Vitamin D3, calcium and reduced risk of fractures and falls
According to the study by the research team of Dr. Cranney A, in most trials, the effects of vitamin D and calcium could not be separated. Vitamin D(3) (>700 IU/day) with calcium supplementation compared to placebo has a small beneficial effect on BMD, and reduces the risk of fractures and falls although benefit may be confined to specific subgroups. Vitamin D intake above current dietary reference intakes was not reported to be associated with an increased risk of adverse events. However, most trials of higher doses of vitamin D were not adequately designed to assess long-term harms(2).

3. Vitamin D, calcium and the importance of other vitamins
Osteoporosis is a major health disorder associated with an increased risk of fracture. Nutrition is among the modifiable factors that influence the risk of osteoporosis and fracture. Calcium and vitamin D play important roles in improving bone mineral density and reducing the risk of fracture. According to the study by American University of Beirut, deficiencies in vitamins C, E, and K are also associated with compromised bone health; this effect may be modified by smoking, estrogen use or hormonal therapy after menopause, calcium intake, and vitamin D(3).

4. Calcium, dairy products, and bone health in children and young adults
In the review of Medline (National Library of Medicine, Bethesda, MD) search conducted for studies published on the relationship between milk, dairy products, or calcium intake and bone mineralization or fracture risk in children and young adults (1-25 years) yielded 58 studies: 22 cross-sectional studies; 13 retrospective studies; 10 longitudinal prospective studies; and 13 randomized, controlled trials found to ne supported of nutrition guidelines focused specifically on increasing milk or other dairy product intake for promoting child and adolescent bone mineralization(4).

5. The dosage of calcium and life style risks
 According to the study by Aarhus University, secondary hyperparathyroidism caused by calcium and vitamin D insufficiency may reduce bone mass and strength and increase fracture risk and should be avoided. Since calcium supplementation has been associated with an increased risk of cardiovascular complications and renal stones, the dose should be tailored to the habitual daily calcium intake. Lifestyle-related risk factors (smoking, alcohol consumption, lack of physical activity and low body weight) should be addressed. The antifracture efficacy of antiresorptive and anabolic treatment for osteoporosis has not been documented in larger randomized controlled studies(5).

6.  Calcium and Physiology and cell biology of acupuncture
In the article presenting a novel model of acupuncture physiology based on cellular calcium activation by an acoustic shear wave (ASW) generated by the mechanical movement of the needle with an acupuncture needle was driven by a piezoelectric transducer at 100 Hz or below, showed that the cell level, the ASW activated intracellular Ca(2+) transients and oscillations in fibroblasts and endothelial, ventricular myocytes and neuronal PC-12 cells along with frequency-amplitude tuning and memory capabilities. In contrast with traditional acupuncture models, the signal source is derived from the total acoustic energy. ASW signaling makes use of the anisotropy of elasticity of tissues as its waveguides for transmission and that cell activation is not based on the nervous system(6).

7. Calcium and cell physiology
According to the study by the University of Florida,  in excitable cells, the coordination of changing Ca(2+) concentrations at global (cellular) and well-defined subcellular spaces through the course of membrane depolarization can now be conceptualized in the context of disease processes such as cardiac arrhythmogenesis. The spatial and temporal dimensions of Ca(2+) signaling are similarly important in non-excitable cells, such as endothelial and epithelial cells, to regulate multiple signaling pathways that participate in organ homeostasis as well as cellular organization and essential secretory processes(7).

8. Calcium and S100 proteins
S100 proteins play a crucial role in multiple important biological processes in vertebrate organisms acting predominantly as calcium signal transmitters.According to the study by the Polish Academy of Sciences, after four Ca(2+) ions bind, it undergoes a dramatic conformational change, resulting in exposure, in each of its two identical subunits, a large hydrophobic cleft that binds to target proteins. It has been shown that abnormal expression of S100A1 is strongly correlated with a number of severe human diseases: cardiomyopathy and neurodegenerative disorders(8).

9. Calcium and aluminum salt
Most humans living in industrialized societies are routinely exposed to bioavailable aluminum salts in the form of additives-in commercially-prepared foods, alum-clarified drinking water, certain pharmaceuticals, sunscreens, and other topical applications. Minute amounts of this aluminum are absorbed into the circulation. Trace aluminum levels cross the blood-brain barrier and progressively accumulate in large pyramidal neurons of the hippocampus, cortex, and other brain regions vulnerable in Alzheimer's disease. According to the study by the St George Hospital Campus,  intraneuronal aluminum interferes with Ca2+ metabolism in the aged brain and describes a way to test this hypothesis. This paper reviews: 1) major changes that occur in brain Ca2+ homeostasis and Ca2+ signaling, subtly with aging and more overtly in Alzheimer's disease; and 2) evidence from the scientific literature that aluminum causes these same changes in neurons(9).

10. calcium and aluminum in Neurodegenerative disorders
Both calcium and aluminum have been implicated in the cell damage and death that occurs in several neurodegenerative disorders including Alzheimer's disease (AD). In the study to examine the effects of experimentally elevated intraneuronal levels of aluminum ([Al]i) and/or calcium ([Ca2+]i) on neuronal degeneration and antigenic alterations in the microtubule-associated protein tau in cell cultures of rat hippocampus and human cerebral cortex, showed that Exposure of cultures to Al3+ alone (200 microM) for up to 6 d did not result in neuronal degeneration. Neurons exposed to the divalent cation ionophore A23187 degenerated within 4 h when Ca2+ was present in the culture medium whether or not Al3+ was present. Measurements of [Ca2+]i using the calcium indicator dye fura-2 demonstrated a direct relationship between increased [Ca2+]i and neuronal degeneration. In contrast, neurons did not degenerate when exposed to A23187 in the presence of Al3+ and the absence of Ca2+, despite a 10-fold elevation in [Al]i as measured by laser microprobe mass spectrometry. Calcium influx, but not aluminum influx, elicited antigenic changes in tau similar to those seen in AD neurofibrillary tangles. Neurons exposed to glutamate in the presence of Al3+ but in the absence of Ca2+ were not vulnerable to injury. Finally, increased [Al]i occurred in neurons that degenerated as the result of exposure to glutamate indicating that aluminum associates with degenerating neurons(10).

11. Neuronal calcium homeostasis in the aging nervous system
Maintenance of the cellular calcium homeostasis plays an important role for neuronal cell function and interneuronal cell to cell communication. Therefore, alterations of the neuronal Ca2+ homeostasis may play a crucial role for brain aging in general and for age-related deficits in cognitive functions particularly.
Numerous studies indicate various disturbances of the Ca2+ homeostasis on different levels like Ca2+ channel properties, 45Ca2+ uptake, or Ca2+ binding proteins. Investigations on alterations of the free intracellular calcium concentration ([Ca2+]i) in presynaptic synaptosomal preparations led to inconsistent results reporting increased or unchanged [Ca2+]i in aged animals, according to the Central Institute of Mental Health, Dept. Psychopharmacology(11).

12. Disruption of calcium homeostasis and Alzheimer's disease (AD)
Oligomerization, conformational changes, and the consequent neurodegeneration of Alzheimer's β-amyloid protein (AβP) play crucial roles in the pathogenesis of Alzheimer's disease (AD). Mounting evidence suggests that oligomeric AβPs cause the disruption of calcium homeostasis, eventually leading to neuronal death, according to the School of Pharmaceutical Sciences, Kyushu University of Health and Welfare(12).

13. BK Channels in Cardiovascular Diseases and Aging
Aging is a major risk factor for cardiovascular diseases, one of the main world-wide causes of death. Several structural and functional changes occur in the cardiovascular system during the aging process and the mechanisms. BK channels are transmembrane proteins that play a key role in many physiological processes, including regulation of vascular tone.In vascular smooth muscle cells, BK opening and the consequent efflux of potassium (K(+)) leads to membrane hyperpolarization, which is followed by the closure of voltage-dependent Ca(2+) channels, reduction of Ca(2+) entry and vasodilatation. BK regulates nitric oxide-mediated vasodilatation and thus is crucial for normal endothelial function(13).

14. Ca(2+) waves regulate blood vessel tone and vasomotion
Agonist-stimulated smooth muscle Ca(2+) waves regulate blood vessel tone and vasomotion.The Pharmacology, and Therapeutics, University of British Columbia, present a first report of endothelin-1 stimulated waves of Ca(2+) depletion from the sarcoplasmic reticulum of vascular smooth muscle cells using a calsequestrin-targeted Ca(2+) indicator and confirmed that these waves are due to regenerative Ca(2+)-induced Ca(2+) release by the receptors for inositol 1,4,5-trisphosphate(14).

15. Calcium ion channel blockers on sperm fertilization
In the stduy to evaluate the effects of calcium ion (Ca2+) channel blockers on male fertility potential, showed that therapeutic administrations of calcium antagonists for hypertension control cause reversible male infertility associated with an IVF failure. A mechanism of inhibition of sperm fertilizing potential through insertion of lipophilic calcium ion antagonists into the lipid bilayer of the sperm plasma membrane is consistent with our in vitro studies(15).

16. Ca(2+)and enzymes
The processes of excitation-contraction (EC) coupling consume large amounts of energy that need to be replenished by oxidative phosphorylation in mitochondria. Since Ca(2+) activates key enzymes of the Krebs cycle in the mitochondrial matrix, it is important to understand the mechanisms and kinetics of mitochondrial Ca(2+) uptake to delineate how in cardiac myocytes, energy supply is efficiently matched to demand. According to the study by Universitätsklinikum des Saarlandes, defects in EC coupling that occur in heart failure disrupt SR-mitochondrial Ca(2+) crosstalk and may cause energetic deficit and oxidative stress, both factors that are thought to be causally involved in the initiation and progression of the disease(16).

17. Calcium and blood clotting
In the study of corn-soybean meal diet fortified with minerals and vitamins (but not vitamin K) was fed to pigs,  levels of Ca and P were achieved by adjusting the amounts of dicalcium phosphate and ground limestone in the diet  by the University of Kentucky, showed that in blood clotting, Prothrombin and whole blood clotting times were increased (P less than .01) in pigs fed high Ca without vitamin K but were normal in pigs fed high Ca with added vitamin K. Similar trends in clotting times occurred in a second experiment. A third experiment was conducted to determine whether the addition of vitamin K could reverse the hemorrhagic condition induced by feeding high dietary Ca for 28 d(17).

18. Calcium in follicle-stimulating hormone signal transduction in Sertoli cells
Sertoli cells play a pivotal role in regulation and maintenance of spermatogenesis. Sertoli cells are hormonally regulated by follicle-stimulating hormone (FSH) acting upon a G-protein-linked cell surface FSH receptor. FSH increases intracellular cyclic AMP but the involvement of other signal transduction mechanisms including intracellular calcium in FSH action are not proven. In the study of freshly isolated rat Sertoli cells for the measurement of cytosolic free ionized calcium levels by dual-wavelength fluorescence spectrophotometry using the calcium-sensitive fluorescent dye Fura2-AM, showed that
cyclic AMP may mediate the FSH-induced rise in cytosolic calcium. The FSH-induced rise in cytosolic calcium required extracellular calcium and was abolished by calcium channel blockers specific for dihydropyridine (verapamil, nicardipine), nonvoltage-gated (ruthenium red) or all calcium channels (cobalt). Thus FSH action on Sertoli cells involves a specific, rapid, and sustained increase in cytosolic calcium which requires extracellular calcium and involves both dihydropyridine-sensitive, voltage-gated calcium channels and voltage-independent, receptor-gated calcium channels in the plasma membranes of rat Sertoli cells(18).

19. Long-term dialysis with low-calcium solution (1.0 mmol/L) in CAPD and hyperparathyroidism
In the prospective, randomized, controlled multicenter study to compare the effects of low-calcium (LCa, dialysate calcium 1.0 mmol/L) versus standard-calcium dialysate solution (SCa, dialysate calcium 1.75 mmol/L) on bone mineral metabolism in continuous ambulatory peritoneal dialysis (CAPD) patients over 2 years of treatment with Calcium carbonate (CaCO3) was given as oral phosphate binder to maintain serum phosphate < 2.0 mmol/L. If hypercalcemia supervened, CaCO3 was exchanged stepwise for aluminium hydroxide (Al(OH)3), until normocalcemia was obtained. Patients received calcitriol (0.25 microgram/day per os) if parathyroid hormone (PTH) exceeded the upper limit of normal by a factor of 2 or more, showed that In CAPD patients low-calcium dialysate solutions can be used successfully over prolonged periods of time with stable control of serum calcium. The risk of hypercalcemia resulting from calcium-containing phosphate binders and the need to use aluminum-containing phosphate binders is markedly diminished. However, there is a certain risk that severe secondary hyperparathyroidism with long-term LCa therapy will develop, even if normocalcemia is maintained(19).

20. Calcium absorption and hemodialysis
In the study of paired calcium absorption tests done before and after 12-13 weeks of 20,000 IU weekly cholecalciferol supplementation in 30 participants with stage 5 CKD on hemodialysis,  calcium absorption was tested with a standardized meal containing 300 mg calcium carbonate intrinsically labeled with (45)Ca; 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were measured. found that patients with stage 5 CKD on hemodialysis had very low calcium absorption values at baseline, and cholecalciferol supplementation that raised 25(OH)D levels to 50 ng/ml had no effect on calcium absorption(20).

21.  Calcium and Vitamin D intake of smokers
In the study conducted by the Geneva University Hospital, Geneva, Switzerland.to determine differences in dietary calcium and vitamin D intakes between female never, former and current smokers of a total of 2319 women resident in Geneva, Switzerland between 1993 and 1997, showed that Female current smokers have lower dietary intakes of calcium and vitamin D than never smokers(21).

22. Calcium and vitamin D nutrition and bone disease of the elderly
Osteoporosis, a systemic skeletal disease characterized by a low bone mass, is a major public health problem in EC member states because of the high incidence of fragility fractures, especially hip and vertebral fracture. According to the study by, The two nutrients essential for bone health are calcium and vitamin D. Reduced supplies of calcium are associated with a reduced bone mass and osteoporosis, whereas a chronic and severe vitamin D deficiency leads to osteomalacia, a metabolic bone disease characterized by a decreased mineralization of bone. Vitamin D insufficiency, the preclinical phase of vitamin D deficiency, is most commonly found in the elderly. The major causes of vitamin D deficiency and insufficiency are decreased renal hydroxylation of vitamin D, poor nutrition, scarce exposition to sunlight and a decline in the synthesis of vitamin D in the skin(22).

23. Calcium deficiency reduces circulating levels of FGF23
Fibroblast growth factor (FGF)-23 is probably the most important regulator of serum phosphate and calcitriol (1,25(OH)2D3) levels.  Fibroblast growth factor (FGF) 23 inhibits calcitriol production, which could exacerbate calcium deficiency or hypocalcemia unless calcium itself modulates FGF23 in this setting. According to the stduy by the IMIBIC, Hospital Universitario Reina Sofia, indicated that In parathyroidectomized rats, an increase in dietary calcium for 10 days increased serum calcium, with an associated increase in FGF23, decrease in calcitriol, and no change in phosphorus. Also in parathyroidectomized rats, FGF23 increased significantly 6 hours after administration of calcium gluconate. Taken together, these results suggest that hypocalcemia reduces the circulating concentrations of FGF23(23).

24. Calcium  in pregnancy.
Significant transplacental calcium transfer occurs during pregnancy, especially during the last trimester, to meet the demands of the rapidly mineralizing fetal skeleton. Similarly, there is an obligate loss of calcium in the breast milk during lactation. Both these result in considerable stress on the bone mineral homeostasis in the mother.  According to the study by Dr. E. V. Kalyani Medical Centre, during pregnancy, increased intestinal absorption of calcium from the gut mainly due to higher generation of calcitriol (1,25 dihydroxy vitamin D) helps in maintaining maternal calcium levels. On the other hand, during lactation, the main compensatory mechanism is skeletal resorption due to increased generation of parathormone related peptide (PTHrP) from the breast. Previous studies suggest that in spite of considerable changes in bone mineral metabolism during pregnancy, parity and lactation are not significantly associated with future risk for osteoporosis(24).

25. Calcium & vitamin D supplementation in women with PCOS
In the study to evaluate the efficacy of calcium & vitamin D supplementation in infertile women suffering from polycystic ovary syndrome (PCOS), and to assess levels of 25-hydroxy vitamin D in these patients, showed that the positive effects of calcium & vitamin D supplementation on weight loss, follicle maturation, menstrual regularity, and improvement of hyperandrogenism, in infertile women(25).

26. Calcium-vitamin D and metformin on polycystic ovary syndrome
In thye study to to evaluate the effects of calcium-vitamin D and metformin on the menstrual cycle and ovulation in patients with polycystic ovary syndrome (PCOS), in atotal of 60 infertile PCOS patients were enrolled in a randomized clinical trial and divided into three equal groups. Group 1 received 1,000 mg of calcium and 400 IU of vitamin D per day, orally. Group 2 received the same as Group 1, plus 1,500 mg/day of metformin. Group 3 received 1,500 mg/day of metformin. The patients were treated for 3 months and followed up for a further 3 months, showed that the effects of metformin and calcium-vitamin D in regulating the menstrual cycle suggest that they could also be effective for the treatment of anovulation and oligomenorrhea, with possible consequences for pregnancy rates in PCOS patients(26).

27. Calcium metabolism & hypercalcemia in adults
Calcium is essential for many metabolic process, including nerve function, muscle contraction, and blood clotting.  According to the study by University of Padua, School of Medicine, Calcium metabolism mainly depends on the activity of parathyroid hormone (PTH). Its secretion is strictly controlled by the ionized serum calcium levels through a negative feed-back, which is achieved by the activation of calcium-sensing receptors (CaSRs) mainly expressed on the surface of the parathyroid cells. The PTH receptor in bone and kidney is now referred as PTHR1. The balance of PTH, calcitonin, and vitamin D has long been considered the main regulator of calcium metabolism, Uncontrolled hypercalcemia may cause renal impairment, both temporary (alteration of renal tubular function) and progressive (relapsing nephrolithiasis), leading to a progressive loss of renal function, as well as severe bone diseases, and heart damages. Advances in the understanding of all actors of calcium homeostasis will be crucial, having several practical consequences in the treatment and prevention of hypercalcemia(27).

28. Calcium and prostate cancer
A high calcium intake, mainly from dairy products, may increase prostate cancer risk by lowering concentrations of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a hormone thought to protect against prostate cancer.According to the study by the Harvard School of Public Health, men who consumed >600 mg Ca/d from skim milk had lower plasma 1,25(OH)(2)D(3) concentrations than did those consuming < or =150 mg Ca/d [71 compared with 85 pmol/L (30.06 compared with 35.64 pg/mL); P = 0.005]. Compared with men consuming < or =0.5 daily servings of dairy products, those consuming >2.5 servings had a multivariate relative risk of prostate cancer of 1.34 (95% CI: 1.04, 1.71) after adjustment for baseline age, body mass index, smoking, exercise, and randomized treatment assignment in the original placebo-controlled trial. Compared with men consuming < or =150 mg Ca/d from dairy products, men consuming >600 mg/d had a 32% higher risk of prostate cancer (95% CI: 1.08, 1.63)(28).

29. calcium and vitamin D and Colon cancer
In the study to investigate whether a high intake of calcium, vitamin D, or dairy products may protect against colon cancer, the authors analyzed data from a prospective cohort study of 35,216 Iowa women aged 55-69 years without a history of cancer who completed a dietary questionnaire in 1986, by the  showed that adjusted for age, intakes of calcium and vitamin D were significantly inversely associated with the risk of colon cancer(29).

30. Calcium protect against ischemic heart disease 
In the study to investigate whether greater intakes of calcium, vitamin D, or milk products may protect against ischemic heart disease mortality, the authors analyzed data from a prospective cohort study of 34,486 postmenopausal Iowa women 55-69 years old and without a history of ischemic heart disease who completed a dietary questionnaire in 1986, showed that a higher intake of calcium, but not of vitamin D or milk products, is associated with reduced ischemic heart disease mortality in postmenopausal women, and reduced risk may be achievable whether the higher intake of calcium is attained by diet, supplements, or both(30).

31. Long term intake of dietary and supplemental calcium and cardiovascular disease
In the study to investigate the association between long term intake of dietary and supplemental calcium and death from all causes and cardiovascular disease, by the Section of Orthopedics, Uppsala University,showed that High intakes of calcium in women are associated with higher death rates from all causes and cardiovascular disease but not from stroke(31).

32. Health risks and benefits from calcium and vitamin D supplementation
In the study to examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality by the Fred Hutchinson Cancer Research Center, Seattle, indicated that among women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio [HR] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 (95 % confidence interval (CI), 0.38-1.00). In combined analyses of CT and OS data, the corresponding HR was 0.65 (95 % CI, 0.44-0.98). Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive(32).

33. Supplemental calcium and colorectal neoplasia

In the study to investigate whether supplemental oral calcium has a suppressant effect on colonic mucosal ornithine decarboxylase (ODC) and tyrosine kinase activities in patients with adenomatous polyps or a history of adenomatous polyps and whether this is affected by age, found that there is an age-related increase in basal rectal mucosal ODC activity in patients with adenomatous polyps which can be suppressed with calcium supplementation p.o., suggesting a role for dietary calcium in the chemoprevention of colorectal neoplasia(33).

34. Calcium and recurrent colorectal adenomas
In a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas of 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examinationby the New England Journal of medicine, found that Calcium supplementation is associated with a significant — though moderate — reduction in the risk of recurrent colorectal adenomas(34).

35. Intake of calcium and vitamin D and breast cancer
In the study to evaluate the total calcium and vitamin D intake in relation to breast cancer incidence among 10 578 premenopausal and 20 909 postmenopausal women 45 years or older who were free of cancer and cardiovascular disease at baseline in the Women's Health Study, showed that t higher intakes of calcium and vitamin D may be associated with a lower risk of developing premenopausal breast cancer. The likely apparent protection in premenopausal women may be more pronounced for more aggressive breast tumors(35).

36. Intravenous calcium and hyperkalemia
Digoxin is an inhibitor of the sodium-potassium ATPase. In overdose, hyperkalemia is common. In the review of the charts of all adult patients diagnosed with digoxin toxicity in a large teaching hospital over 17.5 years with the main outcome measures were frequency of life-threatening dysrhythmia within 1 h of calcium administration, and mortality rate in patients who did vs. patients who did not receive intravenous calcium, showed that among digoxin-intoxicated humans, intravenous calcium does not seem to cause malignant dysrhythmias or increase mortality. We found no support for the historical belief that calcium administration is contraindicated in digoxin-toxic patients(36).
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