InterClinical eNews August 2020, Issue 109
Characteristics of calcium
Calcium ranks fifth, after oxygen, carbon, hydrogen and nitrogen, in the mineral composition of the human body. It makes up 1.9% of the body by weight. We require an average daily positive calcium balance of 180 mg during the first 20 years of growth. Around 99% of total body calcium is located in the skeleton. The remaining 1% is distributed evenly between the teeth and soft tissues, with only 0.1% in the extracellular fluid (ECF).
Calcium ions play a role in most metabolic processes. Calcium salts, in the form of calcium phosphate, provide rigidity to the skeleton with bones serving as a reservoir for the calcium circulating in the ECF. Calcium enters the ECF from the gastrointestinal tract by absorption and from bone by resorption. It leaves via the gastrointestinal tract, the kidney, and skin before entering the bone. Many neuromuscular and other cellular functions depend on the calcium fluxing across cell membranes. Calcium fluxes are important mediators of hormonal effects on target organs through several intracellular signalling pathways. 1
Role in the body
Calcium is a mineral involved in many vital functions. Appropriate calcium intake has shown many health benefits, such as reduction of hypertensive disorders of pregnancy, lower blood pressure particularly among young people, prevention of osteoporosis and colorectal adenomas, lower cholesterol values, and lower blood pressure in the progeny of mothers taking sufficient calcium during pregnancy.
Mechanisms linking low calcium intake and blood pressure are mediated by a rise in parathyroid hormone that increases intracellular calcium in vascular smooth muscle cells leading to vasoconstriction. 1
Although research on the role of calcium has been primarily focused on bone health, which is vital, exploring the effects of dietary calcium and supplementation has recently been given greater attention. 2
Osteoporosis, which heightens fracture risk, is increasing in prevalence worldwide as the number of elderly persons grows. Generally considered a major disease of old age, genetics may contribute to as much as 80% of the set point for peak bone mass. Nevertheless, nutrition and physical activity are important modifiable factors in the development and maintenance of optimal bone mass. 3
Research has continued to uncover more information about the complex mechanisms behind calcium and bone health. A recent study examining the impact of aerobic exercise on female bone health showed that physical activity significantly increased the mean levels of BMD, serum calcium, and parathyroid hormone; and restored homeostasis of bone tissue by restoring bone biomarkers including bone alkaline phosphatase (BAP) and calcium. 4
Osteoporosis type I is a frank deficiency of calcium. Both the thyroid and adrenals can affect calcium status. If they become overactive, they will cause the body to lose calcium and retain phosphorus. Over production of these hormones can block the effects of vitamin D, and in turn, cause poor calcium absorption. However, osteoporosis type II is a condition where the body retains an excessive amount of calcium. An overactive parathyroid causes a rapid increase in the number of osteoclasts. This allows calcium to be drawn from the bone, weakening them. The body then deposits this extra calcium in the soft tissues. 5
Whereas 80 – 90% of bone mineral content is composed of calcium and phosphorus,
other nutrients such as magnesium, copper, zinc, iron, selenium, fluoride, protein, vitamins,
and folate are also required for normal bone metabolism. These nutrients interact, and the effects of these interactions on bone density are complex. Therefore, it is likely that
balanced intakes, and ratios of nutrients, rather than intakes of single nutrients, are most important in developing and maintaining healthy bone. 3
Understanding these complex ratios can enable the support of bone health maintenance. This, combined with an awareness of the effect of the endocrine system (thyroid and parathyroid) on the retention and excretion of calcium and other nutrients, can provide a more holistic insight into bone health. 5
Blood sugar regulation
Calcium is essential for insulin secretion. It is involved in the mechanism of insulin action through the regulation of intracellular calcium levels. 6
The pancreatic b cell has an elaborate and complex set of calcium signalling mechanisms that are capable of generating diverse and extremely precise calcium signals. These signals are coupled in to the b cell’s secretory machinery to produce the precise minute-to-minute control of insulin secretion necessary for body energy homeostasis. 7
Our movements are controlled by skeletal muscles. Other bodily functions require smooth muscle. Contraction of these muscles is controlled by calcium. In the short term, changes in energy efficiency may be largely mediated by the transfer of calcium signals. 8
Calcium released from the sarcoplasmic reticulum regulates the contraction of striated muscles in the heart. Cardiac contractility is regulated by changes in intracellular calcium concentration. Normal function requires that calcium be sufficiently high in systole and low in diastole. For relaxation to occur, calcium must be removed from the cytoplasm. This is largely accomplished by the sodium-calcium exchange. 9
When there is an excess amount of calcium within cardiac cells, contractility increases, and when there is a lesser concentration of calcium within the cardiac cells, contraction will decrease. 10
Blood pressure is regulated by the calcium in vascular smooth muscle through vasoconstriction and variations in the vascular volume of calcium. Low calcium intake triggers a rise in plasma parathyroid hormone levels. This increases intracellular calcium directly, or, through calcitriol activation, and by stimulation of the renin-angiotensin-aldosterone signalling pathway. This produces sodium and water reabsorption and increases vascular volume. In humans and animals with low calcium intake, blood pressure is improved when calcium intake is increased to recommended levels. 11
Innumerable biological processes share calcium as a second messenger in virtually all types of cells, including immune cells. Calcium signalling is of paramount importance to immunity. Increases in calcium concentrations in lymphocytes control complex and crucial functions such as metabolism, proliferation, differentiation, antibody and cytokine secretion and cytotoxicity.
When calcium regulation is altered in lymphocytes it leads to various autoimmune, inflammatory and immunodeficiency syndromes. There are several different types of plasma membrane and organellar calcium permeable channels at work in T-cells. These contribute to highly localised changes in function. The details of these functions are only just beginning to emerge, but it is clear that they fine tune T cell signalling to facilitate complex immune responses. 13
Brain and nervous system
Neurons are the fundamental units of the brain and nervous system and are responsible for receiving sensory input from the external world, for sending motor commands to our muscles, and for relaying the electrical signals required for every step in between. Calcium signalling in neurons plays a key role in synapses and can moderate many changes in cellular function. Calcium signalling can affect gene expression, cell growth, development, survival, and cell death. Calcium also plays a key role in synapses as the trigger for fast neurotransmitter release. 13
Additional roles for calcium
Elevated serum calcium and risk of migraine
A study on the relationship between serum calcium and migraines provided evidence that hypercalcaemia is comorbid with migraine headache diagnoses, and that genetically elevated serum calcium over a lifetime appears to increase the risk of migraine. 14
Iron absorption and calcium
Evidence has shown that calcium inhibits heme absorption at initial mucosal uptake, and heme-induced cytotoxicity and carcinogenesis in the colon. A recent study postulates that the gastrointestinal calcium transporter, TRPV6 might be a transporter of heme and that it is the mechanism that reduces heme absorption in the presence of calcium. 15
In the presence of inflamed gut mucosa the absorption of calcium is reduced. Growing evidence exists for the positive effects of prebiotics on calcium metabolism and bone health. Prebiotic dietary fibres have been shown to increase calcium absorption in the lower intestine. These effects are thought to occur through prebiotic–microbe interactions in the large intestine.
The mechanisms by which prebiotics improve mineral absorption and skeletal health include alterations in gut microbiota composition, production of short-chain fatty acids, altered intestinal pH, biomarker modification, and immune system regulation. Most research supports improved mineral bioavailability from the ingestion of prebiotics; the latest evidence suggesting the presence of an intricate gut–bone signalling axis. 16
Recent advances in our understanding of how the intestinal microbiome contributes to health and disease have generated great interest. This has resulted in the search to develop strategies for modulating the abundance of microbes and to investigate their ability to improve overall human health and prevent pathologies such as osteoporosis. The gut has long been known to regulate bone through absorption of calcium, the key bone mineral. However, it is now clear that modulation of the gut and its microbiome can affect bone density and strength in humans. 17
Yogurt, as a fermented dairy product, is beneficial to health. Besides being a source of protein, minerals, and vitamins, natural yogurt contains high concentrations of probiotics such as Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus. These live microorganisms positively affect health as probiotics have anti-inflammatory and antioxidant effects. At appropriate doses, probiotics can alleviate intestinal conditions such as inflammatory bowel disease. The lactic acid produced during yogurt fermentation increases protein and calcium absorption, and promotes bone mineralisation. 6
Interestingly, taurine has been shown to be involved in regulating calcium binding and transport. It is a powerful agent in regulating and reducing the intracellular calcium levels in neurons. After prolonged L-glutamate stimulation, neurons lose the ability to effectively regulate intracellular calcium. This condition can lead to acute swelling and lysis of the cell, or culminate in apoptosis. Under these conditions, significant amounts of taurine are released from the excited neuron. This extracellular taurine acts to slow the influx of calcium into the cytosol through both transmembrane ion transporters and intracellular storage pools. 18
Cofactors and hormone function
Osteoporosis type I, a frank deficiency of calcium will require calcium supplementation, but this may not be enough to solve the problem. Overactive thyroid and adrenal function can continue to produce a marked loss of calcium from the body. This is where it is important to provide a gentle and bioavailable form of calcium and to provide the necessary co-factors that support absorption.
Calcium glycinate is gentle on the digestive system and an effective form of calcium. Magnesium and vitamin D3 help to increase parathyroid hormone production. Vitamin K2 is required to activate osteocalcin to build bone cells. When vitamin K2 is activated it uses osteocalcin to draw calcium into the bones. When combined with vitamin D3, it helps to inhibit osteoclasts, the cells responsible for bone resorption. 21 Another important cofactor is lysine. In animal studies it has been shown to increase calcium absorption. 22
The TCM herb Eucommia ulmoides can be used to support bone growth. It is actively involved in mechanisms which initiate osteoblasts, enhance osteogenesis, decrease osteoclasts and prevent osteolysis. 23
Osteoporosis type II with increased calcium and retention and overactive parathyroid can cause calcium deposition in the soft tissues. In this case vitamin D supplementation will not resolve the issue. Resolving the underlying endocrine imbalance can improve the utilisation of calcium. Once the parathyroid gland is functioning properly, the calcium imbalance can begin to resolve. Supplementing with ionic calcium phosphate can be a gentle and effective way support this condition due to the balancing effect of phosphorus. 5
Calcium mineral antagonists
Calcium vitamin antagonists
Calcium mineral synergists
How to accurately measure calcium
Determining an accurate level of calcium is difficult. One way that calcium levels are measured is by calculating the mean intake at which intake and output are equal (or the balance is zero). In normal adults the difference between calcium intake and output at high calcium intakes, represents a very small difference between two large numbers, and has too great a margin of error to calculate their requirement effectively. 1
Another way to determine calcium levels is by measuring the total calcium concentration in blood. This also has pitfalls since blood actively maintains its acid/alkaline balance by regulating calcium content. Also, disorders such as those of the kidney can cause hypercalcemia and therefore a serum total calcium test result can greatly underestimates calcium. 19
Studies on epilepsy, hypertension, atherosclerosis, thrombosis in coronary heart disease, breast and lung cancer, premenstrual syndrome, and mineral status in pregnant women have shown that some minerals within individual cells or in tissues, rather than in blood, are more significant indicators. 3
The use of hair tissue as a means of evaluating calcium is useful and effective measure, since the calcium content of hair reflects calcium metabolism in the body. 20
The parathyroid’s influence on calcium retention and excretion
The sensitive process of calcium and phosphate homeostasis is maintained primarily by the healthy functioning of the parathyroid gland. It secretes parathyroid hormone (PTH) in response to low calcium levels detected in blood. The clinical ramifications of irregularities in parathyroid function are significant. Where there is a calcium imbalance (deficiency or excess) it will often be due to an underactive or overactive parathyroid gland, unless of course there is a deficiency in the diet. 10 A parathyroid that over-functions will cause blood calcium to elevate and the excess calcium will deposit into soft tissues of the body. 5 This can result in gallstones, kidney stones, joint stiffness, dry skin and premature aging and wrinkling of the skin. 5 A quick, non-invasive way to discover if there is an excess or deficiency of calcium in the soft tissue is by testing a hair tissue sample.
WHO (World Health Organisation) guidelines recommend calcium supplementation of 1.5 – 2 g/day to pregnant women from populations with low intake; however, a newer review showed that the lower supplementation of 500mg/day during pregnancy had effects similar to those of supplementation with higher doses. This may be due to the absorption rate of calcium. 11 Osteoporosis Australia recommends supplemental doses of 500-600mg/day.
Calcium is one of the body’s most vital minerals because it is required for both structure and function. While deficiency can have an enormous impact on health, so can an excess. It is regulated in the blood by the parathyroid gland. Since subclinical parathyroid disorders are not unusual, calcium excess or deficiency can often be an issue. Hair tissue mineral analysis is one of the best, most reliable ways to assess calcium balances in the body, as well as indicate which form of calcium may be best suited to each individual patient’s needs.
1 World Health Organization. Vitamin and Mineral Requirements in Human Nutrition, 2nd ed.; WHO: Geneva, Switzerland, 2004.
2 Belizan, J.M.; Villar, J. (1980) The relationship between calcium intake and edema-, proteinuria-, and hypertension-gestosis: An hypothesis. Am. J. Clin. Nutr. , 33, 2202–2210.
3 Song, C. H., Barrett-Connor, E., Chung, J. H., Kim, S. H., & Kim, K. S. (2007). Associations of Calcium and Magnesium in Serum and Hair with Bone Mineral Density in Premenopausal Women. Biological Trace Element Research, 118(1), 1–9. doi:10.1007/s12011-007-0011-2
4 Al Dahamsheh, Z., Al Rashdan, K., Al Hadid, Awni., Jaradat, R., Al Bakheet, M., Bateineh, Z. S. (2019) The impact of Aerobic Exercise on Femal Boneh Health Indicators, Med. Arch. 73(1): 35-38 doi:10.5455/medarh.2019.73.75-38
5 Watts, D. Trace elements and other essential nutrients, 1995 Ch. 10, p 117-123
6 Jeon, J., Jang, J., & Park, K. (2018). Effects of Consuming Calcium-Rich Foods on the Incidence of Type 2 Diabetes Mellitus. Nutrients, 11(1), 31. doi:10.3390/nu11010031
7 Satin, L. S. (2000). Localized Calcium Influx in Pancreatic β-Cells: Its Significance for Ca2+-Dependent Insulin Secretion from the Islets of Langerhans. Endocrine, 13(3), 251–262. doi:10.1385/endo:13:3:251
8 Saleh Al-Menhaliab, A., Banua, S., Angelovace, P. R., Barcarud, A., Horvatovich, P., Abramov, A. Y., Jaganjac, M. (2020) Lipid peroxidation is involved in calcium dependent upregulation of mitochondrial metabolism in skeletal muscle. Biochimica et Biophysica Acta (BBA) Volume 1864, Issue 3.
9 Yamada, Y., Namba, K. & Fujii, T. (2020) Cardiac muscle thin filament structures reveal calcium regulatory mechanism. Nat Commun 11, 153. doi.org/10.1038/s41467-019-14008-1
10 Khan, M., Jose, A., Sharma, S. (2020) Physiology, Parathyroid Hormone (PTH). StatPearls Publishing
11 Cormick, G., Belizn, J. M. (2019) Calcium Intake and Health. Nutrients 11, 1606; doi:10.3390/nu11071606
12 Wang, H., Zhang, X., Xue, L., Xing, J., Jouvin, M.-H., Putney, J. W. Kinet, J.-P. (2016). Low-Voltage-Activated Ca V 3.1 Calcium Channels Shape T Helper Cell Cytokine Profiles. Immunity, 44(4), 782–794. doi:10.1016/j.immuni.2016.01.015
13 Burgoyne, R. D., Helassa, N., McCue, H. V., & Haynes, L. P. (2019). Calcium Sensors in Neuronal Function and Dysfunction. Cold Spring Harbor Perspectives in Biology, a035154. doi:10.1101/cshperspect.a035154
14 Yin, P., Anttila, V., Siewert, K. M., Palotie, A., Smith, G. D., Voight, B. F. (2017) Serum calcium and risk of migraine: a Medelian randomisation study. Hum Mol Genet 26(4): 820-828. doi: 10.1093/hmg/ddw416
15 Latunde-Dada, G. O. (2016) Is the calcium transporter a potential candidate for heme transport? Medical Hypotheses. doi.org/10.1016/j.mehy.2016.004
16 Whisner, C. M., & Castillo, L. F. (2017). Prebiotics, Bone and Mineral Metabolism. Calcified Tissue International, 102(4), 443–479. doi:10.1007/s00223-017-0339-3
17 McCabe, L., Britton, R. A., & Parameswaran, N. (2015). Prebiotic and Probiotic Regulation of Bone Health: Role of the Intestine and its Microbiome. Current Osteoporosis Reports, 13(6), 363–371. doi:10.1007/s11914-015-0292-x
18 Foos, T. M., & Wu, J.-Y. (2002). Neurochemical Research, 27(1/2), 21–26. doi:10.1023/a:1014890219513
19 Pieter Evenepoel, Bert Bammens, Kathleen Claes, Dirk Kuypers, Björn K.I. Meijers and Yves Vanrenterghem CJASN November 2010, 5 (11) 2085-2092; DOI: https://doi.org/10.2215/CJN.02460310
20 Bacso, J., Uzonyi, I., & Katz, S. A. (1987). Use of hair as a biopsy tissue for calcium. Biological Trace Element Research, 12(1), 383–387. doi:10.1007/bf02796694
21 Plaza SM, Lamson DW. Vitamin K2 in bone metabolism and osteoporosis. Altern Med Rev. 2005;10(1):24-35
22 Xiao, C.-W., Wood, C., & Bertinato, J. (2018). Dietary supplementation with l-lysine affects body weight and blood hematological and biochemical parameters in rats. Molecular Biology Reports. doi:10.1007/s11033-018-4492-1
23 Hussain, T., Tan, B., Liu, G., Oladele, O. A., Rahu, N., Tossou, M. C., & Yin, Y. (2016). Health-Promoting Properties ofEucommia ulmoides: A Review. Evidence-Based Complementary and Alternative Medicine, 2016, 1–9. doi:10.1155/2016/5202908