Calcium
Introduction
Calcium (Ca) is a mineral that is commonly used by organisms and is necessary for life. In blood it is mostly found as the soluble ion Ca2+ or bound to transport proteins. Calcium is obtained from diet and is found abundantly in many foods including dairy products (milk), green leafy vegetables (spinach), bread (fortified flour) and bony fish (sardines).
Most people know that calcium is essential in bone structure but it is also involved in building teeth, regulating muscle contraction and in blood clot formation. Calcium also has a function as a co-factor for many enzymatic reactions, as a secondary messenger that regulates cell function and as a neurotransmitter. Calcium regulation inside the body is very important to ensure health and wellness.
In the following sections calcium function in the body, calcium metabolism, calcium regulation, blood calcium quantification and calcium diseases will be discussed in detail.
Calcium Function in the Body
Calcium plays various roles in the body which include:
-
Bone health since around 99% of the calcium in the human body is in the bones and teeth.
-
Calcium is essential for the development, growth, and maintenance of bone.
-
Muscle contraction
-
Cardiovascular system
-
Blood clotting.
-
Calcium’s role in muscle function includes maintaining the action of the heart muscle.
-
Calcium relaxes the smooth muscle that surrounds blood vessels.
-
Calcium is a co-factor for many enzymes.
Studies have also suggested that consuming enough calcium can result in:
-
A lower risk of developing conditions involving high blood pressure during pregnancy
-
Lower blood pressure in young people
-
Lower blood pressure in those whose mothers who consumed enough calcium during pregnancy
-
Improved cholesterol values
-
A lower risk of colorectal adenomas, a type of non-cancerous tumour
Sources:
Newman, T. (2020). Calcium: Health benefits, foods, and deficiency. Retrieved from https://www.medicalnewstoday.com/articles/248958
Figure 1
The benefits calcium has on the human body and their underlying physiological processes.
Calcium Metabolism
Depending on the metabolic rate of Calcium ions (Ca2+), the requirements of these ions may vary according to the method of regulation taking place. Such regulatory mechanisms include:
1) Intestinal absorption
2) Renal reabsorption
3) Bone turnover
Thus, calcium metabolism is regulated by the gut, kidneys and bone.
Calcium metabolism is engaged/disengaged according to the concentration calcium ions present in the serum component of blood.
Such a process is triggered via the secretion of the hormones:
-
Parathyroid Hormones (PTH) which are secreted from the parathyroid glands in response to low calcium levels.
-
Calcitriol, also known as 1,25-dihydroxycholecalciferol (1,25 (oh)2d), which is the active form of Vitamin D, along with the expression of their respective receptors which, in combination, regulate calcium homeostasis by regulating: intestinal absorption, renal reabsorption and bone turnover.
The rate of calcium metabolism in bones is dependent on the rate of bone formation. For example, this is usually increased at a younger age when significant bone formation is taking place, whilst the rate decreases as age increases when the bones have fully developed. Hence, children exhibit a positive bone balance during which the rate of bone formation is greater than the rate of calcium reabsorption, whilst elderly persons have a negative bone balance during which the rate of bone growth is less than that of calcium reabsorption. This bone balance can be altered by exercise, anabolic drugs, and factors promoting bone growth over calcium reabsorption.
Intestinal absorption
This is a process by which calcium ions are taken up into the body via the small intestines. Such ions can be absorbed by two methods being the active or the passive pathway.
-
As the name states, the active pathway requires energy (in the form of ATP) to create an imbalance of calcium ions and facilitate uptake via specific protein channels into the endothelial intestinal cells.
-
Whereas the passive pathway requires no ATP as they are able to slowly diffuse directly into the epithelial cells by passing through the cell membrane.
The molecule which decides which process of the two above is to be used is Calcitrol. This is always depending on the levels of calcium ions within the blood.
The regulatory role played by the kidneys in calcium metabolism is by the process of excretion. This process is controlled by tubular calcium reabsorption and filtered calcium load. This process is in part also dependent on the increased or decreased secretion of serum phosphate within the kidneys.
An increase in the level of calcium causes a decrease in the secretion of parathyroid hormone leading to lower levels of Calcitriol 1,25(OH)2D. The reduction in concentration of secretion both of these hormones gives rise to an increase in serum phosphate levels by tubular reabsorption. The exact opposite of this sequence of events occurs when the level of calcium is low. Consequently, phosphate absorption or excretion regulates calcium excretion or absorption, respectively.
Sources:
-
Bootman, M. D., Collins, T. J., Peppiatt, C. M., Prothero, L. S., MacKenzie, L., De Smet, P., . . . Lipp, P. (2001). Calcium signalling—an overview. Seminars in Cell & Developmental Biology, 12(1), 3-10. doi:10.1006/scdb.2000.0211
-
Christensen, S. E., Nissen, P. H., Vestergaard, P., Heickendorff, L., Brixen, K., & Mosekilde, L. (2008). Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: A follow-up study on methods. Clinical Endocrinology (Oxford), 69(5), 713-720. doi:10.1111/j.1365-2265.2008.03259.
-
McCormick, C. C. (2002). Passive diffusion does not play a major role in the absorption of dietary calcium in normal adults. The Journal of Nutrition, 132 (11), 3428-3430. doi:10.1093/jn/132.11.3428
-
Peacock, M. (2010). Calcium metabolism in health and disease. Clinical Journal of the American Society of Nephrology, 5(Supplement 1), S23-S30. doi:10.2215/cjn.05910809
-
Talmage, R. V., & Mobley, H. T. (2008). Calcium homeostasis: Reassessment of the actions of parathyroid hormone. General and Comparative Endocrinology, 156(1), 1-8. doi:10.1016/j.ygcen.2007.11.003
-
Touchberry, C. D., Green, T. M., Tchikrizov, V., Mannix, J. E., Mao, T. F., Carney, B. W., . . . Wacker, M. J. (2013). FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. American Journal of Physiology: Endocrinology and Metabolism, 304(8), E863-E873. doi:10.1152/ajpendo.00596.2012
Encyclopedia of Endocrine Diseases. Academic Press. 2018. p. 344. ISBN 9780128122006
Figure 2
Graphical overview showing the pathways through which blood calcium is regulated.
Calcium Regulation
Calcium Balance
The net difference between the intake and output of calcium is referred to as the calcium balance. Calcium is found in all tissues, however, the bone and teeth contain 99% of body calcium. Therefore, the calcium balance mainly indicates the skeletal tissue balance.
A positive calcium balance value means that the body is adding bone, a zero value means bone equilibrium and a negative value means bone loss. During growth, calcium balance is typically positive as the individual is amassing tissue, while during involution, the value is negative as the tissue mass is declining. A healthy young adult has a neutral bone balance because the formation and reabsorption of bone are in equilibrium. Factors which enhance bone formation in adults include exercise, anabolic and anti-resorptive drugs and a number of conditions such as ‘hungry bone’ syndrome and osteoblastic prostate cancer. A negative bone balance can be promoted via a sedentary lifestyle and sex steroid deficiency.
Calcium-regulated hormones control the calcium balance via an integrated pathway. The main hormones involved are the parathyroid hormone (PTH), calcitonin and vitamin D in which their target tissues are the intestines, bone and kidneys.
Calcium Homeostasis
Calcium homeostasis is regulated by two hormones which are important for the control of calcium transport in the gut, kidney and bone and for maintaining ionized extracellular calcium levels. The two hormones that are involved are the parathyroid hormone (PTH) and 1,25(OH)2D which work together with the following receptors: PTH receptor (PTHR), vitamin D receptor (VDR) and calcium- sensing receptor (CaR).
Calcium Homeostasis is regulated as follows:
Low serum calcium levels -> CaR is inactivated -> Increase in PTH secretion -> in turn acts on PTHR in kidney -> allows an increase in tubular calcium reabsorption.
Increase in PTH levels -> Inc secretion of 1,25(OH)2D -> activates VDR in gut -> increase of calcium absorption in parathyroid glands -> decrease of PTH secretion.
Decrease in calcium level -> CaR inactivation in kidney -> increase in calcium reabsorption -> increase the effect of PTH – This causes a negative feedback loop by restoring serum calcium levels.
Sources:
-
Heaney, R. P. (1999). CHAPTER 3 - aging and calcium balance. In C. J. Rosen, J. Glowacki & J. P. Bilezikian (Eds.), The aging skeleton (pp. 19-26). San Diego: Academic Press. Retrieved from http://www.sciencedirect.com/science/article/pii/B9780120986552500053
-
Negrea, L. A. (2019). CHAPTER 75 - hypocalcemia and hypercalcemia. Nephrology secrets (fourth edition) (pp. 526-531). Oxford: Elsevier.
Peacock, M. (2010). Calcium metabolism in health and disease. Clinical Journal of the American Society of Nephrology, 5(Supplement 1), S23-S30.
Calcium Diseases
Hypocalcemia and hypercalcemia are terms used clinically to refer to abnormally low and high serum calcium concentrations. It should be noted that, because about one half of serum calcium is protein bound, abnormal serum calcium, as measured by total serum calcium, may occur secondary to disorders of serum proteins rather than as a consequence of changes in ionized calcium. Hypercalcemia and hypocalcemia indicate serious disruption of calcium homeostasis but do not on their own reflect calcium balance. They can be classified by the main organ responsible for the disruption of calcium homeostasis, although clinically more than one mechanism is invariably involved.
Intestinal Calcium Absorption
-
Binding agents such as cellulose, phosphate, and oxalate. A variety of diseases of the small bowel, including sprue and short bowel syndrome, can result in severe calcium malabsorption.
-
Absorptive hypercalcemia occurs from conditions that produce increased serum 1,25(OH)2D levels as occurs in sarcoidosis, increased serum 25(OH)D (25-hydroxyvitamin D) levels from vitamin D poisoning, or excessive intake of calcitriol or its analogs. Absorptive hypercalcemia readily develops in children and patients with chronic kidney disease (CKD) when they receive amounts of dietary calcium that exceed the ability of their kidneys to filter and excrete the calcium load.
-
Absorptive hypocalcemia caused solely by a low dietary calcium intake is rare, because of the homeostatic mechanisms. However, absorptive hypocalcemia is common in states of low, or inappropriately low, serum 1,25(OH)2D as occurs in chronic vitamin D deficiency, osteomalacia, and rickets or in impaired 1,25(OH)2D production as occurs in CKD.
Bone Calcium Remodeling
-
Bone continuously remodels by coordinated cellular mechanisms to adapt its strength to the changing needs of growth and physical exercise. Old, damaged, and unneeded bone is removed by resorption, and new bone is subsequently deposited by formation. Diseases affecting either or both of these processes lead to disturbed calcium homeostasis.
-
Remodeling hypercalcemia results from increased net bone resorption as occurs in osteoclastic metastatic bone cancer, primary hyperparathyroidism, and vitamin D poisoning. In CKD patients with adynamic bone disease, hypercalcemia is readily produced because the bone is unable to take up calcium by formation.
-
Remodeling hypocalcemia results from increased net bone formation as occurs in post parathyroidectomy “hungry bone syndrome” and osteoblastic metastatic bone cancer. It has been hypothesized that bone can release to, and remove calcium from, the circulation by active mechanisms separate from the remodeling system. However, although bone acts as a temporary buffer to take up and release serum calcium, the mechanism is largely passive and driven by the serum calcium concentration itself.
Renal Calcium Excretion
-
Renal calcium excretion is regulated by two main mechanisms: tubular calcium reabsorption and filtered calcium load. Disruption of either or both of these mechanisms leads to abnormal calcium homeostasis. In CKD, disturbances in calcium homeostasis are common and, as GFR decreases, disturbances in calcium homeostasis increase.
-
Tubular reabsorptive hypercalcemia arises from a sustained increase in tubular calcium reabsorption as occurs in primary hyperparathyroidism, sodium depletion, thiazide medications, and inactivating mutations in the CaR (calcium-sensing receptor).
-
Tubular reabsorptive hypocalcemia arises from a sustained decrease in tubular calcium reabsorption as occurs in postsurgical hypoparathyroidism, abnormalities in the PTHR complex, and activating CaR mutations.
-
GFR hypercalcemia develops when the input of calcium to the circulation exceeds its removal by the kidney's filtration rate independent of the tubular calcium reabsorption rate. This readily occurs in children and patients with CKD. In states of reduced GFR, even a normal input of calcium into the circulation from gut or bone can result in hypercalcemia.
Sources:
-
Peacock, M. (2010). Calcium metabolism in health and disease. Clinical Journal of the American Society of Nephrology, 5 (Supplement 1), S23-S30.
Quantifying Blood Calcium
Calcium blood test:
-
Total calcium, which measures the calcium attached to specific proteins in the blood and the ionized calcium
-
Ionized calcium is the measurement of the calcium that is unattached or "free" from these proteins.
-
If the results are not in normal range then further tests need to be carried out to determine the cause
Parathyroid hormone (PTH) test - a blood test is carried out to quantify PTH which determines if abnormal calcium levels are due to the parathyroid gland.
A PTH test is most often used along with calcium testing to:
-
Diagnose hyperparathyroidism, a condition in which your parathyroid glands produce too much parathyroid hormone
-
Diagnose hypoparathyroidism, a condition in which your parathyroid glands produce too little parathyroid hormone
-
Find out whether abnormal calcium levels are being caused by a problem in the parathyroid glands
-
Monitor kidney disease
If the PTH level is higher than the normal range this could indicate:
-
A parathyroid gland growth (hyperplasia) or a parathyroid tumor.
-
A low level of calcium in the blood. A low blood calcium level can be caused by kidney disease, kidney failure, severe vitamin D deficiency, or an inability of the intestines to absorb calcium from food.
-
Some types of cancer, such as lung, kidney, pancreatic, or ovarian cancer.
If the PTH level is lower than the normal range then that could indicate:
-
Damage to the parathyroid gland, which can by caused by neck surgery or radiation treatments.
-
A rare disease, such as sarcoidosis or histiocytosis X.
-
An overdose of vitamin D or calcium.
-
Cancer, such as lymphoma or multiple myeloma .
-
A low magnesium level.
A blood test can also be carried out to determine the level of vitamin D in the blood since vitamin D aids in Ca uptake (they work together).
-
Two forms of vitamin D can be measured in the blood, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. The 25-hydroxyvitamin D is the major form found in the blood and is the relatively inactive precursor to the active hormone, 1,25-dihydroxyvitamin D. Because of its long half-life and higher concentration, 25-hydroxyvitamin D is commonly measured to assess and monitor vitamin D status in individuals.
-
One of vitamin D’s major roles is to control the absorption of calcium from the intestines into the bloodstream.
-
A high level of 1,25-dihydroxyvitamin D may occur when there is excess parathyroid hormone or when there are diseases, such as sarcoidosis or some lymphomas, that can make 1,25-dihydroxyvitamin D outside of the kidneys.
Sources:
-
AACC. (2020). Vitamin D tests. Retrieved from https://labtestsonline.org/tests/vitamin-d-tests
WebMD. (n.d.). What is a parathyroid hormone blood test? Retrieved from https://www.webmd.com/a-to-z-guides/parathyroid-hormone-blood-test#1
