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Subject 101: Calcium and phosphate homeostasis

Calcium and phosphate homeostasis

Calcium and phosphate are necessary for many physiological processes, the most obvious of which is skeletal mineralization.¹1 The homeostasis of calcium and phosphate therefore plays an important role in diseases such as osteoporosis and rickets.² Calcium and phosphate homeostasis are interconnected, as the regulating hormones and organs necessary for absorption, storage and excretion partially overlap. This may lead to confusion among students and clinicians alike. We therefore discuss a simple method to memorize the basics in this subject 101.

How is the story usually told?

There are four main hormones involved in regulating calcium and phosphate levels: parathormone (PTH), calcitriol (activated vitamin D), fibroblast growth factor member 23 (FGF23) and calcitonin. These hormones elicit effects on several organs; i.e. the kidneys, gastrointestinal (GI) tract and skeletal metabolism. A detailed overview can be found in TABLE 1.

PTH is produced by the parathyroid glands.2,3 It induces an increased release of calcium and phosphate from the bones, an increased renal reabsorption of calcium and a decreased renal absorption of phosphate.4 It also stimulates vitamin D3 activation in the kidneys, leading to increased intestinal absorption of calcium and phosphate.3,5

Vitamin D3 is activated by a conversion in the skin, liver and kidneys into calcitriol (1,25-dihydroxycholecalciferol). 3 With regard to calcium and phosphate, calcitriol increases active absorption in the intestines and reabsorption in the kidneys, and increased activity of osteoblasts, thereby inducing FGF23 synthesis.2,4,5

Calcitonin is produced by parafollicular cells (C-cells) of the thyroid. It decreases plasma calcium by inhibiting osteoclast activity and formation. 1 However, the decrease in plasma calcium leads to excretion of PTH which overrides the effect of calcitonin.6 Also, the decrease in formation of osteoclasts leads to a similar effect on osteoblast activity.6 Therefore, the effect of calcitonin is very limited in humans.1 FGF23 is produced by osteoblasts and osteocytes. It decreases renal reabsorption of phosphate, calcitriol production and PTH production.2,3,5,7,8

Table 1 Overview of hormones involved in calcium and phosphate homeostasis. Abbreviations: Ca = Calcium, P = phosphate, PTH = parathormone, FGF23 = fibroblast growth factor member 23

How to remember this? A mnemonic approach

Instead of trying to remember the effects of hormones on this complex system, it can help to understand the role each hormone plays. We can illustrate this by personifying each hormone and asking ourselves how and when they need to help the body.

Pragmatic PTH has the same attitude towards calcium as pragmatic people have towards money: you have it to use it. So when serum levels of calcium drop, PTH uses the body’s calcium “savings” from the bone, increases “income” in the GI tract and decreases “expenses” in the kidney to maintain a steady state. Overall, PTH leads to an increase in serum calcium and a decrease in serum phosphate.5,6

Conscientious Calcitriol makes sure that calcium and phosphate is put to good use, nothing goes to waste. It stimulates the intestines and kidneys to hold on to as much calcium and phosphate as they can, and stimulates osteoblasts, which use the minerals to increase bone matrix. To prevent dysregulation it stimulates FGF23-synthesis. Overall, calcitriol increases serum calcium and phosphate, and ensures that the increase is guided towards the skeletal metabolism.3

Insurgent Calcitonin has little power but gets in everybody’s way as much as possible. It especially vexes calcitriol by trying to get rid of phosphate and calcium. It focuses mainly on decreasing renal reabsorption of calcium and phosphate, and prevents the minerals from being released from the bones by inhibiting osteoclasts. These effects lead to a decrease in serum levels of both calcium and phosphate, which in turn will stimulate PTH release.4,5

Fresh FGF23 is crazy about Flushing out phosphate and is the new kid on the block. However, like any new kid, we do not really understand how it works exactly. When the phosphate or calcitriol levels rise too much, FGF23 ensures renal excretion of phosphate and a downregulation of calcitriol and PTH synthesis.4,8 This leads to an overall decrease in serum phosphate.7

With this in mind the effects of increased and decreased levels of these hormones in various diseases are logically deductible.

What effect would you expect of a vitamin D (and therefore calcitriol) deficiency?

Vitamin D deficiency can lead to rickets (called osteomalacia in adults), a disease in which bones do not mineralise correctly. This causes skeletal malformations in children and pathological fractures in adults. Vitamin D deficiency is thought to be associated with a number of other diseases that are beyond the scope of this article.

Limitations

The personification of these hormones is of course not scientifically accurate. It is merely a tool to understand and memorize the principles of this regulatory system. It is also an oversimplification. There are a large number of other hormones, such as thyroid hormone, growth hormone, gonadal and adrenal steroids, and minerals, such as magnesium, which play a role in calcium and phosphate homeostasis. Nevertheless, this approach can help clarify the basic structure of a complex endocrine network.

E.M. Corazolla & J.S. ten Kulve

References

  1. Shaker, JL and Deftos, L. Calcium and Phosphate Homeostasis. In: De Groot, L. J., Chrousos, G., Dungan, K. et al. (editors). Endotext [Internet]. South Dartmouth (MA): MDText..com, Inc.; 2000- . Updated 2018 Jan 19
  2. Blau, JE, and Collins, MT. The PTH-Vitamin D-FGF23 axis. Reviews in Endocrine and Metabolic Disorders. 2015;16(2):165–174.
  3. Goltzman, D, Mannstadt, M, and Marcocci, C. Physiology of the Calcium-Parathyroid Hormone-Vitamin D Axis. In Vitamin D in Clinical Medicine 2018;50:1-13.
  4. Bergwitz, C, and Jüppner, H. Regulation of Phosphate Homeostasis by PTH, Vitamin D, and FGF23. Annual Review of Medicine. 2010;61(1):91–104.
  5. Lederer, E. Regulation of serum phosphate. Journal of Physiology. 2014;592(18):3985–3995.
  6. Hogan, J and Goldfarb, S. Regulation of Calcium and Phosphate Balance. In: UpToDate. (08.03.2018). Available here
  7. Jongh, RT De, Vervloet, MG, Bravenboer, N, et al. Chronische botpijn door verhoogde FGF23-productie. Nederlandse Tijdschrift Voor Geneeskunde. 2013;157.
  8. Silver, J, and Naveh-Many, T. FGF23 and the parathyroid. Advances in Experimental Medicine and Biology. 2012;728:92–99.

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