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Front Horm Res. Basel, Karger, 2018, vol 50, pp 1–13 (DOI: 10.1159/000486060)
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Physiology of the Calcium-Parathyroid Hormone-Vitamin D Axis
David Goltzmana · Michael Mannstadtb · Claudio Marcoccic
aDepartment of Medicine, McGill University and McGill University Health Centre, Montreal, QC, Canada; bEndocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; cDepartment of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Abstract
Classic endocrine feedback loops ensure the regulation of blood calcium. Calcium in the extracellular fluid (ECF) binds and activates the calcium sensing receptor (CaSR) on the parathyroid cells, leading to an increase in intracellular calcium. This in turn leads to a reduced parathyroid hormone (PTH) release. Hypocalcemia leads to the opposite sequence of events, namely, lowered intracellular calcium and increased PTH production and secretion. PTH rapidly increases renal calcium reabsorption and, over hours to days, enhances osteoclastic bone resorption and liberates both calcium and phosphate from the skeleton. PTH also increases fibroblast growth factor 23 (FGF23) release from mature osteoblasts and osteocytes. PTH stimulates the renal conversion of 25-hydroxyvitamin D (25[OH]D) to 1,25(OH)2D, likely over several hours, which in turn will augment intestinal calcium absorption. Prolonged hypocalcemia and exposure to elevated PTH may also result in 1,25(OH)2D-mediated calcium and phosphorus release from bone. These effects restore the ECF calcium to normal and inhibit further production of PTH and 1,25(OH)2D. Additionally, FGF23 can be released from bone by 1,25(OH)2D and can in turn reduce 1,25(OH)2D concentrations. FGF23 has also been reported to decrease PTH production. When ECF calcium is in the hypercalcemic range, PTH secretion is reduced and renal 1,25(OH)2D production is decreased. In addition, the elevated calcium per se stimulates the renal CaSR, thus inducing calciuria. Therefore, suppression of PTH release and 1,25(OH)2D synthesis and stimulation of the renal CaSR lead to reduced renal calcium reabsorption, decreased skeletal calcium release, and decreased intestinal calcium absorption, resulting in the normalization of the elevated ECF calcium.
© 2018 S. Karger AG, Basel
Distribution of Calcium in Body Compartments
The adult body contains approximately 1 kg of calcium (Ca), of which 99% is located in the mineral phase of bone, and 1% is located in the blood, extracellular fluid (ECF), and soft tissues.
Calcium in Blood
Calcium in blood is partly (45%) bound to protein, especially albumin, in a pH-dependent manner, and partly (10%) complexed to anions such as phosphate (PO4) and citrate [1]. Approximately 45% circulates as a free or ionized fraction and is the biologically active portion of total blood Ca. Although only the ionized Ca is available to enter cells and activate cellular processes, most clinical laboratories report total serum Ca concentrations. Concentrations of total Ca in normal serum generally range between approximately 2.12 and 2.62 mM (8.5 and 10.5 mg/dL) with levels above this considered hypercalcemic and levels below this considered hypocalcemic. Ionized concentrations can be measured, and the reference range is 1.16–1.31 mM (4.65–5.25 mg/dL). When protein concentrations, and especially albumin concentrations, fluctuate, total Ca levels may vary, whereas the ionized Ca may remain relatively stable. During venipuncture, dehydration, or hemoconcentration may increase serum albumin and falsely elevate total serum Ca measurements. However, changes in total Ca, when albumin levels are increased or decreased, can be “corrected” mathematically. Alterations in blood pH can change the equilibrium constant of the albumin-Ca complex, even in the presence of a normal serum albumin, with acidosis reducing the binding and alkalosis augmenting it. A major shift in serum protein or pH, therefore, requires direct measurement of the ionized Ca level to determine the physiologic serum calcium level.
Calcium in Cells
The concentration of Ca in the cellular cytoplasm is about 10–6 M, whereas the ECF Ca concentration is approximately 10–3 M. This creates a 1,000-fold concentration gradient across the plasma membrane that favors Ca entry into the cell. Additionally, there is an electrical charge of about 50 mV across the plasma membrane, with the cell interior negative. The cell must, therefore, defend against these chemical and electrical gradients across the plasma membrane, which greatly favor Ca entry in order to preserve viability. Several mechanisms are utilized to prevent Ca-induced cell death. These include extrusion of Ca from the cell by ATP-dependent energy driven Ca pumps and Ca channels, and by Na-Ca exchangers. In addition, intracellular Ca may be bound to proteins in the cytoplasm, endoplasmic reticulum (ER), and mitochondria. The Ca bound in these sites can not only buffer intracellular Ca, but also maintain cytoplasmic Ca levels and create pulsatile peaks of Ca to mediate membrane receptor signaling that regulate a variety of biologic systems.
Calcium in Bone
Bone is the major reservoir of Ca in the body. The majority of skeletal Ca is located in the mineral phase of bone as hydroxyapatite [Ca10(PO4)6(OH)2] [2]. The hydroxyapatite crystal plays a critical role in the mechanical weight-bearing properties of bone and serves as a source of Ca to support a variety of Ca-dependent biological systems and to maintain blood ionized Ca within the normal range.
Hormones
