Parathyroid Hormone and Vitamin D: Keeping Calcium in Balance

A blood result shows that a patient's calcium is falling. Before the level moves very far, the parathyroid glands have already noticed.

We often think of calcium as something stored in bone, but the small amount circulating outside cells is being used continuously. Calcium helps determine how excitable nerves and muscle cells are. It enters cells during excitation-contraction coupling, allowing skeletal and cardiac muscle to contract, and it participates in intracellular signalling and blood coagulation. The concentration in extracellular fluid therefore has to be kept within a narrow range.

Not all calcium measured in blood is in the same form. Some is bound mainly to albumin, some is complexed with small anions, and roughly half circulates as free ionised calcium. It is this ionised fraction that is biologically active and that the parathyroid glands respond to. If albumin is low, total calcium can fall even when ionised calcium has not fallen to the same extent. This is why routine blood results may include albumin-adjusted calcium, while direct ionised calcium measurement is useful in particular clinical situations.

Keeping ionised calcium stable involves several organs. The parathyroid glands sense the calcium concentration, the kidneys decide how much calcium and phosphate leave the body and activate vitamin D, the intestine controls how much calcium enters from food, and bone provides a large mineral reservoir. Parathyroid hormone, or PTH, links these responses together.

The parathyroid glands are continuously sampling extracellular calcium

Most people have four parathyroid glands lying on the posterior surface of the thyroid. Their chief cells carry calcium-sensing receptors, often shortened to CaSR, in their cell membranes. These receptors respond directly to extracellular ionised calcium.

When calcium is within range, activation of the calcium-sensing receptor restrains PTH secretion. When ionised calcium falls, that restraint is reduced and PTH secretion rises rapidly. As calcium is restored, calcium-sensing receptor activation increases again and PTH falls. The gland is therefore continuously adjusting its output rather than simply switching on when calcium becomes severely low.

PTH then acts mainly at the kidney and bone. The intestine joins the response indirectly because PTH changes vitamin D metabolism in the kidney.

The kidney does much more than stop calcium being lost

Calcium is filtered at the glomerulus, but most filtered calcium is reclaimed as tubular fluid moves through the nephron. PTH fine-tunes this by increasing calcium reabsorption, particularly in the distal nephron. When extracellular calcium is falling, less calcium is therefore allowed to leave the body in urine.

Phosphate is handled differently. PTH reduces phosphate reabsorption in the proximal tubule by reducing sodium-phosphate cotransport, so more phosphate remains in tubular fluid and is excreted.

Calcium and phosphate are closely linked. Bone mineral contains both. If PTH increases mineral release from bone, calcium and phosphate can both enter extracellular fluid. At the same time, PTH promotes renal phosphate loss. This helps increase the availability of ionised calcium without simply retaining the accompanying phosphate.

The kidney has another role that changes the whole response: it converts vitamin D into its active hormonal form.

Vitamin D has to be processed before it can do this job

Vitamin D can be produced in the skin following ultraviolet B exposure or obtained from dietary sources, but neither route produces active calcitriol immediately. Vitamin D first travels to the liver, where it is converted to 25-hydroxyvitamin D. This is the main circulating form and the form usually measured when vitamin D status is assessed.

25-hydroxyvitamin D then reaches the kidney. In the proximal tubule, the enzyme 1-alpha-hydroxylase converts it to 1,25-dihydroxyvitamin D, known as calcitriol. Calcitriol is the active hormonal form of vitamin D.

PTH stimulates this renal activation step. A fall in calcium detected by the parathyroid glands can therefore change the amount of active vitamin D being produced by the kidneys. Calcitriol can then alter calcium absorption in the intestine.

Calcitriol also feeds back on the parathyroid glands and suppresses PTH production. Calcium homeostasis is therefore a set of interacting feedback loops rather than a simple one-way chain.

What does calcitriol change in the intestine?

Imagine calcium sitting in the lumen of the small intestine after a meal. For that calcium to help restore extracellular calcium, it has to cross the intestinal epithelium and enter the circulation.

Calcitriol binds to vitamin D receptors in intestinal cells and changes expression of proteins involved in calcium transport. In the traditional model of active transcellular absorption, calcium enters across the apical surface through calcium-permeable channels including TRPV6. Calcium-binding proteins such as calbindin help handle calcium within the cell, while calcium is moved across the basolateral membrane towards the blood, importantly through the ATP-dependent calcium pump PMCA1b.

The biology is more complex than one channel carrying every calcium ion. Calcium can also cross between intestinal cells by paracellular routes, and research shows that individual transport proteins can be partly compensated for. The physiological result is clearer: calcitriol changes the intestinal epithelium so dietary calcium can be absorbed more efficiently, particularly when the body needs to conserve calcium.

Calcitriol also promotes intestinal phosphate absorption. Normal bone mineralisation needs an adequate supply of both calcium and phosphate.

Bone is not a passive calcium store

Almost all of the body's calcium is in the skeleton, largely within hydroxyapatite crystals that give mineralised bone its strength. But bone is living tissue. Small areas are continually being removed and replaced through remodelling.

Osteoclasts resorb mineralised bone. Osteoblast-lineage cells coordinate new bone formation, but they also help regulate osteoclast development. This is where PTH enters the process.

PTH does not simply bind to an osteoclast and make it release calcium. PTH receptors are expressed on osteoblast-lineage cells. With sustained PTH signalling, these cells alter signals controlling osteoclast formation, including increasing receptor activator of nuclear factor kappa-B ligand, or RANKL. RANKL interacts with RANK on osteoclast precursors and promotes their differentiation and activity. The net effect of sustained PTH exposure is increased bone resorption, releasing calcium and phosphate from mineralised bone.

The pattern of PTH exposure matters. Intermittent PTH exposure can affect bone differently from continuously raised PTH, which is why describing PTH simply as a hormone that breaks down bone is misleading. In calcium homeostasis, sustained PTH elevation provides a way of defending extracellular calcium when supply is inadequate.

Vitamin D also cannot be reduced to putting calcium into bone. Adequate vitamin D supports mineralisation largely by maintaining the calcium and phosphate supply available to the skeleton. In vitamin D deficiency, intestinal calcium absorption becomes less efficient. PTH may then rise to defend extracellular calcium through renal conservation and increased bone turnover. Blood calcium can therefore remain relatively preserved while the skeleton is carrying more of the burden.

Follow one fall in calcium through the whole system

Imagine ionised calcium begins to fall. Calcium-sensing receptor activation on the parathyroid chief cells falls with it, so PTH secretion increases.

At the kidney, PTH increases calcium conservation and phosphate excretion. It stimulates 1-alpha-hydroxylase, increasing calcitriol production. Calcitriol travels to the intestine and increases the capacity to absorb dietary calcium. At bone, sustained PTH signalling can increase resorption and make stored calcium available to extracellular fluid.

As ionised calcium rises, the signal that started the response weakens. Calcium-sensing receptor activation increases and PTH secretion falls. Calcitriol also suppresses PTH synthesis and parathyroid activity. The system is constantly adjusted rather than waiting for calcium to become severely abnormal.

Phosphate is woven through this regulation too. PTH promotes phosphate loss at the kidney, while calcitriol promotes phosphate absorption from the intestine. Fibroblast growth factor 23, or FGF23, also participates. Produced mainly by bone cells, FGF23 promotes renal phosphate excretion and suppresses calcitriol production. You do not need FGF23 to follow the basic PTH response to falling calcium, but it shows why mineral homeostasis is a network rather than a two-hormone switch.

The blood results make more sense once the feedback loop is clear

Consider a patient with raised calcium. If the feedback system is working normally, high calcium should suppress PTH. A PTH concentration that remains raised, or is inappropriately normal rather than suppressed, therefore points towards PTH-dependent hypercalcaemia. Primary hyperparathyroidism is the classic example. NICE recommends measuring PTH with a concurrent albumin-adjusted serum calcium and interpreting the two together.

Now reverse the picture. If calcium is genuinely low, the normal response is for PTH to rise. In hypoparathyroidism that response is absent or inadequate. Renal calcium conservation under PTH control is reduced, phosphate excretion falls and renal activation of vitamin D is reduced. The accompanying PTH and phosphate results therefore help show which part of the regulatory system has failed.

Vitamin D deficiency produces a different disturbance. Less vitamin D means less effective support for intestinal calcium absorption. As calcium balance becomes harder to maintain, PTH can rise appropriately. This is secondary hyperparathyroidism: the parathyroid glands are responding to a problem elsewhere rather than secreting autonomously. Higher PTH helps defend extracellular calcium, but prolonged compensation can increase bone turnover.

Chronic kidney disease disrupts several parts of the system at once. As functioning renal mass declines, phosphate handling becomes impaired and calcitriol production falls. Reduced calcitriol contributes to impaired intestinal calcium absorption, while changes in phosphate, calcium, FGF23 and vitamin D signalling stimulate progressive parathyroid activity. Chronic kidney disease-mineral and bone disorder is therefore much more than a problem of high phosphate or low vitamin D. The kidney has lost part of its central coordinating role in mineral homeostasis.

When calcium, phosphate, PTH, vitamin D and renal function are requested together, read them as a conversation between organs. Ask what the calcium concentration should be doing to PTH, whether the kidneys can respond normally, whether active vitamin D can be produced, and whether phosphate is being retained or excreted. The individual numbers begin to describe the physiology rather than sitting on the screen as unrelated results.

References

National Institute for Health and Care Excellence (2024) Hyperparathyroidism (primary): diagnosis, assessment and initial management (NG132).

Shaker, J.L. and Deftos, L. (2023) Calcium and Phosphate Homeostasis. Endotext. MDText.com.

Bikle, D.D. (2024) Vitamin D: Production, Metabolism, and Mechanism of Action. Endotext. MDText.com.

Kidney Disease: Improving Global Outcomes (KDIGO) (2017) Clinical Practice Guideline Update for Chronic Kidney Disease-Mineral and Bone Disorder.