What is the role of parathyroid hormone (PTH) in regulating calcium levels in the blood?

Role of Parathyroid Hormone in Calcium Regulation

Parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in the body, acting on bone, kidneys, and indirectly on the intestines to increase serum calcium levels while promoting phosphate excretion, thereby maintaining calcium homeostasis. 1, 2

PTH Structure and Metabolism

• PTH is synthesized in the chief cells of the parathyroid glands as a 115-amino acid peptide precursor (pre-proPTH), which is cleaved to proPTH and finally to the biologically active 84-amino acid peptide that is secreted into circulation 1
• The first 34 amino acids and the formation of an alpha helix are crucial for PTH's biological activity 1
• PTH circulates as both the full-length 84-amino acid peptide and as multiple C-terminal fragments, which arise from liver metabolism and direct secretion from the parathyroid gland 1
• The plasma half-life of full-length PTH is very short (2-4 minutes), while C-terminal fragments have a half-life 5-10 times longer with normal kidney function 1

Mechanism of Action

• PTH binds to specific high-affinity cell-surface receptors (PTH1R) in target tissues, primarily bone and kidney 2
• Low serum calcium levels stimulate PTH secretion through the calcium-sensing receptor (CaSR) in the parathyroid gland 1
• PTH secretion is also influenced by serum phosphate levels, vitamin D metabolites, and FGF23 1

Effects on Target Organs

Bone Effects

• PTH binding to PTH1R in bones stimulates the release of calcium and phosphate from bone into circulation 1
• In intermittent exposure (as with once-daily administration of teriparatide), PTH stimulates new bone formation on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity 2
• Continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation 2

Kidney Effects

• In the kidneys, PTH increases calcium reabsorption while inhibiting phosphate reabsorption 3
• PTH binding to PTH1R in the proximal tubule decreases phosphate reabsorption by reducing the abundance of sodium phosphate cotransporters in the apical membrane, leading to phosphaturia 3, 4
• In the thick ascending limb and distal tubule, PTH increases calcium permeability and reabsorption 4
• PTH stimulates the hydroxylation of 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D (calcitriol) by activating renal 1α-hydroxylase 1, 5

Intestinal Effects (Indirect)

• The PTH-stimulated production of 1,25-dihydroxyvitamin D increases intestinal absorption of calcium through binding to the vitamin D receptor 1
• This indirect effect on intestinal calcium absorption is an important component of PTH's overall action to increase serum calcium levels 6

Integrated Calcium Homeostasis

• When serum calcium levels decrease, PTH secretion increases, which then:

  1. Increases calcium release from bone 1
  2. Enhances calcium reabsorption in the kidneys 4
  3. Stimulates 1,25-dihydroxyvitamin D production, increasing intestinal calcium absorption 1
  4. Promotes phosphate excretion in the urine 3

• These coordinated actions result in increased serum calcium levels without significantly affecting phosphate concentration 1

Clinical Implications

• Disorders of PTH secretion lead to disruptions in calcium homeostasis:

  • Hyperparathyroidism results in hypercalcemia, increased bone resorption, and hypophosphatemia 7
  • Hypoparathyroidism leads to hypocalcemia, which can manifest as tetany, paresthesias, and seizures 1, 7

• In chronic kidney disease (CKD), as kidney function declines:

  • The phosphaturic effect of PTH becomes increasingly important 3
  • When kidney function severely deteriorates (CKD Stage 4), the maximum phosphaturic effect of PTH is reached, and serum phosphorus levels begin to rise despite elevated PTH 3
  • This represents a failure of the normal compensatory response 3

Common Pitfalls and Caveats

• PTH measurement can be complicated by the presence of multiple fragments and post-translational modifications:

  • C-terminal fragments accumulate in kidney disease and may interfere with PTH measurement 1
  • Oxidation and phosphorylation of PTH can render it biologically inactive 1
  • Current immunoassays may overestimate or underestimate bioactive PTH due to these factors 6

• The pattern of PTH exposure is critical for its skeletal effects:

  • Intermittent exposure (as with therapeutic teriparatide) is anabolic to bone 2
  • Continuous elevation (as in hyperparathyroidism) can be catabolic to bone 2