What is the mechanism of action of Parathyroid Hormone (PTH)?

Mechanism of Action of Parathyroid Hormone (PTH)

Parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism, acting through binding to specific high-affinity PTH1 receptors on target tissues to increase serum calcium levels through three main mechanisms: increasing calcium reabsorption in the kidneys, stimulating bone calcium release, and enhancing intestinal calcium absorption via vitamin D activation. 1, 2, 3

PTH Structure and Synthesis

• PTH is synthesized in the chief cells of the parathyroid glands as a 115-amino acid peptide precursor (pre-proPTH)
• Pre-proPTH is cleaved to proPTH, which is further cleaved to the biologically active 84-amino acid PTH 1
• The first 34 N-terminal amino acids and formation of an alpha helix are crucial for biological activity 1, 3
• PTH has a very short half-life (2-4 minutes), while C-terminal fragments have longer half-lives (5-10 times longer) 1

Primary Mechanisms of Action

1. Effect on Kidneys

• PTH binds to PTH1R in the distal and proximal renal tubules to:
  • Increase calcium reabsorption
  • Decrease phosphate reabsorption (phosphaturic effect)
  • Stimulate 1-α-hydroxylase (CYP27B1) to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (active form) 1, 2, 3

2. Effect on Bone

• PTH binds to PTH1R on osteoblasts and osteocytes to:
  • Stimulate release of calcium and phosphate from bone into circulation
  • With intermittent exposure (e.g., once-daily administration), preferentially stimulate osteoblastic activity over osteoclastic activity 1, 3
  • Improve trabecular microarchitecture and increase bone mass and strength 3

3. Effect on Intestine (Indirect)

• PTH indirectly increases intestinal calcium absorption by:
  • Stimulating renal production of 1,25-dihydroxyvitamin D
  • 1,25-dihydroxyvitamin D then increases intestinal calcium absorption through binding to vitamin D receptors 1, 2

Regulation of PTH Secretion

• Hypocalcemia is sensed via calcium-sensing receptors (CaSR) on parathyroid glands, triggering PTH release 1, 2
• Low 1,25-dihydroxyvitamin D levels increase PTH secretion 2
• Hyperphosphatemia directly stimulates PTH secretion 2
• FGF23 (fibroblast growth factor 23) suppresses PTH secretion 1

Clinical Implications

• Pattern of exposure matters: intermittent PTH (as in teriparatide therapy) stimulates bone formation, while continuous excess (as in hyperparathyroidism) may be detrimental to the skeleton 3
• In chronic kidney disease, decreased kidney function leads to phosphate retention, decreased active vitamin D production, and secondary hyperparathyroidism 4
• PTH measurement is important in diagnosing parathyroid disorders, but standardization challenges exist between different assay methods 1

Pathological States

• Hyperparathyroidism: Excessive PTH secretion leads to increased serum calcium, bone resorption, and potential complications including skeletal disease, renal involvement, and neuromuscular symptoms 5
• Hypoparathyroidism: Insufficient PTH secretion results in hypocalcemia, hyperphosphatemia, and symptoms like tetany, hyperactive reflexes, and paresthesia 5

Understanding PTH's mechanism of action is crucial for managing disorders of calcium metabolism and for therapeutic applications such as teriparatide in osteoporosis treatment.