What hormones regulate calcium homeostasis?

Hormonal Regulation of Calcium Homeostasis

Three primary hormones regulate calcium homeostasis: parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (calcitriol), and fibroblast growth factor 23 (FGF23), which act in a coordinated manner on bone, kidney, intestine, and parathyroid glands to maintain serum calcium levels. 1

Primary Regulatory Hormones

Parathyroid Hormone (PTH)

PTH is the principal regulator of calcium homeostasis, secreted in response to hypocalcemia detected by calcium-sensing receptors on parathyroid chief cells. 1

PTH increases serum calcium through three distinct mechanisms:

• Kidney effects: PTH binds to PTH1R in the distal and proximal renal tubules, increasing calcium reabsorption while simultaneously decreasing phosphate reabsorption 1

• Bone effects: PTH binding to PTH1R in bone stimulates release of both calcium and phosphate from bone into circulation 1

• Indirect intestinal effects: PTH stimulates the enzyme 1-α-hydroxylase (CYP27B1) in the kidney to convert 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D, which then increases intestinal calcium absorption 1, 2

The biologically active portion resides in the first 34 amino acids of the 84-amino acid PTH molecule, with amino acids 1-7 being critical for receptor binding and biological activity 3

1,25-Dihydroxyvitamin D (Calcitriol)

Calcitriol is the most active form of vitamin D and primarily increases serum calcium by stimulating intestinal calcium absorption through binding to the vitamin D receptor (VDR). 1, 2

The activation pathway involves sequential hydroxylation:

• First hydroxylation: Vitamin D3 (cholecalciferol) is hydroxylated in the liver by 25-hydroxylase to form 25-hydroxyvitamin D 1, 2

• Second hydroxylation: 25-hydroxyvitamin D undergoes hydroxylation in kidney mitochondria by 1-α-hydroxylase (CYP27B1) to produce the active 1,25-dihydroxyvitamin D 1, 2

• Intestinal action: Calcitriol binds to VDR in intestinal mucosa, stimulating calcium transport and absorption 1, 2

• Feedback regulation: Calcitriol negatively regulates PTH synthesis in the parathyroid glands, completing a feedback loop 4

Physiological daily production of calcitriol is normally 0.5 to 1.0 mcg, with higher production during periods of increased bone synthesis such as growth or pregnancy 2

Fibroblast Growth Factor 23 (FGF23)

FGF23 is secreted by osteocytes and osteoblasts and serves as a counter-regulatory hormone, primarily controlling phosphate homeostasis but indirectly affecting calcium regulation. 1

FGF23 actions include:

• Phosphate excretion: FGF23 binds to the FGF23 receptor with its cofactor Klotho in the kidneys, increasing phosphate excretion into urine 1

• Vitamin D suppression: FGF23 inhibits CYP27B1, thereby decreasing production of 1,25-dihydroxyvitamin D 1

• PTH suppression: FGF23 suppresses PTH secretion from the parathyroid gland 1

• Stimulation triggers: FGF23 is released in response to high concentrations of phosphate, PTH, and 1,25-dihydroxyvitamin D 1

Integrated Regulatory Feedback Loop

The three hormones function in a tightly coordinated feedback system where hypocalcemia triggers PTH release, which then activates vitamin D and mobilizes calcium from multiple sources. 1

The regulatory cascade operates as follows:

• Hypocalcemia detection: Calcium-sensing receptors on parathyroid cells detect low serum calcium and trigger PTH secretion 1, 5

• PTH response: Elevated PTH increases renal calcium reabsorption, stimulates bone calcium release, and activates vitamin D production 1

• Vitamin D activation: Increased 1,25-dihydroxyvitamin D enhances intestinal calcium absorption and provides negative feedback to suppress further PTH secretion 1, 4

• FGF23 modulation: High phosphate, PTH, or 1,25-dihydroxyvitamin D levels stimulate FGF23, which then reduces vitamin D production and increases phosphate excretion 1

Secondary Regulatory Factors

Calcitonin

Calcitonin is produced by parafollicular cells of the thyroid and inhibits bone resorption, though its role in normal human calcium homeostasis remains uncertain. 6, 7

• Calcitonin acts as a calcitonin receptor agonist, causing marked transient inhibition of bone resorption 6

• Single doses decrease serum calcium within normal limits by reducing osteoclast number and activity 6

• The clinical significance in normal physiology is disputed, as its absence (post-thyroidectomy) does not cause obvious calcium dysregulation 7

Clinical Implications and Pitfalls

When interpreting calcium regulatory hormone levels, clinicians must recognize that PTH assays differ significantly between generations, with second-generation "intact PTH" assays overestimating biologically active PTH by detecting inactive C-terminal fragments. 3

Critical considerations include:

• Assay variability: Second-generation assays measure both full-length PTH and the 7-84 PTH fragment (which lacks biological activity), while third-generation assays specifically measure only full-length 1-84 PTH 3

• CKD-specific targets: In chronic kidney disease, attempting to maintain PTH in the "normal" range can cause adynamic bone disease; stage-specific targets must be used instead 3

• Vitamin D forms: The 25-hydroxyvitamin D level (not the active 1,25-dihydroxyvitamin D) is used to diagnose vitamin D deficiency because it has a longer half-life and more accurately reflects vitamin D stores 1

• Sequential monitoring: Always use the same assay in the same laboratory for trend monitoring, as measurements can vary up to 47% between different assay generations 3