Calcium Homeostasis for the FRCS Orth

Courtesy: Quen Tang, FRCS Orth

Calcium homeostasis refers to the regulation of serum calcium levels within a narrow physiological range, which is essential for bone health, neuromuscular function, blood coagulation, and cellular signaling.

---

Hormones Involved in Calcium Homeostasis

Three major hormones regulate calcium balance:

1. Parathyroid hormone

2. Vitamin D

3. Calcitonin

---

Target Organs of Calcium-Regulating Hormones

These hormones primarily act on 3 organ systems:

1. Gastrointestinal tract

2. Kidneys

3. Bone

---

Parathyroid Hormone

Secretion

• Secreted by the chief cells of the parathyroid glands.

• Released in response to low serum calcium levels.

---

Actions of Parathyroid Hormone

Effects on the Gastrointestinal Tract

• Indirectly increases calcium absorption through activation of vitamin D.

• Phosphate absorption from the gut is increased secondary to vitamin D activation.

---

Effects on Bone

• Increases osteoclastogenesis and bone resorption.

• Osteoclast activity is increased through 3 mechanisms:

1. Stimulation of osteoblast differentiation

   • Osteoblasts express receptor activator of nuclear factor kappa B ligand.

   • This binds to receptors on pre-osteoclasts, converting them into mature osteoclasts.

2. Inhibition of osteoprotegerin

   • Osteoprotegerin is a competitive inhibitor of receptor activator of nuclear factor kappa B ligand.

   • Parathyroid hormone suppresses osteoprotegerin, removing inhibition of osteoclast formation.

3. Upregulation of receptor activator of nuclear factor kappa B ligand expression

   • Enhances osteoclast maturation and activity.

• Bone resorption leads to breakdown of the inorganic extracellular matrix.

• Calcium and phosphate are released into the circulation.

---

Effects on the Kidneys

• Increases activity of 1 alpha hydroxylase enzyme.

• Converts 25-hydroxy vitamin D to its active form, 1,25-dihydroxy vitamin D.

• Increases renal calcium reabsorption.

• Decreases renal phosphate reabsorption, increasing phosphate excretion.

---

Net Effect of Parathyroid Hormone

• Increase in serum calcium

• Decrease in serum phosphate

---

Vitamin D

Sources

• Synthesized in the skin under ultraviolet light exposure.

• Obtained from dietary sources.

---

Metabolism

• Converted in the liver to 25-hydroxy vitamin D (inactive form).

• Further converted in the kidneys to 1,25-dihydroxy vitamin D (active form).

---

Actions of Active Vitamin D

Effects on the Gastrointestinal Tract

• Increases calcium absorption.

• Increases phosphate absorption.

---

Effects on Bone

• Stimulates parathyroid hormone secretion.

• Increases osteoclastic activity indirectly via parathyroid hormone.

• Promotes mobilization of calcium from bone when required.

---

Effects on the Kidneys

• Increases renal calcium reabsorption.

• Increases renal phosphate reabsorption.

---

Net Effect of Vitamin D

• Increase in serum calcium

• Increase in serum phosphate

---

Calcitonin

Secretion

• Released from parafollicular cells of the thyroid gland.

• Secreted in response to elevated serum calcium levels.

---

Actions of Calcitonin

Effects on the Gastrointestinal Tract

• No significant effect.

---

Effects on Bone

• Inhibits osteoclast activity.

• Acts opposite to parathyroid hormone.

• Reduces bone resorption.

---

Effects on the Kidneys

• Decreases renal reabsorption of calcium.

• Decreases renal reabsorption of phosphate.

---

Net Effect of Calcitonin

• Decrease in serum calcium

• Decrease in serum phosphate

---

Rickets and Osteomalacia

Pathophysiology

• Decreased dietary or endogenous vitamin D leads to reduced calcium absorption.

• Hypocalcemia stimulates parathyroid hormone secretion.

• Secondary hyperparathyroidism develops.

• Increased osteoclastic activity results in defective bone mineralization.

---

Clinical Outcome

• In children: Rickets

• In adults: Osteomalacia

---

Vitamin D–Dependent Rickets

Type 1 Vitamin D–Dependent Rickets

• Caused by deficiency of 1 alpha hydroxylase enzyme.

• Inability to convert 25-hydroxy vitamin D to active 1,25-dihydroxy vitamin D.

• Results in hypocalcemia.

• Secondary hyperparathyroidism develops.

• Leads to rickets.

---

Type 2 Vitamin D–Dependent Rickets

• Caused by resistance of intracellular receptors to 1,25-dihydroxy vitamin D.

• Active vitamin D levels are normal or elevated, but target tissues are unresponsive.

• Results in hypocalcemia.

• Elevated parathyroid hormone levels.

• Leads to rickets.

---

Summary

• Calcium homeostasis is regulated by parathyroid hormone, vitamin D, and calcitonin.

• These hormones act primarily on the gut, kidneys, and bone.

• Parathyroid hormone and vitamin D increase serum calcium, while calcitonin lowers it.

• Disruption of vitamin D metabolism leads to rickets in children and osteomalacia in adults.

• Understanding these mechanisms is essential for diagnosing and managing metabolic bone disorders.