Calcium and Phosphate Regulation Summary

Calcium and Phosphate Regulation

Distribution of Calcium

• Calcium is primarily stored in bones (99%), with smaller amounts in intracellular fluid (ICF) and extracellular fluid (ECF).

• Total plasma calcium: 9-10.5 mg/dl

• Forms of calcium in ECF/Plasma:

  • Non-diffusible (protein-bound): 41% (primarily albumin)

  • Diffusible (ionized and complexed to anions): 59%

  • Includes calcium complexed with bicarbonate, citrate, phosphate

• Ionized calcium is the physiologically active form.

Calcium Functions

• Muscle contraction (skeletal, cardiac, smooth)

• Blood clotting: Activates clotting factors.

• Nerve impulse transmission: Influences neurotransmitter release and neuronal excitability.

• Bone formation: Important for hydroxyapatite crystal formation

• Second messenger in signaling pathways: e.g., calmodulin activation

• Enzyme cofactor: Participates in enzymatic reactions

• Stabilizing resting membrane potential:

  • $↓$ Serum $Ca^{2+}$ $→$ $↑$ membrane excitability (hypocalcemia leads to tetany)

  • $↑$ Serum $Ca^{2+}$ $→$ $↓$ membrane excitability (hypercalcemia leads to muscle weakness)

Non-ionized vs. Ionized Calcium

• Non-ionized Calcium:

  • Bound to proteins (albumin) and complexed with anions.

  • Serves as a reserve.

• Ionized Calcium:

  • Free calcium, biologically active.

  • Crucial for muscle contraction, nerve function, blood clotting, and enzyme activity.

Calcium and Albumin Binding

• Binding is pH-dependent.

• Alkalosis: Low ionized $Ca^{2+}$ (more protein binding)

• Acidosis: High ionized $Ca^{2+}$ (less protein binding)

Phosphate

• Plasma concentration: ~4 mg/dL.

• Essential for ATP, cAMP, phospholipid bilayer, and nucleic acid structure.

• Forms: Ionized (50%) and Un-ionized (50%).

• Tightly regulated with calcium.

Effects of Altered Calcium and Phosphate

• Slight changes in calcium can cause immediate physiological effects.

• Chronic hypo-calcemia or hypo-phosphatemia decreases bone mineralization, leading to osteomalacia or rickets.

Hypocalcemia

• Increases nerve excitability due to increased neuronal membrane permeability to sodium ions.

• Symptoms: tetany, paresthesias, spasms, seizures, Chvostek's and Trousseau's signs.

Hypercalcemia

• Decreases nerve excitability (decreased sodium permeability).

• Symptoms: Stones (kidney stones), bones (bone pain), groans (abdominal pain, constipation), thrones (polyuria), psychiatric overtones (anxiety, cognitive dysfunction).

Vitamin D

• Promotes calcium absorption in the intestine by increasing the production of calcium-binding proteins.

• Promotes bone calcification in smaller quantities.

• Extreme quantities cause bone absorption by increasing osteoclast activity.

Parathyroid Hormone (PTH)

• Increases plasma calcium levels and decreases phosphate levels.

• Acts on kidneys, bone, and intestine.

• Increases calcium and phosphate resorption from bone (activates osteoclasts).

Calcitonin

• Decreases blood calcium and phosphate levels.

• Opposite effect to PTH; inhibits osteoclast activity.

Bone Cells

• Osteoblasts: Bone forming cells; synthesize and secrete bone matrix (osteoid).

• Osteocytes: Osteoblasts surrounded by calcified matrix; sense mechanical stress and regulate bone remodeling.

• Osteoclasts: Bone eroding cells; resorb bone by secreting acids and enzymes.

Bone Turnover

• RANK/RANK-L/OPG system regulates osteoclast activity.

  • More RANK-L/MCSF $→$ More osteoclast activity

  • More OPG $→$ Less osteoclast activity

Bone Formation

• Wolf's Law: Bones become thicker and stronger with stress, and thinner and weaker without stress; bone adapts to mechanical loading.

Vitamin D Metabolism

• Vitamin D $→$ Liver (25-hydroxycholecalciferol) $→$ Kidney (1,25-dihydroxycholecalciferol/calcitriol).

• PTH stimulates 1α-hydroxylase in the kidney to produce calcitriol.

PTH Regulation

• Decreased extracellular calcium $→$ Increased PTH secretion.

• Calcium-sensing receptor (CaSR) in parathyroid cells detects calcium levels; regulates PTH secretion based on serum calcium.