Hormonal Control of Calcium Metabolism

Overview of Calcium and Phosphate Metabolism

Purpose and Clinical Agenda

The primary objective of this lecture is to understand the coordinated regulation of calcium ($Ca^{2+}$) and phosphate ($PO_4^{3-}$) levels by three key hormones ($1,25(OH)_2 D_3$, Parathyroid Hormone, and Calcitonin) to maintain cellular homeostasis.

Roles of Phosphate in the Body

Phosphate is essential for several physiological and structural functions:

• Nucleotides: Essential component of DNA and RNA.
• Oxidative Phosphorylation: Key element in the production of ATP ($ext{Adenosine Triphosphate}$).
• Buffer System: Acts as an intracellular and urinary buffer.
• Protein/Lipid Modification: Component of phosphoproteins and phospholipids.
• Structure: A major structural component of teeth and bone.

Roles of Calcium in the Body

Calcium is critical for various systemic and cellular processes:

• Nerve Impulse Transmission: Essential for neurotransmitter release.
• Excitation-Contraction Coupling: Required for muscle fiber contraction in skeletal, cardiac, and smooth muscle.
• Blood Clotting: Acts as a cofactor (Factor IV) in the coagulation cascade.
• Signal Transduction: Functions as a secondary messenger in many intracellular signaling pathways.
• Fertilization: Involved in the processes triggering egg activation.

Calcium Distribution and Pathophysiology

Distribution of Calcium in Plasma

Normal plasma calcium levels range between $8.5-10.5 ext{ mg/dL}$. Plasma calcium exists in several forms:

• Protein-bound ($40\%$): Primarily bound to albumin; this fraction is not filtered by the kidney.
• Ultrafilterable ($60\%$): This portion can pass through the glomerular membrane.     * Complexed to anions ($10\%$): Complexed with substances like citrate and phosphate.     * Ionized $Ca^{2+}$ ($50\%$): The biologically active form that is homeostatically regulated.

Endocrine Emergency: Acute Hypocalcemia

Defined as plasma $Ca^{2+}$ levels below $8.5 ext{ mg/dL}$.

Symptoms and Signs

1. Neuromuscular Excitability: Increased excitability can lead to generalized hypocalcemic tetany, seizures, and potentially asphyxia if laryngeal muscles are affected.
2. Clinical Signs:     * Trousseau Sign: Carpopedal spasm induced by inflating a blood pressure cuff above systolic pressure.     * Hyperreflexia: Twitching, muscle cramps, tingling, and numbness.
3. Blood Clotting: Decreased efficiency of the clotting cascade.
4. Cardiovascular System (CVS): Decreased cardiac contractility and hypotension.

Mechanism of Excitability

Low extracellular calcium concentrations ($[Ca^{2+}]_o$) affect voltage-gated $Na^+$ channels.

• Low $Ca^{2+}$ levels lower the threshold potential for initiating an action potential.
• This allows depolarization to occur more easily, resulting in increased neuronal excitability.

Management and Causes

• Management: Life-threatening cases are treated with intravenous (I.V.) Calcium-gluconate. Less severe cases are managed with increased oral calcium and Vitamin D intake.
• Causes: Deficiency in Parathyroid Hormone (PTH) secretion or action, Vitamin D deficiency, or surgical loss of the parathyroid glands.

Endocrine Emergency: Hypercalcemic Crisis

Defined as plasma calcium levels exceeding $14 ext{ mg/dL}$.

Symptoms and Mechanism

1. Cardiac Arrhythmias.
2. Depressed Neuromuscular Excitability: Manifests as lethargy, fatigue, and muscle weakness.
3. Bone Health: Leads to osteoporosis if left untreated.

• Mechanism: High extracellular calcium inhibits voltage-gated sodium channels, thereby decreasing neuronal excitability.

Management and Causes

• Management: Administration of bone loss inhibitors to decrease the mobilization of calcium from the skeletal system.
• Causes: Most commonly caused by Primary Hyperparathyroidism (often via a tumor).

Sources, Sinks, and Calcium Balance

Calcium Flux in the Body

• Storage: Bone contains approximately $1,000 ext{ g}$ of calcium.
• Ingestion: Typical intake is $1 ext{ g/day}$.
• Absorption: Without Vitamin D, only $10-15\%$ of ingested calcium is absorbed. Normal absorption is approximately $0.5 ext{ g/day}$.
• Excretion:     * Fecal: $0.83 ext{ g/day}$ (representing unabsorbed dietary Ca and secreted Ca).     * Urinary: $0.17 ext{ g/day}$.
• Remodeling: Bone formation and resorption both occur at a rate of approximately $0.55 ext{ g/day}$.

Balance Calculations

• Total Loss per day: $0.17 ext{ g (urine)} + 0.33 ext{ g (G.I. secretion)} = 0.5 ext{ g}$.
• Neutral Balance: If diet provides $1.0 ext{ g}$ and absorption is $50\%$, net intake is $0.5 ext{ g}$, resulting in equilibrium.
• Deficit: If diet provides $0.6 ext{ g}$ and absorption is $50\%$, net intake is $0.3 ext{ g}$, resulting in a $0.2 ext{ g/day}$ deficit.

Dietary Guidelines

• FDA Recommendations:     * Under age 70: $1,000 ext{ mg/day}$.     * Over age 70: $1,200 ext{ mg/day}$.
• Sources: Dairy, fortified plant milks, cheese, yogurt, calcium-fortified orange juice, broccoli, almonds, canned sardines, and leafy greens.

Bone Physiology and Cellular Composition

Bone Structure

• Composition: A collagenous matrix impregnated with hydroxyapatites ($Ca_{10}(PO_4)_6(OH)_2$).
• Compact (Cortical) Bone: Makes up the outer layer; accounts for $80\%$ of total bone mass.
• Trabecular (Spongy) Bone: Found inside the cortical bone; accounts for $20\%$ of total bone mass.

Bone Cells and Hormone Receptors

1. Osteoblasts: Bone-forming cells that secrete collagen to form a matrix that subsequently calcifies. They express PTH Receptors (PTH-R) and Vitamin D Receptors (VDR).
2. Osteocytes: Differentiated osteoblasts that have become surrounded by bone matrix. They possess long processes and also express PTH-R.
3. Osteoclasts: Multinucleated cells responsible for digesting and resorbing previously formed bone. They express Calcitonin Receptors (CT-R).

Vitamin D Metabolism and Regulation

Synthesis and Activation

1. Skin: Sunlight (UV light) converts 7-dehydrocholesterol to Vitamin $D_3$.
2. Liver: Conversion to $25-(OH) D_3$ by the enzyme 25-hydroxylase. This has a half-life of approximately $15 ext{ hours}$.
3. Kidney: Final activation to 1,25-(OH)$_2 D_3$ (Calcitriol) by the enzyme 1-$\alpha$-hydroxylase.     * This step is stimulated by PTH and low plasma levels of calcium and phosphate.     * It is inhibited by high levels of calcitriol (negative feedback).

Physiological Effects of Vitamin D

The primary action of Vitamin D is to provide calcium and phosphate to the ECF for bone mineralization.

• Intestine: Significantly increases absorption of dietary $Ca^{2+}$ and phosphate ($PO_4^{3-}$) via transporters like NPT (Sodium Phosphate Transporter).
• Kidney: Promotes renal reabsorption of both calcium and phosphate (though these effects are relatively weak).
• Bone: Synergistically works with PTH to mobilize $Ca^{2+}$ and phosphate; promotes mineralization of new bone in the absence of PTH (especially during youth).
• Parathyroid Gland: Decreases the synthesis of pre-pro-PTH.

Deficiency: Rickets

Vitamin D deficiency in children leads to Rickets, characterized by:

• Poor bone mineralization.
• Bowing of the femur due to the inability of the skeleton to support weight.
• Historically treated with Heliotherapy (sun exposure).

Parathyroid Hormone (PTH)

Synthesis and Secretion

• Type: Peptide hormone ($84 ext{ amino acids}$); the N-terminus contains the biologic activity.
• PTHrP (PTH-related peptide): Produced by certain cancer tissues; can bind to PTH-R and lead to hypercalcemia.
• Synthesis Pathway: Prepropeptide $\rightarrow$ pro-PTH $\rightarrow$ active PTH.
• Regulation:     * Calcium Sensing Receptor (CaSR): A G-protein coupled receptor (GPCR) on parathyroid cells.     * Increased extracellular $Ca^{2+}$ binds to CaSR, increasing intracellular $Ca^{2+}$, which suppresses PTH secretion and gene transcription of preproPTH.     * Magnesium: Both very low and very high levels of $Mg^{2+}$ inhibit PTH secretion.     * Phosphate: High plasma $[PO_4^{3-}]$ stimulates PTH secretion.

Physiological Effects of PTH

The goal of PTH is to make calcium available in the plasma and eliminate excess phosphate.

• Kidney:     * Increases renal reabsorption of $Ca^{2+}$ in the distal tubule.     * Phosphaturic action: Inhibits the Na/Phosphate cotransporter in the proximal tubule, increasing phosphate excretion.
• Bone:     * Intermittent pulses: Promote bone formation.     * Continuous exposure: Promotes bone resorption by stimulating osteoblasts to produce RANKL (Receptor Activator of Nuclear Factor $\kappa$B Ligand).     * RANKL binds to RANK on pre-osteoclasts, causing them to differentiate into mature, bone-resorbing osteoclasts.     * Osteoprotegerin (OPG): A decoy receptor that inhibits RANKL; its production is stimulated by estrogen.

Calcitonin

Characteristics and Mechanism

• Source: Produced by C-cells (parafollicular cells) of the thyroid gland.
• Stimulus: Secreted when plasma calcium levels exceed $9.5 ext{ mg/dL}$.
• Structure: Peptide hormone ($32 ext{ amino acids}$).
• Function: Antagonizes the effects of PTH and Vitamin D; decreases plasma calcium and phosphate.

Specific Actions

• Bone: Directly inhibits osteoclasts via CT-R, thereby decreasing bone resorption.
• Kidney: Increases urinary excretion of $Ca^{2+}$ by inhibiting reabsorption and stimulating secretion via the Na/Ca exchanger in the basolateral membrane. It also stimulates 24-$\alpha$-hydroxylase, which leads to a decrease in active Vitamin D.

Clinical Significance

Calcitonin is considered less vital than PTH for minute-to-minute calcium regulation in adults.

• Deficiency (post-thyroidectomy) or excess (medullary carcinoma) does not typically lead to significant disruptions in calcium metabolism.
• It is most important during periods of rapid growth, post-prandially (to prevent hypercalcemia), and during pregnancy to protect the maternal skeleton.

Questions & Discussion

Q: Ingestion of $0.5 ext{ g}$ calcium per day will lead to:

• A: A deficit in our calcium balance. (Because total daily loss via urine and G.I. secretion is $0.5 ext{ g}$, and only a fraction of the $0.5 ext{ g}$ ingested would be absorbed, leaving the body in a net deficit).

Q: What would you expect serum calcium and phosphate levels to be in someone who is Vitamin D deficient?

• A: Both calcium and phosphate will be low. (Vitamin D is required for the absorption of both minerals in the intestine).

Q: Sustained high plasma PTH will lead to all the following EXCEPT:

• A: Increased bone mass density. (High, sustained PTH promotes bone resorption/osteoporosis, not increased density).

Q: During a surgical removal of the thyroid gland, the parathyroid glands were accidentally removed. Which of the following might be expected as a result?

• A: Hyperphosphatemia. (Loss of PTH means the phosphaturic effect is lost, so the kidneys cannot effectively excrete phosphate, leading to high plasma levels).