Parathyroid Endocrinology & Calcium Regulation

Calcium Homeostasis:

Essential for:

• bones and teeth

• all cells

• nerve and muscle function

• blood clotting

3 hormones responsible (a 3 chapter “story”):

• Parathyroid hormone (PTH)

• Calcitonin

• 1,25(OH)₂Vitamin D₃ (calcitriol or “Vitamin D”)

Distribution of Calcium

Total body calcium = 1 kg

• 99% bone + teeth

• 0.9% soft tissue cells

• 0.1% ECF

  • 0.05% protein-bound or in inorganic complexes

  • 0.05% free ionized (≈500 mg)

• Only free ionized Ca²⁺ is bioactive

Calcium Regulation

Both plasma (ECF) concentration of ionized calcium and total body calcium are regulated:

• Free ionized Ca (0.05%) in ECF by:

  • Exchange between bone and ECF

  • Renal excretion

  • Minute-to-minute regulation

• Total body Ca by:

  • GI absorption of Ca

  • Renal excretion

  • Long-term regulation

Calcium Regulation Compartments

• Small intestine (dietary calcium)

• ECF

• Bone (storage)

• Kidney (excretion)

• Cells (low levels of calcium)

Parathyroid Gland Histology

Chief cells and oxyphil cells:

• Chief cells have a calcium ion sensing receptor!

Parathyroid Hormone (PTH)

• A peptide hormone (84 aa)

• Control by a negative feedback loop:

  • PTH synthesis & secretion stimulated by low plasma ionized Ca2+

  • PTH raises free ionized Ca2+ in ECF

  • PTH activity is essential for life

• PTH acts on bone, kidneys, and - via Vit.D - GI tract

PTH Response to Changes in Plasma Calcium

PTH secretion goes down as plasma Ca goes up

PTH Effects on Bone

Bone remodelling (...ongoing throughout life; complete skeletal turnover every 10 years)

• Osteoblasts create new bone by secreting organic matrix – osteoid – and then mineralizing it with calcium phosphate crystals

• Osteocytes arise from entombed osteoblasts; involved in calcium regulation, but do not create bone

• Osteoclasts dissolve bone (bone resorption) by solubilizing the crystals

Osteoblasts

Create bone throughout life → bone deposition

1. Dividing chondrocytes add length to bone

2. Chondrocytes produce cartilage

3. Old chondrocytes disintegrate

4. Osteoblasts lay down bone on top of cartilage

• Epiphyseal plate is the site of bone growth

Osteoclasts

Dissolve bone → bone resorption

• Secrete acid and enzymes → dissolve bones (apical membrane)

PTH Stimulates:

• Movement of ionized calcium from bone fluid to ECF (fast response time)

• Bone dissolving activity of osteoclasts (slower response time; coincident release of calcium and phosphate)

• Tips bone remodelling in favour of resorption

In a fast exchange:

Calcium is moved from the labile pool in the bone fluid into the plasma by PTH-activated calcium pumps located in the osteocytic-osteoblastic bone membrane

In a slow exchange:

Calcium is moved from the stable pool in the mineralized bone into the plasma through PTH-induced dissolution of the bone by osteoclasts

Osteocytic-osteoblastic Bone Membrane

Formed by filmy cytoplasmic extensions of interconnected osteocytes and osteoblasts

RANK Ligand (RANKL) Binding:

1. Stimulates macrophages/osteoclasts

2. Differentiation of macrophages into osteoclasts + suppression of osteoclast apoptosis

3. Increased osteoclast action

4. Osteoclast action outpaces osteoblast action

5. Decreases bone mass

Osteoprotegerin (OPG)

1. When RANKL is bound to OPG, it is not available to bind with RANK

2. Blocks action of RANK

3. Decreases osteoclast action

4. Osteoblast action outpaces osteoclast action

5. Increases bone mass

PTH Effects on Kidneys

• PTH increases renal reabsorption of calcium (decreases urinary calcium excretion)

  • and increases excretion of phosphate

• PTH induces activation of Vitamin D

Calcitonin

Effects on bone remodelling opposite to PTH:

• A peptide hormone (32 aa)

• Decreases movement of ionized calcium from bone fluid to ECF

• Inhibits activity of osteoclasts; therefore, decreases bone resorption

• Increases renal calcium excretion

Inverse regulation of PTH and Calcitonin release:

Act through the same calcium-sensing receptor mechanism

When plasma calcium is low:

Parathyroid glands increase PTH and increase plasma calcium

When plasma calcium is high:

Thyroid C cells increase calcitonin and decrease plasma calcium

Vitamin D

• Bioactive form is 1,25(OH)₂ Vitamin D₃

  • Calcitriol

• Derived from inactive vitamin D produced in skin by action of sunlight; present in some foods

• The biologically inactive precursor is called 7-dehydrocholesterol

• Vitamin D is a steroid hormone

Vitamin D activated by addition of 2 hydroxyl groups:

• 1st OH added in liver → 25-OH Vitamin D

• 2nd OH added in kidneys → 1,25(OH)₂ Vitamin D₃

• Promotes intestinal absorption of calcium and phosphate

Kidney hydroxylation enzyme is stimulated by:

• PTH

• Low plasma ionized calcium

• Low plasma ionized phosphate

• Prolactin (during lactation)

• Final product: VitD₃= (1,25 (OH)₂ D₃) = Calcitriol

When plasma ionized calcium is high, renal hydroxylation:

Produces an inactive form: 24, 25(OH)₂ Vit D₃

Effects of Activated Vitamin D3:

• Increases total body calcium by increasing GI absorption of calcium

  • Dose-dependent response

  • Slow, long-lasting response

  • Adjusts Ca2+ intake from diet to match needs via changes in ratio of active/inactive Vit D

• Increases ECF ionized calcium by enhancing response of bone to PTH (resorption)

Problems of Calcium Homeostasis

• Hyperparathyroidism

• Hypoparathyroidism

• Vitamin D deficiency

• Osteoporosis

Hypoparathyroidism

• A rare condition usually caused by autoimmune disease or physical damage to the glands

• Low PTH secretion results in low plasma ionized calcium level:

• Causes increased neuromuscular excitability by increasing nerve membrane permeability to Na+

  • Paresthesia (e.g., “pins and needles” sensation)

  • Tetany (muscle spasms)

  • Potentially lethal due to failure of respiration

Hyperparathyroidism

• Primary form usually due to hypersecreting parathyroid tumour

  • Hypercalcemia results from high PTH

• Due to chronic renal disease or vitamin D deficiency causing hypocalcemia

  • Hypocalcemia causes high PTH production

High PTH level with elevated Ca²⁺ causes:

• Depressed muscle and nerve excitability:

  • High ECF [Ca2+]

• Increased risk of fractures

  • Demineralization of bone

• Risk of kidney stones

  • High concentration of calcium in renal filtrate

Hyperparathyroidism with Vitamin D Deficiency

• Impairs GI absorption of calcium

• Resulting high PTH causes bone demineralization

  • In children, result is rickets

  • In adults, result is called osteomalacia

• Vitamin D supplementation is a consideration for Northern residents

Skin Pigmentation Affects Vitamin D Production

2007 study of U. Toronto students:

• Plasma Vit D levels measured in Jan/Feb

• Results by ethnic origin:

  • European ancestry – 34% were deficient (<30ng/ml)

  • East Asian – 85% deficient

  • South Asian – 93% deficient

  • African – 100% deficient

Vitamin D Deficiency:

• Elevated risk of cancer, cardiovascular disease, autoimmune disease, multiple sclerosis, osteoporosis…

• Meta-analysis of 18 controlled experiments showed that Vit D supplements lower risk of premature death by 7%

1,25-(OH)₂-Vitamin D₃ Activates more than 1000 Different Genes in at Least a Dozen Cell Types Including:

• Bone

• Breast

• Fat

• Intestine

• Immune cells

• Kidneys

• Liver

• Neurons

• Pancreas

• Parathyroid gland

• Prostate

• Skin keratinocytes

Vitamin D3 receptor is expressed everywhere in the body!

Osteoporosis - Brittle Bones

• Condition in which bone resorption is greater then bone formation

• Reduced osteoblast activity, increased osteoclast activity

• Plasma calcium, phosphate, PTH, and Vitamin D levels are usually normal

• Results in reduction of bone mass

Osteoporosis occurs in both men and women:

• Estrogen inhibits bone resorption by decreasing osteoclast activity and increasing osteoblast activity

• Increased incidence in post-menopausal women when estrogen levels are reduced

Osteoporosis prevention includes:

• Getting adequate calcium and Vitamin D throughout life

• Doing weight-bearing exercise

• Not smoking