Calcium, Phosphate Metabolism and Hormonal Control

• Hormonal control influences calcium and phosphate metabolism, as well as bone physiology

Hormonal Control

• 1,25-Dihydroxycholcalciferol, a steroid derived from vitamin D, facilitates calcium absorption from the intestine.
• Parathyroid hormone (PTH), produced by the parathyroid glands, promotes calcium mobilization from bone.
• PTH increases phosphate excretion and calcium reabsorption in the kidney.
• Calcitonin, from the thyroid gland, inhibits bone resorption.
• PTH increases the plasma concentration of calcium, while calcitonin decreases it.

Calcium

• 99% of the body's calcium is stored in bones.
• Plasma calcium concentration is 2.5 mmol/l.
• Nondiffusible calcium is protein-bound at 1.1 mmol/l.
• Diffusible calcium is 1.4 mmol/l.
• Ionized calcium is 1.2 mmol/l.
• Calcium, when complexed with HCO3 or citrate, measures 0.2 mmol/l.
• Calcium functions include being a second messenger, aiding in blood coagulation and muscle contraction, and contributing to the excitability of nerves and muscles, and bone structure.

Calcium Metabolism

• Between 30-80% of ingested calcium is absorbed in the upper small intestine.
• The kidney filters calcium freely, reabsorbing almost 99% of it.
• 65% of calcium reabsorption occurs in the proximal tubule (PT).
• 35% of calcium reabsorption takes place in the ascending limb of the loop of Henle and distal tubule (DT), regulated by PTH.
• There is no calcium secretion in the kidneys.

Phosphorus

• Approximately 90% of phosphorus is found in bones.
• Phosphorus is an element in vital compounds like ATP, cAMP, 2,3-DPG, and nucleic acids.
• (De)phosphorylation regulates cell functions.
• Phosphorus acts as a phosphate buffer.
• Plasma phosphorus is composed by 2/3 in organic form and 1/3 inorganic form.

Phosphorus Metabolism

• The kidney freely filters inorganic phosphorus.
• Active transport mainly occurs in the proximal tubule (60–70%).
• PTH inhibits phosphorus reabsorption in the kidney.
• In the GIT, inorganic phosphorus is absorbed in the duodenum and small intestine via active transport and diffusion, stimulated by vitamin D.

Bone Physiology

• Bone is a specialized form of connective tissue containing calcium and phosphorus.
• Crystals consist of calcium and phosphorus, including magnesium, sodium, potassium, and carbonate.
• The main crystal form is hydroxyapatite.
• The matrix consists of collagen fibers, mainly Type I collagen.
• The ground substance includes hyaluronic acid, chondroitin sulfate, and ECF.
• Mature bone is structured around osteons, or Haversian systems.

Compact Bone

• The outer layer of bone
• Most dense with 80% of body bone mass
• Contains resting osteocytes and Haversian canals with vessels.

Spongy Bone

• Found inside the cortex, 20% of body bone mass
• Has bone trabeculae with many bone cells on surface
• High metabolic activity
• Nutrients diffuse from bone ECF to trabeculae.

Osteoblasts and Osteoclasts

• Osteoblasts and osteoclasts facilitate bone formation and resorption in the bone marrow.
• Osteoblasts are bone-forming cells derived from stem cells.
• Osteoblasts secrete collagen (type I), proteins, and alkaline phosphatase.
• Osteoblasts differentiate into osteocytes.
• Osteoclasts are responsible for bone erosion and resorption of the bone and originate from monocytes.
• Osteoclasts attach to bones via integrins, creating a sealing zone facilitated by an H+ pump that lowers the pH to 4.
• This process causes hydroxyapatite dissolution and collagen breakdown by acid proteases, releasing digested products into the ISF.
• Bone undergoes constant resorption and formation, with about 5% of bone mass being remodeled at any one time, a process that takes about 100 days.

Vitamin D

• Vitamin D is derived from sterols produced by UV light.
• Vitamin D-binding protein (DBP, globulin) transports vitamin D3 and its derivatives in plasma.
• Vitamin D is converted to 25-hydroxycholecalciferol in the liver.
• PTH stimulates the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (the active form of vitamin D) in the kidney.

Vitamin D Effects

• As a steroid, it interacts with receptors to increase calcium channel activities.
• It promotes calbindin-D and calcium-ATPase gene transcription.
• Calbindin-D is a protein that binds calcium.
• It assists calcium transport in the intestine, brain, and kidney.
• Intestine facilitates calcium and phosphorus resorption.
• Kidney promotes calcium and phosphorus reabsorption.
• Bones enhances calcium and PO4 release.

Regulation of Calcium

• PTH, prolactin, GH, estrogens, and calcitonin increase calcium.
• T-hormones decreases calcium.

Vitamin D Deficiency

• Insufficient sun exposure, kidney diseases, fat malabsorption and genetic mutations decrease vitamin D levels.
• Rickets results in hypocalcemia and is present in children.
• Osteomalacia presents as less bones in adults.

Parathyroid Hormone (PTH)

• Parathyroid glands secrete PTH.
• The parathyroid glands have a rich vascularization with two types, 2 chief cells and 2 oxyphil cells
• Chief cells secrete PTH and contains large number of secretory granules.
• Synthesis: preproPTH → prePTH (EPR) → PTH (GA) → secretory granules (polypeptide)
• The hormone has a half-life of 10 minutes, is degraded in the liver, and excreted by the kidney.

PTH Effects

• As a membrane receptor, PTH causes adenylyl cyclase activation
• cAMP and PLC activation increase intracel. Ca2+ and PKC activation
• Bones reabsorb bone (osteoclasts) mobilizing Calcium
• Kidneys promote calcium reabsorption in the distal tubule but decreasing phosphate.
• PTH Increases formation of 1,25 dihydroxy and absorption from the intestine

Regulation of Secretion

• Negative feedback increases calcium in plasma
• 1,25-Dihydroxycholcalciferol (vitamin D) decreases PTH secretion.

Disorders of PTH Secretion

• In PTH excess, primary hyperparathyroidism is caused by tumors on the glands
• Hypercalcemia, hypophosphatemia, bone demineralization and hypercalciuria can occur
• In PTH Deficiency, PTH is essential for life
• Parathyroidectomy can result to low plasma calcium and hypocalcemic tetany
• Spasms of skeletal muscles can occur

Calcitonin

• Calcitonin is derived from thyroid gland and parafollicular cells:
• It is a peptide, and has 10 min half life
• It reduces bone resorption.

Calcitonin Effects and Regulations

• Reduces bone resorption reducing osteoclast number
• Increases Calcium excretion, and reduces calcium and phosphate in plasma
• Increases plasma Ca2+, and secretin secretion