Calcium in endocrinology and bone metabolism

Question 1

Briefly describe calcium

Answer 1

• From Latin word “calx” meaning lime (lime = calcium oxide)
• Group 2 of periodic table (number 20/ alkaline earth element)
• Reactive metal/ 2 electrons in outer shell/makes ionic bonds readily
• 5th most abundant element in the human body
  
  • after oxygen, carbon, hydrogen, and nitrogen
• About 1-1.2kg in adult body
• 99% in bone and teeth (only very small component in blood)

Question 2

List sources of calcium in the body

Answer 2

• Food and water
  
  • Dairy/ fortified soy products/bones/vegetables/supplements
  • 300mg calcium in 1 cup milk or 2 slices cheese or 200g yoghurt
• Absorption
  
  • Dissolves in the stomach
  • 2 methods of absorption in the small intestine
    
    • Transcellular active transport process in duodenum and upper jejunum
    • Paracellular passive process throughout the intestine

Question 3

Outline calcium absorption

Answer 3

• Phytic acid and oxalic acid bind calcium in GIT and reduce absorption
  
  • High levels in spinach, collard greens, sweet potato, beans
• Phosphate and soluble fiber also bind and reduce absorption
• Coffee/caffeine minimal reduction in calcium absorption (approx. 4mg per cup cf 300mg content of a cup of milk)
• Percentage of calcium absorbed reduces as dose increases above 500mg in one event

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### GIT

• 1000mg ingested in a day results in 400mg absorbed
• 200mg lost by intestinal secretions
• 200mg net absorption
  
  • (approx. 200mg lost in urine if in balance)

Question 4

Describe the direct and indirect effects of 1,25 (OH)2 Vitamin D

Answer 4

• Indirectly affects paracellular (passive) absorption
  
  • Activates protein kinase C which alters the structure of intracellular tight junctions thereby increasing permeability to calcium
• Main action by direct effect on active absorption (transcellular)
  
  • Calcium moves down calcium concentration gradient via calcium channel into apical section of microvillae (passive)
  • calcium rapidly/reversibly bound to calmodulin-actin-myosin 1 complex
  • Moves to basolateral area by microvesicular transport
  • Saturation of the complex reduces the calcium gradient and reduces calcium absorption but 1,25 (OH)₂ vit D upregulates synthesis of Calbindin which upload calcium-calmodulin complexes
  • As calbindin-calcium complex dissociates the free intracellular calcium is extruded from cell by sodium-calcium exchanger
    - i.e. 1,25OH2 changes gradient of free calcium internal to the cell ∴ allows more calcium to flux into cell as apparent free calcium within the cell is reduced (has been bound)

Question 5

Describe calcium excetion - urine

Answer 5

Urine
- 100-300mg/day (adult with normal renal function)
- Ultrafiltrate ionized and complexed calcium (not protein-bound)
- 10g calcium filtered per day (but only 0.1g in urine per day)
- 98-99% reabsorbed
- 60-70% in proximal convoluted tubule
- 20% loop of Henle
- 10% distal convoluted tubule
- 5% collecting duct

• Proximal tubular reabsorption (60-70% of filtered calcium)
  
  • 80% passive/solvent drag
  • Remaining active transport processes regulated by parathyroid hormone (PTH) and calcitonin
• No calcium reabsorption in thin segment of Loop of Henle
• Thick ascending limb (10% of filtered calcium)
  
  • mostly passive absorption (paracellular) but calcium sensing receptor present in basolateral membrane influences permeability to calcium
  • The small component active absorption is PTH and calcitonin sensitive
• Distal tubule reabsorbs calcium only by transcellular route
  
  • Distal convoluted tubule (10%)
  • Collecting duct (5%)
  • Only 15% of the filtered calcium but the major site for regulation

Question 6

Describe calcium loss via faeces and sweat

Answer 6

• Faeces
  
  • 2.1mg/kg/day in adults
• Sweat
  
  • 8-265 mg/L
  • Profuse sweating average 20mg calcium/hour lost (6.2 mg/hr in a comfortable environment)

Question 7

Describe the distribution of calcium

Answer 7

• Bone and teeth 99%
  
  • 1% freely exchangeable with calcium in the extracellular compartment
  • Cell organelles 0.9% (mitochondria and endoplasmic reticulum)
    
    • Intracellular signaling
    • Enzyme activation
    • Muscle contraction
  • Extracellular 0.1% (plasma)
    
    • 48% ionized, 46% protein-bound, 7% complexed fractions
      
      • Protein bound – albumin, globulins
      • Complexed fractions bound to phosphate, citrate
    • Ionized component tightly regulated

Question 8

Describe the effects of pH changes on calcium change

Answer 8

• in acidosis, pH drops and proton concentration increases
• Calcium concentration increases
• at high H, H+ displaces Ca from negatively charged amino acids on proteins
• Ca unbinds not only from plasma, but also from protein on endothelial membrane and sub-endothelial space (significant volume)
• pH also affects solubility products e.g. Ca-phosphates, Ca-carbonates etc.

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• in alkalosis, pH increases, and proton concentration decreases
• Calcium concentration decreases
• At low H, Ca is exchanged for H+ at negatively charged amino acids on proteins

Question 9

Describe PTH and its actions

Answer 9

Parathyroid Hormone
- 4 Parathyroid glands in neck (occas 5th)
- High blood flow
- Calcium sensing receptor
- Secrete PTH in response to minor downward trend in serum calcium
- PTH has direct effect on bone and kidney to resorb calcium
- Indirect effect on GIT calcium absorption via upregulation 1,25 (OH)₂Vit D

Parathyroid Hormone

• Kidney
  
  • Increases calcium resorption at ascending Loop of Henle, distal convoluted tubule, and collecting duct
• Bone
  
  • Increases bone release of calcium in 2 ways
    
    • Rapid phase within minutes- osteoblasts and osteocytes (overlie bone formation/bone fluid)
      
      • PTH binds to receptors on these cells and the osteocytic membrane pumps calcium ions from bone fluid into extracellular fluid
    • Slower phase over days – osteoclasts resorbing bone
      
      • mature osteoclasts do not have PTH receptors
      • PTH stimulates differentiation of immature osteoclasts (they have both PTH and vitamin D receptors)

Question 10

Describe the role of vitamin D

Answer 10

Vitamin D

• 7-dehydrocholesterol in skin plus UVB radiation (lower layers of epidermis)
  
  • produces cholecalciferol (base vitamin D)
• Cholecalciferol at the liver plus 25-hydroxylase
  
  • Produces 25 hydroxyvitamin D (25 OH VitD) – clinically measured more than 1,25 Vit D
• 25 OH vitamin D at kidney (and other sites) plus 1⍺ hydroxylase
  
  • Produces 1,25 (OH)₂ Vitamin D - the potent form
• Excess UVB induces enzymes that degrade cholecalciferol (prevents toxicity)

Question 11

Describe role of Vitamin D (cont’d)

Answer 11

• 1,25 (OH)₂ Vitamin D levels increased by PTH activating renal 1⍺-hydroxylase
  
  • Synthesis at renal proximal tubule
  • Action at distal tubules (plus bone and GIT)
• 1,25 (OH)₂ Vit D increases GIT Ca absorption (active and passive)
• 1,25 (OH)₂ Vit D increases bone resorption

Question 12

Describe the role of calcitonin

Answer 12

• From thyroid parafollicular cells (cf follicular cells which make thyroid hormone)
• In theory opposes PTH and reduces serum calcium by
  
  • Inhibition of osteoclasts and therefore reduction of bone resorption
  • Reducing renal calcium resorption
• However, no obvious clinical effect of excess/deficient calcitonin in humans

Question 13

Describe bone metabolism

Answer 13

• Bone matrix (protein)
  
  • predominantly type 1 collagen (also osteocalcin and osteopontin)
• Hydroxyapatite (mineral)
  
  • Ca₅(PO₄)₃(OH)
  • Bone mineral 50% volume (70% weight) of bone
  • Deposited in highly regulated manner into the organic matrix
• Osteoclasts
  
  • derived from macrophages/ resorb bone
• Osteoblasts
  
  • mesenchymal derived/ form bone/ synthesise collagen and other proteins
  • Organized connected groups of osteoblasts produce hydroxyapatite
• Osteocytes
  
  • Have mechanoreceptors used to coordinate bone repair
• Growing skeleton
  
  • Longitudinal growth until epiphyses close from pubertal hormone exposure
  • Continue to increase bone mass and accumulate calcium until age 30
  • Peak bone mass age 30
• Grown skeleton
  
  • Slow bone loss after 30 (both matrix and mineral)
  • Accelerated loss after menopause for approx. 10 years
  • Accelerated loss with some illnesses and medications

Question 14

Describe pathology of bone metabolism

Answer 14

• Osteoporosis vs osteomalacia vs rickets
  
  • Osteoporosis is reduced matrix and reduced mineral (matched) ie less bone
  • Osteomalacia is reduced mineral but not reduced matrix ie unmineralized bone
  • Rickets is unmineralized bone in growing bone (child)
    
    • Usually bowing of weight-bearing limbs