E8

• Functions of the skeleton


  • Mechanical (support and muscle attachments)
  • Protective (for vital organs and marrow)
  • Metabolic (ion homeostasis, especially calcium and phosphate)
• Bone


  Specialized connective tissue with extracellular matrix able to calcify, containing collagen fibres, non-collagenous proteins, and hydroxyapatite crystals
• Cell types within bone


  • Osteoblasts (bone forming cells)
  • Osteoclasts (bone resorbing cells)
  • Osteocytes (embedded in calcified bone matrix)
  • Bone lining cells (involved in bone remodelling)
• Bone remodelling cycle (trabecular bone)


  1. Resting surface

  2. Bone resorption

  3. Reversal phase (cement line formation)

  4. Bone formation (osteoid)

  5. Bone formation (osteoid-mineralisation front)

  6. Resting surface (new packet)
• Calcium


  Essential for bone mineral deposition, muscle contraction, blood clotting, and nerve impulse transmission
• Hypocalcaemia symptoms include paraesthesia, muscle spams, cramps, tetany, circumoral numbness, and seizures
• Parathyroid glands


  Regulate calcium and phosphate levels by secreting PTH in response to low calcium and high phosphate
• Actions of PTH


  • Increases calcium reabsorption in renal distal tubule
  • Increases intestinal calcium absorption (via activation of vitamin D)
  • Increases calcium release from bone (stimulates osteoclast activity)
  • Decreases phosphate reabsorption
• Parathyroid hormone (PTH)


  84 amino acid peptide with biological activity in first 34 amino acids, half-life 8 mins, acts through PTHR1 G-protein-coupled receptor
• PTH increases distal tubular reabsorption of calcium and stimulates production of the active form of vitamin D
• PTH enhances bone resorption by stimulating osteoclasts
• Hypocalcaemia


  Makes parathyroid glands increase PTH secretion, which increases bone resorption, increases urinary phosphate, decreases urinary calcium, increases 1,25D3 production, and increases calcium and phosphate absorption
• Hyperphosphatemia


  Makes parathyroid gland increase PTH secretion, which increases bone resorption, increases urinary phosphate, decreases urinary calcium, increases 1,25D3 production, and increases calcium and phosphate absorption
• Vitamin D


  Essential in intestinal calcium absorption and calcium homeostasis, important in osteoblast differentiation/osteoclastogenesis to increase bone remodelling
• Vitamin D or calcium deficiency leads to osteomalacia (low mineral content)
• Vitamin D assay


  Assesses 25(OH)D3, not the active 1,25D3 form
• Calcitonin


  Produced by thyroid c-cells, inhibits bone resorption by direct effect on osteoclasts, not essential for life
• Metabolic bone diseases


  • Hyperparathyroidism
  • Vitamin D/Calcium Deficiency (rickets/osteomalacia)
  • Renal Osteodystrophy
  • Osteoporosis
• Primary hyperparathyroidism


  • Parathyroid tumour (usually benign adenoma) causing hypercalcaemia and low serum phosphate
• Secondary hyperparathyroidism


  • Caused by renal disease (increased phosphate, decreased activation of vitamin D)
• Tertiary hyperparathyroidism


  • Long-standing secondary HPT leads to irreversible parathyroid hyperplasia
• Vitamin D or calcium deficiency leads to osteomalacia (low mineral count) due to lack of mineralisation of osteoid
• Rickets/osteomalacia


  • Rickets affects growing skeleton, osteomalacia affects adults, both result in weak, soft bone
• Causes of rickets and osteomalacia include dietary/lack of sunlight, and rarely inherited defects
• Renal osteodystrophy is caused by reduced renal mass leading to decreased urinary phosphate and 1,25D3 production, increased urinary calcium, hyperphosphatemia, hypocalcaemia, and increased PTH secretion
• Osteoporosis


  • Loss of bone mass/density leading to increased fracture risk, gradual decline with age, rapid decline in post-menopausal women due to oestrogen deficiency
• Long term consequences of spinal osteoporosis


  • Osteopaenic/osteoporotic (postmenopausal woman without fracture)
  • Established osteoporosis (postmenopausal woman with fracture)
  • Severe osteoporosis (postmenopausal woman with 2 or more fractures)
  • Kyphotic spine (bent/more curved)