MEtabolism+Ortho

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MEtabolism+Ortho

  1. 1. Bone Metabolism CM Robinson Senior Lecturer Royal Infirmary of Edinburgh
  2. 2. Outline <ul><li>Normal bone structure </li></ul><ul><li>Normal calcium/phosphate metabolism </li></ul><ul><li>Presentation and investigation of bone metabolism disorders </li></ul><ul><li>Common disorders of bone metabolism </li></ul>
  3. 3. Normal Bone Structure <ul><li>What are the normal types of bone in the mature skeleton? </li></ul><ul><li>Lamellar </li></ul><ul><ul><li>Cortical </li></ul></ul><ul><ul><li>Cancellous </li></ul></ul><ul><li>Woven </li></ul><ul><ul><li>Immature </li></ul></ul><ul><ul><li>Healing </li></ul></ul><ul><ul><li>Pathological </li></ul></ul>
  4. 4. <ul><li>What is the composition of bone? </li></ul><ul><li>The matrix </li></ul><ul><ul><li>40% organic </li></ul></ul><ul><ul><ul><li>Type 1 collagen (tensile strength) </li></ul></ul></ul><ul><ul><ul><li>Proteoglycans (compressive strength) </li></ul></ul></ul><ul><ul><ul><li>Osteocalcin/Osteonectin </li></ul></ul></ul><ul><ul><ul><li>Growth factors/Cytokines/Osteoid </li></ul></ul></ul><ul><ul><li>60% inorganic </li></ul></ul><ul><ul><ul><li>Calcium hydroxyapatite </li></ul></ul></ul><ul><li>The cells </li></ul><ul><ul><li>osteo-clast/blast/cyte/progenitor </li></ul></ul>
  5. 5. Bone structure <ul><li>Structure of lamellar bone? </li></ul><ul><li>Structure of woven bone? </li></ul>
  6. 6. Bone turnover <ul><li>How does normal bone grow…….. </li></ul><ul><ul><li>In length? </li></ul></ul><ul><ul><li>In width? </li></ul></ul><ul><li>How does normal bone remodel? </li></ul><ul><li>How does bone heal? </li></ul>
  7. 7. Bone turnover <ul><li>What happens to bone………. </li></ul><ul><ul><li>in youth? </li></ul></ul><ul><ul><li>aged 20-40’s? </li></ul></ul><ul><ul><li>aged 40+? </li></ul></ul><ul><ul><li>aged over 70? </li></ul></ul>
  8. 8. Calcium metabolism <ul><li>What is the recommended daily intake? </li></ul><ul><li>1000mg </li></ul><ul><li>What is the plasma concentration? </li></ul><ul><li>2.2-2.6mmol/L </li></ul><ul><li>How is calcium excreted? </li></ul><ul><li>Kidneys - 2.5-10mmol/24 hrs </li></ul><ul><li>How are calcium levels regulated? </li></ul><ul><li>PTH and vitamin D (+others) </li></ul>
  9. 9. Phosphate metabolism <ul><li>Normal plasma concentration? </li></ul><ul><li>0.9-1.3 mmol/L </li></ul><ul><li>Absorption and excretion? </li></ul><ul><li>Gut and kidneys </li></ul><ul><li>Regulation </li></ul><ul><li>Not as closely regulated as calcium but PTH most important </li></ul>
  10. 10. PTH <ul><li>Physiological role </li></ul><ul><li>Production related to plasma calcium levels </li></ul><ul><li>Control of calcium levels </li></ul><ul><ul><li>target organs </li></ul></ul><ul><ul><ul><li>bone - increased Ca/PO4 release </li></ul></ul></ul><ul><ul><ul><li>kidneys </li></ul></ul></ul><ul><ul><ul><ul><li>increased reabsorption of Ca </li></ul></ul></ul></ul><ul><ul><ul><ul><li>increased excretion of PO4 </li></ul></ul></ul></ul><ul><ul><ul><li>gut - indirect increase in calcium reabs by stimulting activation of vitamin D metabolism </li></ul></ul></ul>
  11. 11. Calcitonin <ul><li>Physiological role </li></ul><ul><li>Levels increased when serum Ca >2.25mmol/L </li></ul><ul><li>Target organs </li></ul><ul><ul><li>Bone - suppresses resorption </li></ul></ul><ul><ul><li>Kidney - increases excretion </li></ul></ul>
  12. 12. Vitamin D (cholecalciferol) <ul><li>Sources of vit D </li></ul><ul><li>Diet </li></ul><ul><li>u.v. light on precursors in skin </li></ul><ul><li>Normal daily requirement </li></ul><ul><li>400IU/day </li></ul><ul><li>Target organs </li></ul><ul><ul><li>bone - increased Ca release </li></ul></ul><ul><ul><li>gut - increased Ca absorption </li></ul></ul>
  13. 13. <ul><li>Normal metabolism </li></ul><ul><li>Vit D </li></ul><ul><li>25-HCC (Liver) </li></ul><ul><li>Ca/PTH </li></ul><ul><li>1,25-DHCC 24,25-DHCC </li></ul><ul><li>(Kidney) (Kidney) </li></ul>
  14. 14. Factors affecting bone turnover <ul><li>Other hormones </li></ul><ul><li>Oestrogen </li></ul><ul><ul><li>gut - increased absorption </li></ul></ul><ul><ul><li>bone - decreased re-absorption </li></ul></ul><ul><li>Glucocorticoids </li></ul><ul><ul><li>gut - decrease absorption </li></ul></ul><ul><ul><li>bone - increased re-absorption/decreased formation </li></ul></ul><ul><li>Thyroxine </li></ul><ul><ul><li>stimulates formation/resorption </li></ul></ul><ul><ul><li>net resorption </li></ul></ul>
  15. 15. Factors affecting bone turnover <ul><li>Local factors </li></ul><ul><li>I-LGF 1 (somatomedin C) </li></ul><ul><ul><li>increased osteoblast prolifn </li></ul></ul><ul><li>TGF </li></ul><ul><ul><li>increased osteoblast activity </li></ul></ul><ul><li>IL-1/OAF </li></ul><ul><ul><li>increased osteoclast activity (myeloma) </li></ul></ul><ul><li>PG’s </li></ul><ul><ul><li>increased bone turnover (#’s/inflammn) </li></ul></ul><ul><li>BMP </li></ul><ul><ul><li>bone formation </li></ul></ul>
  16. 16. Factors affecting bone turnover <ul><li>Other factors </li></ul><ul><li>Local stresses </li></ul><ul><li>Electrical stimuln </li></ul><ul><li>Environmental </li></ul><ul><ul><li>temp </li></ul></ul><ul><ul><li>oxygen levels </li></ul></ul><ul><ul><li>acid/base balance </li></ul></ul>
  17. 17. Bone metabolic disorders <ul><li>Presentation? </li></ul><ul><li>Skeletal abnormality </li></ul><ul><ul><li>osteopenia - osteomalacia/osteoporosis </li></ul></ul><ul><ul><li>osteitis fibrosa cystica - replacement of bone with fibrous tissue usually due to PTH excess </li></ul></ul><ul><li>Hypercalcaemia </li></ul><ul><li>Underlying hormonal disorder </li></ul><ul><li>When to investigate? </li></ul><ul><ul><li>Under 50 </li></ul></ul><ul><ul><li>repeated fractures or deformity </li></ul></ul><ul><ul><li>systemic features or signs of hormonal disorder </li></ul></ul>
  18. 18. Bone metabolic disorders <ul><li>Assessment </li></ul><ul><li>History </li></ul><ul><ul><li>duration of sx </li></ul></ul><ul><ul><li>drug rx </li></ul></ul><ul><ul><li>causal associations </li></ul></ul><ul><li>Examn </li></ul><ul><li>X-rays - plain and specialist (cort index/Singh index/DEXA) </li></ul><ul><li>Biochemical tests </li></ul><ul><li>Bone biopsy </li></ul>
  19. 19. Biochemical tests <ul><li>Which investigations? </li></ul><ul><li>Ca/PO4 - plasma/excretion </li></ul><ul><li>Alkaline phosphatase/osteocalcin (o’blast activity) </li></ul><ul><li>PTH </li></ul><ul><li>vit D uptake </li></ul><ul><li>hydroxyproline excretion </li></ul>
  20. 20. Osteoporosis <ul><li>Definition? </li></ul><ul><li>Decrease in bone mass per unit volume </li></ul><ul><li>Fragility (perfn of trabecular plates) </li></ul><ul><li>Primary (post-menopausal/senile) Secondary </li></ul>
  21. 21. Primary osteoporosis <ul><li>Post-menopausal </li></ul><ul><li>Aetiology? </li></ul><ul><li>Menopausal loss 3% vs 0.3% previously </li></ul><ul><li>Loss of oestrogen - incr osteoclastic activity </li></ul><ul><li>Risk factors? </li></ul><ul><li>Race </li></ul><ul><li>Heredity </li></ul><ul><li>Build </li></ul><ul><li>Early menopause/hysterectomy </li></ul><ul><li>Smoking/alcohol/drug abuse </li></ul><ul><li>?Calcium intake </li></ul>
  22. 22. Primary osteoporosis <ul><li>Post-menopausal </li></ul><ul><li>Clinical features? </li></ul><ul><li>Prevention and treatment? </li></ul><ul><li>General health measures/diet </li></ul><ul><li>HRT </li></ul><ul><li>Bisphosphonates </li></ul><ul><li>Calcium </li></ul><ul><li>Vitamin D </li></ul>
  23. 23. Primary osteoporosis <ul><li>Senile </li></ul><ul><li>Aetiology? </li></ul><ul><li>7-8th decade steady loss of 0.5% </li></ul><ul><li>physiological manifestation of aging </li></ul><ul><li>Risk factors? </li></ul><ul><li>Prolonged uncorrected post-menopausal loss </li></ul><ul><li>chronic illness </li></ul><ul><li>urinary insuff </li></ul><ul><li>muscle atrophy </li></ul><ul><li>diet def/lack of exposure to sun/mild osteomalacia </li></ul>
  24. 24. Primary osteoporosis <ul><li>Senile </li></ul><ul><li>Clinical features? </li></ul><ul><li>as for post-menopausal </li></ul><ul><li>Treatment? </li></ul><ul><li>general health measures </li></ul><ul><li>treat fractures </li></ul><ul><li>as for post-menopausal (HRT not acceptable) </li></ul>
  25. 25. Secondary Osteoporosis <ul><li>Aetiology? </li></ul><ul><li>Nutrition - scurvy, malnutr,malabs </li></ul><ul><li>Endocrine - Hyper PTH, Cush, Gonad, Thyroid </li></ul><ul><li>Drug induced - steroid, alcohol, smoking, phenytoin </li></ul><ul><li>Malignancy - ca’tosis, myeloma (o’clasts), leukaemia </li></ul><ul><li>Chronic disease - RA, AS, TB, CRF </li></ul><ul><li>Idiopathic - juvenile, post-climacteric </li></ul><ul><li>Genetic -OI </li></ul><ul><li>Clin features? </li></ul><ul><li>Investigation? </li></ul><ul><li>Treatment? </li></ul>
  26. 26. Osteomalacia <ul><li>Definition? </li></ul><ul><li>Rickets - growth plates affected, children </li></ul><ul><li>Osteomalacia - incomplete mineralisation of osteoid, adults </li></ul><ul><li>Types - vit D def, vit-D resist (fam hypophos) </li></ul><ul><li>Aetiology? </li></ul><ul><li>Decr intake/production(sun/diet/malabs) </li></ul><ul><li>Decreased processing (liver/kidney) </li></ul><ul><li>Increased excretion (kidney) </li></ul>
  27. 27. Osteomalacia <ul><li>Clinical features? </li></ul><ul><li>In child </li></ul><ul><li>In adult </li></ul><ul><li>Investign </li></ul><ul><li>Ca/PO4 decr, alk ph incr, Ca excr decr </li></ul><ul><li>Ca x PO4 <2.4 </li></ul><ul><li>Bone biopsy </li></ul>
  28. 28. Osteomalacia <ul><li>Types </li></ul><ul><li>Vitamin D deficient </li></ul><ul><li>Hypophosphataemic </li></ul><ul><ul><li>growth decr +++ and severe deformity with wide epiphyses </li></ul></ul><ul><ul><li>x-linked dominant </li></ul></ul><ul><ul><li>decreased tubular reabs of PO4 </li></ul></ul><ul><ul><li>Ca normal but low PO4 </li></ul></ul><ul><ul><li>Rx PO4 and vit D </li></ul></ul>
  29. 29. Osteomalacia vs osteoporosis <ul><li>Osteomal Osteopor </li></ul><ul><li> Ageing fem, #, decreased bone dens </li></ul><ul><li>Ill Not ill </li></ul><ul><li>General ache Asympt till # </li></ul><ul><li>Weak muscles normal </li></ul><ul><li>Loosers nil </li></ul><ul><li>Alk ph incr normal </li></ul><ul><li>PO4 decr normal </li></ul><ul><li>Ca x PO4 <2.4 Ca x PO4 >2.4 </li></ul>
  30. 30. Hyperparathyroidism <ul><li>Excessive PTH </li></ul><ul><li>Due to prim (adenoma), sec (hypocalc), tert (second hyperact -> autonomous overact) </li></ul><ul><li>Osteitis due to fibr repl of bone </li></ul><ul><li>Clin feat - hypercalc </li></ul><ul><li>Invest - Calc incr, PO4 decr, incr PTH </li></ul><ul><li>Rx surg </li></ul>
  31. 31. Renal osteodystrophy <ul><li>Combination of </li></ul><ul><li>osteomalacia </li></ul><ul><li>secondary PTH incr </li></ul><ul><li>osteoporosis/sclerosis </li></ul><ul><li>CF - renal disorder, depends on predom pathology </li></ul><ul><li>Rx - vit D or 1,25-DHCC </li></ul><ul><li>renal disorder correction </li></ul>
  32. 32. Pagets <ul><li>Bone enlargement and thickening </li></ul><ul><li>Incr o-clast/blast activity -> increased tunrover </li></ul><ul><li>Aet - unknown but racial diff ?viral </li></ul><ul><li>CF - M=F, >50, ache but not severe unless fracture or tumour </li></ul><ul><li>Inv - x-ray app characteristic, alk ph is increased and increased hydroxyproline in urine </li></ul><ul><li>Rx - bisphos, calcitonin </li></ul>
  33. 33. Endocrine disorders <ul><li>Cushings </li></ul><ul><li>Hypopituitarism - GH def - prop dwarf or Frohlich adiposogenital syndrome </li></ul><ul><li>Hyperpituitarism - gigantism or acromegaly </li></ul><ul><li>Hypothyroidism - cretinism or myxoedema </li></ul><ul><li>Hyperthyroidism - o’porosis </li></ul><ul><li>Pregnancy - backache, CTS, rheumatoid improves SLE gets worse </li></ul>

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