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Year 2 Collin > Musc 3 - The biochemistry of metabolic bone disease > Flashcards

Musc 3 - The biochemistry of metabolic bone disease Flashcards

1
Q

What are the 3 ways in which MBDs cause changes in bone density and strength

A
  1. Increase bone resorption
  2. Decrease bone formation
  3. Alter bone structure
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2
Q

What are the biochemical investigations performed in bone disease?

A

Ca, corrected Ca (albumin), phosphate, alkaline phosphatase - all to measure bone profile

Creatinine to measure renal function

Parathyroid hormone, 25-hydroxyvitamin D (for parathyroid)

Ca/Po3 in urine

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3
Q

Biochemical changes in osteoporosis

A

Bone formation: H/N

Bone resorption: HH

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4
Q

Biochemical changes in osteomalacia

A

Ca: N/L
Phosphate: L
Alkaline phosphatase: H

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5
Q

Biochemical changes in Pagets

A

Ca: N/(H)
Alkaline Phosphatase: HHH (but Phosphate is normal)
Bone formation: HH

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6
Q

Biochemical changes in primary hyperparathyroidism

A

Ca: H
Phosphate: N/L
Alkaline phosphatase: N/H
Bone resorption: HH

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7
Q

Biochemical changes in renal osteodystrophy

A

Ca: L/N
Phosphate: H
Alkaline phosphatase: H

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8
Q

Biochemical changes in metastases

A

Ca: H
Phosphate: H
Alkaline phosphatase: H
Bone resorption: H

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9
Q

What is the general formula for hydroxyapatite

A

Just learn this by googling

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10
Q

How is cancellous/trabecular/spongy bone metabolically active?

A
  1. Remodelling

2. Continuous exchange of ECF with bone reserve

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11
Q

What is the formula for corrected calcium?

A

Corrected calcium = (Ca conc) + 0.02(45-(albumin conc))

This compensates for protein levels

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12
Q

Serum calcium is a measure of TOTAL calcium which includes?

A
  1. Free Ca - the active form
  2. Complexed - to Phosphate and citrate
  3. Protein bound to albumin
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13
Q

When do problems with the corrected calcium score occur?

A

When there is acid base disturbance -

hyperventilation causes alkalosis - which causes Ca to bind to protein - hence free Ca drops - causes tingling

(Venous stasis may also falsely elevate levels)

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14
Q

What is the ratio of protein bound: free: complexed Ca?

A

Protein bound = 46%

Free: 47%

Complexed: 7%

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15
Q

If plasma Ca drops - PTH secreted very quickly. What effects does PTH have?

A

PTH acts on 2 systems:

  1. Bone -
    - acute release of available Ca not in hydroxyapatite crystals
    - more long-term increase in osteoclast activity to reabsorb bone
  2. Kidney -
    - increased Ca reabsorption in DCT (only place where Ca absorption is under hormonal control)
    - Increased Phosphate excretion (through inhibition of NAP cotransporter in PCT)
    - Stimulates 1-alpha-hydroxylase activity -> increasing Vit D production (increased calcitriol) -> increased gut reabsorption of Ca. Also decreased 24-hydroxylase activity
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16
Q

Name 4 material properties of bone that makes it strong?

A
  1. Cross-linking
  2. Woven bone or lamellar bone? (Woven = disorganised bone where lamellae not organised along stress lines
  3. Mineralisation - greater mineralisation as bone ages (Vit D deficiency reduces this)
  4. Microcracks - stresses in mortal lines due to exercise
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17
Q

2 examples of woven bone is more prominent (where lamellae are not organised along the stress line

A
  1. Acute haling

2. Pagets

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18
Q

What are the aspects that make bone strong

A
  1. Mass
  2. Material properties
  3. Microarchitecture - relevant in trabecular bone
  4. Macroarchitecture - genetic
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19
Q

Describe changes in bone mass as we age

A

Peak bone mass in mid-20s, this mass is stable till 40. Men have a slower decrease in bone mass

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20
Q

What can cause cortical thickening

A

Exercise - it also causes change in trabecular volumetric BMD

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21
Q

Bone has a structure to absorb energy. What does irreversible plastic deformation lead to?

A

Microfractures - they help to dissipate the excess energy

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22
Q

What happens if microfractures accumulate?

A

Bone strength is compromised

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23
Q

What does each osteon represent

A

A previous remodelling event - bone remodelling is where micro fracture areas are repaired

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24
Q

How is bone remodelling activated?

A

Microcracks cross canaliculi - this cuts the osteocyte processing - causing osteocyte apoptosis

This signals surface-lining cells + other osteocytes to release local factors - attracting cells from blood and marrow into remodelling compartment

Resorption phase - osteoclasts generated locally and resorb matrix and microcrack. Osteoblasts then deposit new lamellar bone.

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25
Q

What do osteoblasts that are trapped in the matrix become?

A

They become osteocytes - some osteoblasts die, some form new flattened osteoblast lining ells

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26
Q

Which type of bone has a large blood supply with a large SA?

A

Trabecular bone

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27
Q

Where is Ca lost and where is it gained?

A

Lost in kidneys

Gained in GIT

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28
Q

Hypomagnesaemia may lead to?

A

Low PTH and hypocalcaemia

PTH is Mg dependent

29
Q

How does PTH cause bone resorption?

A

Through the RANK system - causes osteoblasts to express RANKL - osteoclast progenitors bind to RANKL using RANK-receptor - causes differentiation of osteoclasts to activated osteoclasts

30
Q

What are the causes of primary hyperparathyroidism

A
  1. Parathyroid adenoma
  2. Parathyroid hyperplasia
  3. Familial syndromes
31
Q

What is primary hyperparathyroidism

A

1 hyperparathyroidism = elevated Ca with PTH elevated or upper Half of normal range

(hypercalcaemia + high PTH = not normal)

32
Q

What are the symptoms of primary HPT (due to high Ca)

A

Thirst, polyuria, tiredness/fatigue, muscle weakness

33
Q

What is a good way to remember the symptoms of 1 HPT

A

Stones (renal colic), abdominal moans (constipation, pancreatitis) and psychic grans (depression, drowsy, impaired concentration)

Patients may also have fractures due to resorption

34
Q

Why does high serum calcium cause diuresis?

A

It inhibits transporters in the ALoH - decreasing water reabsorption

35
Q

How can diuresis (in 1 HPT) result in increased stone risk?

A

Hypercalcuria - increases stone risk as a result of increased PTH

36
Q

What can chronically elevated PTH levels cause

A
  1. Increased cortical bone resorption —> increased fracture risk
37
Q

Explain the biochemical test results for primary HPT

A
  1. Increased serum Ca - absorption from GIT
  2. Decreased serum phosphate - stimulation of PTH to increase renal excretion in PCT
  3. PTH in upper half of normal / elevated
  4. Increased urine Ca excretion
38
Q

Vitamin D is metabolised by?

A

The liver and kidney

39
Q

What are the actions of Vit D?

A

Bone - acts with PTH to increase osteoclastic osteolysis

Intestine - Increases Ca and Phosphate absorption

Kidneys - facilitates PTH action in DCT - increase Ca reabsorbtion

Increases osteoblast differentiation and bone formation

40
Q

Explain the feedback of Vit D

A

Feeds back to the PT gland directly to reduce PTH secretion

41
Q

Active Vit D levels are not measured directly, how is it measured?

How is it difficult to establish a normal range for Vit D?

A

25 OH-Vit D (Calcidiol) measured

Most people are Vit D deficient (very hard to have toxic Vit D levels)

42
Q

What is rickets

What are the symptoms of rickets

A

Inadequate Vit D activity = defective mineralisation of cartilaginous growth plate

Bone pain/tenderness, muscle weakness

43
Q

What are the causes of osteomalacia/rickets?

A
  1. Dietary - lack of ergocalciferol, lack of sunlight
  2. GI - SI malabsorption, some drugs induce CYP450 which metabolises Vit d
  3. Renal - chronic renal failure
  4. Rare hereditary - 1-alpha hydroxyls deficiency
44
Q

Describe the biochemistry in osteomalacia/rickets

A 
Ca = N/L
P = N/L
Alk P = H
25 (OH) Vit D = L
PTH = H
Phosphatase in urine = H
45
Q

In rickets/osteomalacia, what else causes Phosphate loss in the PCT?

How?

A

FGF-23

Produced by osteoblasts - I inhibits activation of Vit D by 1-alpha-hydroxylase

46
Q

Renal phosphate loss may also occur when Ca and Vit D levels are normal in osteomalacia. Why?

A

Kidneys forced to lose phosphate

47
Q

What is isolated hypophosphataemia

A

X-linked hypophosphatemia rickets - mutations leading to high levels of FGF-23

48
Q

FGF-23 usually inhibited by PHEX - which is produced by osteoblasts. Mutations in PHEX can cause?

A

Renal phosphate wasting

49
Q

How can PCT damage cause less Vit D production?

A

Phosphaturia - stops 1-alpha-hydroxylation of Vit D

50
Q

Where is the enzyme 1-alpha hydroxylase found?

A

PCT of kidney

51
Q

What are the 2 types of osteoporosis and list some causes

A

High turnover - increased bone resorption > formation. Due to oestrogen deficiencies/HPT/hyperthyroidism/hypogonadism/ heparin

Low turnover - decreased bone formation, more decreased than bone resorption. Caused by liver disease/heparin

52
Q

Which substances can cause increased bone resorption + decreased bone formation?

A

Glucocorticoids

53
Q

How can oestrogen deficiency cause menopausal bone loss?

It is typically trabecular bone lost in early menopause

A
  1. Increases number of remodelling units - imbalance with increased resorption relative to formation
  2. Remodelling errors - deeper and more resorption puts leading to trabecular perforation and excess cortical removal
  3. Decreased osteocyte sensing
54
Q

In primary osteoporosis, serum biochemistry should be normal. So why is it done?

A

To exclude other causes

55
Q

What should be checked for osteoporosis (other causes)

A
  1. Vit D deficiency
  2. Secondary endocrine causes
  3. Exclude multiple myeloma
  4. May have high urine calcium
56
Q

What is the best predictor of fracture risk?

A

BMD - DEXA scan used

57
Q

How is the T score measured

A

Measured BMD - young adult mean BMD all divided by young adult SD

58
Q

What are the 2 most common fractures

A
  1. Vertebrae

2. Hip

59
Q

How are bone markers different from BMD

A
  1. Dynamic (unlike BMD) and divided into markers of formation and resorption
60
Q

Explain the process of bone formation

A
  1. Chains of type 1 collagen (made by osteoblasts) join together and extension peptides are cut off
    - extension peptides can be measured in blood (e.g. P1NP)
  2. 3 hydroxylysine molecules on adjacent tropocollagen fibrils condense - form pyridinium ring linkage - can be used to measure bone resorption - serum CTX, urine NTX
61
Q

Which bone formation marker is commonly used?

What is used in the diagnosis of?

A

Alkaline phosphatase

Used to diagnose -

Pagets, osteomalacia, bony metastases

62
Q

P1NP can be used as a predictor of response to?

A

Anabolic treatments

63
Q

What are the types of BSAP and what does it to

A

It is tissue specific - can be liver or bone

BSAP = essential for mineralisation and regulates concentration of phosphocompounds

64
Q

When are BSAP concentrations increased

A
  1. Pagets disease
  2. Osteomalacia
  3. Bone metastases
  4. HPT
  5. Hyperthyroidism
65
Q

What is CKD-MBD

A

Chronic Kidney Disease - Mineral Bone Disorder

Skeletal remodelling disorders caused by CKD - contribute to heterotypic calcification, especially vascular

Usually disorders in mineral metabolism accompanying CKD play the major role in the excess mortality of CKD

66
Q

Which 3 things can CKD decrease?

A
  1. Skeletal anabolism
  2. Decreases osteoblast function
  3. Bone formation rates
67
Q

2 biochemical signs of renal osteodystrophy?

A
  1. Increased serum phosphate

2. Reduction in 1,25 Vit D (calcitriol)

68
Q

What happens to compensate for renal osteodystrophy

A

Secondary HPT - but this is unsuccessful and hypocalcaemia develops

This may then develop into parathyroid glands secreting PTH autonomously (3 HPT) - inducing hypercalcaemia

69
Q

Parathyroid hyperplasia develops alongside decline in which organ function?

Year 2 Collin (114 decks)

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