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Y2 Musculoskeletal > Metabolic Bone Disease - Biochemistry > Flashcards

Metabolic Bone Disease - Biochemistry Flashcards

1
Q

What makes the bone strong

A

Mass
Material properties (mineral and matrix)
Microarchitecture
Macro-architecture

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2
Q

Describe the age related changes in bone mass

A

Peak bone mass reached during mid 20s
Stable around the 40s where consolidation occurs
Declines at around after 40
Men have a slower loss than women, who lose fast in early menopause

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3
Q

What are biochemical investigations in bone disease

A

Bone profile (calcium, corrected calcium/albumin, phosphate, alkaline phosphatase)

Renal function (PTH, 25-hydroxy vit D)

Urine (calcium/phosphate, NTX)

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4
Q

Summarise the bone remodelling cycle

A

A microcrack crosses the canaliculi and severs the osteocyte processes, inducing osteocyte apoptosis
This signals to the surface lining cells, which release factors to recruit cells from the blood and marrow to the remodelling compartment
Osteoclasts are generated locally and resorb the matrix and the mitrocrack
Then osteoblasts deposit new lamellar bone
Osteoblasts that become trapped in the matrix become osteocytes

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5
Q

What is the ‘corrected’ calcium level?

A

This compensates for changes in protein level (if proteins are high, it compensates down)

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6
Q

How is corrected calcium calculated

A

corrected calcium = calcium + 0.02(45-albumin)

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7
Q

What is the normal range for serum calcium concentration and describe the distribution of calcium.

A

2.15-2.56 mmol/L

46% plasma protein bound (albumin)
47% free calcium
7% complexes (with phosphate or citrate)

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8
Q

Describe the effects of PTH in:

a. Bone
b. Kidneys

A

Bone
Acute release of available calcium
Stimulation of osteoclasts and inhibition of osteoblasts
Increased bone resorption (decreased bone mass) through the RANK system

Kidneys
Increased calcium reabsorption in the distal tubule
Increased phosphate excretion
Increased stimulation of 1-alpha hydroxylase (increasing calcitriol production)

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9
Q

Where does the PTH-mediated increase in calcium reabsorption take place in the nephron?

A

Distal convoluted tubule

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10
Q

Where does the PTH-mediated increase in phosphate excretion take place in the nephron?

A

Proximal convoluted tubule

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11
Q

What electrolyte is PTH dependent on

A

Magnesium

Hypomg leads to low PTH and hypocalcaemia (important for alcoholics)

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12
Q

What is the half life of PTH

A

8 minutes

Short half-life ; allows intraoperative sampling

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13
Q

What can PTH receptor be activated by

A

PTHrP and PTH

PTHrp cis produced by some tuours, and so hypercalcaemia may be first presenting feature ie small cell ca lung

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14
Q

How does the parathyroid gland monitors serum Ca

A

Calcium-sensing receptor

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15
Q

What is the relationship between PTH levels and Ca2+ levels in vivo and describe the minimum and set point

A

Steep inverse sigmoidal curve

MINIMUM: even at high calcium levels there is base-line PTH secretion

SET-POINT: point of half maximal suppression of PTH; steep part of slope;
Small perturbation causes large change PTH

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16
Q

What are the causes of primary hyperparathyroidism

A

Parathyroid adenoma
Parathyroid hyperplasia
parathyroid CA
Familial syndromes (MEN1, MEN 2A, HPT-JT)

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17
Q

Which age group (+ gender ratio) does primary hyperparathyroidism affect

A

50s
3:1 female to male
2% of post-menopausal develop

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18
Q

How is primary hyperparathyroidism diagnosed

A

Elevated total/ionised calcium with PTH levels elevated (or in upper half of normal range)

Corrected calcium > 2.6mmol/l

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19
Q

What are the clinical features of primary hyperparathyroidism

A 
Thirst polyuria
Tiredness, fatigue, muscle weakness 
Stones
Abdominal moans
Psychic groans
20
Q

What is the danger of high serum calcium

A

Can cause diuresis

May become a medical emergency

21
Q

What are the risks of a chronically elevated PTH

A

Increase stone risk
Increases cortical bone resorption
Increased fracture risk

22
Q

What are the biochemical findings in primary hyperthyroidism

A

Increased calcium
Decreased phosphate
Elevated PTH (or in upper range)
Increased urine calcium excretion

23
Q

What is the half life of vit D binding proteins

A

3 days

Then filtered by kidney

24
Q

Describe the effects of calcitriol on kidneys and small intestine

A

Kidneys
Increased Ca2+ and phosphate reabsorption (Stimulated by increased phosphate absorption from small intestine) in the DISTAL tubule

Small intestine
Increase Ca2+ and phosphate absorption in the duodenum

25
Q

Explain how vitamin D is synthesised

A
  1. 7-dehydrocholesterol is converted to cholecalciferol by UV light (or cholecalciferol acquired from diet)
  2. Converted to 25-cholecalciferol in the liver
  3. Conversion to Calcitriol in the kidney by 1-alpha-hydroxylase
  4. Calcitriol acts on small intestine, bone and kidney
26
Q

What are the effects of vitamin D on the bone and kidney

A

Bone - Acts on osteoblasts to increase formation of osteoclasts through RANKL
Increases osteoblast differentiation and bone formation

Kidney - facilitates PTH action increase Ca reabsorption in distal tubule

27
Q

What are the signs and symptoms of rickets

A

Symptoms
Bone pain and tenderness (axial)
Muscle weakness (proximal)
Lack of play

Signs
Age dependent deformity
Myopathy
Hypotonia
Short stature
Tenderness on percussion
28
Q

What are the vitamin D related causes of rickets/osteomalacia

A

Dietary

GI - small bowel malabsorption, pancreatic insufficiency, liver/biliary disturbance

Chronic renal failure

Rare hereditary
type 1 - 1a-hydroxylase
type 2 - defective VDR for calcitriol

29
Q

For each of the following state whether it would be high, low ornormal in the serum of a Rickets patient:

a. Calcium
b. Phosphate
c. Alkaline Phosphatase
d. 25-OH cholecalciferol
e. PTH
f. URINE phosphate

A

a. Calcium - low/normal
b. Phosphate - low/normal
c. Alkaline Phosphatase - high
d. 25-OH cholecalciferol - low
e. PTH - high
f. URINE phosphate - high

High urine phosphate
Glycosuria, aminoaciduria, high pH, proteinuria

30
Q

What can cause PCT phosphate loss

A

FGF-23

PTH

31
Q

Where is FGF-23 produced and what effect does it have that is the same and unlike PTH

A

osteoblast lineage cells, long bones
Like PTH - causes Phosphate loss
Unlike PTH - inhibits activation of Vit D by 1 alpha-hydroxylate

32
Q

What does the damaging of the kidney proximal tubule cause

A

Phosphaturia

Stops 1-alpha-hydroxylation of vitamin D

33
Q

What are the causes of Fanconi’s syndrome

A

Multiple myeloma

Heavy metal poisoning: lead, mercury

Drugs: tenofovir, gentamycin

Congenital disease: Wilsons, glycogen storage diseases

34
Q

How does oestrogen deficiency lead to a decrease in bone mineral density

A

Increases the number of remodelling units
Causes remodelling imbalance with increased bone resorption (90%) compared to formation (45%) due to enhanced osteoclast survival and activity
Deeper and more resorption pits
Decreased osteocyte sensing

35
Q

What do deep resorption pits in bone lead to

A

Trabecular perforation and cortical excess excavation

36
Q

How is osteoporosis diagnosed

A

Serum biochem should be normal if primary. Exclude all other causes.

  1. Check for vit D deficiency
  2. Check for secondary endocrine causes
  3. Exclude multiple myeloma
  4. May have high urine calcium
37
Q

What can be used biochemically to assess the activity of bone

A

Markers of none formation and resorption which are dynamic

38
Q

What is the best predictor of fracture risk and what is used to measure it

A 
Bone density (BMD) 
represents 70% of total risk

DEXA

39
Q

What makes up collagen type 1 and what cell is it produced by

A

2 alpha-1, 1 alpha-2

Osteoblast

40
Q

What can be used as a marker of bone formation that is linked to collagen production?

A

P1NP = Procollagen type 1 N-terminal Propeptide

Extension peptides that are cut off during collagen synthesis

41
Q

What can be used as a measure of bone resorption that is linked to collagen production?

A

Pyridinium ring linkage

These can be used to measure bone resorption; serum CTX, urine NTX

3 hydroxylysine molecules on adjacent tropocollagen fibrils condense
to form a PYRIDINIUM ring linkage

42
Q

Why is a corrected calcium used

A

Hyperventilating → alkalosis which causes more Ca to bind to protein so that free levels drop
Venous stasis may falsely elevate LEVELS

43
Q

What happens if rickets/vit D deficiency is left untreated

A

Leads to hypocalcaemia
Leads to neuromuscular irritability and seizures
Leads to bradycardia which may lead to arrhythmias and heart failure

44
Q

What are the issues with using bone markers is diagnosis

A

Reproducibility: CV 20%
Positive association with age
Need to correct for Cr
Diurnal variation in urine markers (peak 4-8am)

45
Q

What are the uses of bone markers

A

Common use is alkaline phosphatase

Paget’s
Osteomalacia
Boney metastases (prostate with PSA)

46
Q

What is BSPA and what disorders may cause an increase in it

A

Bone-specific alkaline phosphatase

Increased in	
	→ Paget’s disease
	→ Osteomalacia
	→ Bone metastases
	→ Hyperparathyroidism
	→Hyperthyroidism
47
Q

How does renal osteodystrophy cause hypercalcaemia

A
  1. GFR drops
  2. Increased serum phosphate
  3. Reduction in 1,25 Vit D/ calcitriol
  4. Secondary hyperparathyroidism develops to compensate
  5. Hypocalcaemia develops
  6. Parathyroid become autonomous and causes hypercalameia

Y2 Musculoskeletal (9 decks)

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