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LCRS Musculoskeletal > Metabolic Bone Disease: Biochemistry > Flashcards

Metabolic Bone Disease: Biochemistry Flashcards

1
Q

what is metabolic bone disease?

A

a group of diseases that cause a change in bone density and bone strength by:
o Increasing bone reabsorption.
o Decreasing bone formation.
o Altering bone structure (and may be associated with disturbances in mineral metabolism).

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2
Q

what are the 5 common MBDs?

A 
primary hyperparathyroidism 
rickets/osteomalacia
osteoporosis
Paget's Disease
renal osteodystrophy
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3
Q

what are the general metabolic symptoms of MBDs?

A

hypo-/hypercalcaemia

hypo-/hyperphosphataemia

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4
Q

what are the general bone symptoms of MBDs?

A

bone pain
deformity
fractures

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5
Q

what does metabolic activity of the bone include?

A

Cancellous bone is metabolically active with 5% remodelling at any one time (total skeleton over 7 years).
There is also a continuous exchange of ECF with the bone fluid reserve.

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6
Q

what factors make bone strong?

A
  • mass
  • material properties e.g. cross-linked collagen
  • microarchitecture e.g. trabecular thickness
  • microarchitecture e.g. hip axis length
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7
Q

how can the structure and function of bone be assessed?

A
  • bone histology
  • biochemical tests
  • bone mineral densitometry
  • radiology
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8
Q

at what age do men and women start losing bone after the consolidation stage?

A

42

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9
Q

Why do women pass the fracture threshold?

A

menopause

men will never go below the fracture threshold

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10
Q

what is the sexual dimorphism in bone growth ?

A

male bone growth is appositional while in women new bone forms inside the bone marrow

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11
Q

why does constant bone remodelling occur?

A

they are cracks that occur frequently between the osteons

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12
Q

how are osteoclasts and osteoblasts involved in repairing micro-fractures?

A
  1. Osteoclasts reabsorb damage.
  2. Osteoblasts lay down new bone.
  3. Osteoblasts absorbed in laying down bone, act as mechanoreceptors for future fractures.
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13
Q

what origin do osteoclasts have?

A

haematopoietic (therefore last weeks)

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14
Q

what origin do osteoblasts have?

A

stem cells (therefore last months)

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15
Q

what are the biochemical investigations that can be done for primary hyperparathyroidism?

A

serum:
o Bone profile – calcium, corrected calcium (albumin), phosphate, ALP.
o Renal function – creatinine, PTH, 25-OH VitD (liver product)

urine:
o Calcium/Phosphate, NTX.

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16
Q

what does corrected calcium consider?

A

the calcium bound to albumin

correct ca= [ca]+0.02(45-[albumin])

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17
Q

when is calcium forced to bind to albumin?

A

blood alkalosis

- hyperventilating patient will have alkaline blood and therefore less free calcium

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18
Q

basic information about PTH

A

o 84aa peptide – only N1-34 are active.
o Mg2+-dependant.
o T1/2 = 8 minutes.
o PTH receptor is activated by PTHrP.

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19
Q

how does the parathyroid gland monitor serum calcium concentration?

A

via calcium-sensing receptor

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20
Q

what is the PTH/Ca2+ suppression mechanism like?

A

there is a baseline secretion of PTH at all times even at high calcium levels

a set point is the point of half-maximal suppression of PTH enabling small changes in calcium to precipitate large PTH changes

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21
Q

what effect that PTH have on the kidneys?

A

drives calcium absorption in the DCT of the kidney via TRPV5

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22
Q

what is the effect of PTH on the bone?

A

bone reabsorption via the RANK system

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23
Q

What are the main causes of primary hyperparathyroidism?

A

o Parathyroid adenoma (80% normally just one gland)

o Parathyroid hyperplasia (20%

o Parathyroid cancer (<1%)

o Familial syndromes (MEN1= 2%, all 4 glands may be affected in MEN1)
(MEN 2A, HPT-JT rare-phaeochromocytomas, adenomas in glands)

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24
Q

what is the biochemical diagnosis of primary hyperparathyroidism?

A

elevated total/ionised calcium with PTH levels frankly elevated or in the upper normal range (still not physiologically normal)

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25
Q

what are the clinical features of primary hyperparathyroidism?

A

hypercalcaemia
- stones: Renal colic –>Nephrocalcinosis –>CRF.

  • bones
  • abdominal groans: Dyspepsia, pancreatitis, constipation, nausea, anorexia.
  • psychic moans: Depression, impaired concentration, coma.
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26
Q

what is hypercalcaemia primary hyperparathyroidism the same as physiologically?

A

its the same as taking the diuretic frusemide

high calcium shuts down the K channels as K is recycled to absorb calcium normally via paracellular reabsorption

this leads to dehydration as less Na is reabsorbed

this is the same mechanism in frusemide, a loop diuretic (triple transporter inhibitor

27
Q

what are you at risk of with chronically high PTH?

A

increases stone risk, cortical bone reabsorption and fracture risk.

28
Q

what may also change along with serum calcium and phosphate in primary hyperparathyroidism?

A

creatinine may be elevated also

29
Q

what is the half life of vitamin D binding protein?

A

3 days

then filtered by kidney

30
Q

what activates TRPV6 to reabsorb calcium in the gut?

A

1, 25(OH)2Vit-D i.e.calcitriol

31
Q

where does most of the calcium reabsorption occur?

A

o Reabsorption via channel or paracellular.
o 20-60% via the duodenum, jejunum and colon.
o Mostly passive but up to 40% active transport.

32
Q

what are the main actions of vitamin D? [5]

A

o Reabsorb calcium and phosphate in the gut – TRPV6, calbindin.
o Acts on osteoblasts to increase formation of clasts through RANKL.
o Increase osteoblast differentiation.
o Facilitate PTH action in DCT – TRPV5, calbindin.
o Feedbacks on parathyroid to reduce PTH secretion.

33
Q

what level of vitamin D is required for muscle function?

A

> 70-75 nmol/L

less than 50 is deficient

34
Q

what is rickets?

A

defective mineralisation of the cartilaginous growth plate (before a low calcium) due to vitamin D deficiency

35
Q

what are the main symptoms of rickets

A
  • axial bone pain

- proximal myopathy

36
Q

what are the signs of rickets?

A
  • age-dependant deformity
  • myopathy
  • hypotonia
  • short stature
  • tenderness on percussion.
  • Chvostek’s and Trousseau’s signs on inspection.
37
Q

what are the causes of rickets?

A
  • dietary
  • GI (malabsorption, pancreatic/liver disturbance
  • drugs (phenytoin, phenobarbitone, orlistat)
  • renal (CRF)
  • rare hereditary (VitD-dependant rickets).
38
Q

what are the two types of vit-D dependent rickets?

A

o Type 1 VitD-dependant rickets – deficiency of 1-alpha-hydroxylase.

o Type 2 VitD-dependant rickets – defective VitD-R for calcitriol.

39
Q

what is the biochemical diagnosis for rickets?

serum and urine

A 
o	Serum – 
N/LOW calcium
N/LOW phosphate
HIGH ALP
LOW calcitriol
HIGH PTH (compensatory).
o	Urine – 
HIGH phosphate
glycosuria
aminoaciduria
high pH
proteinuria.
40
Q

what factors leads to phosphate loss in osteomalacia and how?

A

FGF-23 (fibroblast growth factor) and PTH

  • inhibit the phosphate/NA co-transporter
  • co-transporter is located in the PCT
  • increased phosphate excretion

FGF-23 inhibits NPT2a and NPT2c
PTH inhibits NPT2a

41
Q

where is phosphate fully filtered and only reabsorbed?

A

PCT

42
Q

what produces FGF-23?

what other effect does FGF-23 have other than cause phosphate loss?

A

osteoblasts
inhibits the activation of Vit-D by 1-alpha-hydroxylase and therefore calcitriol formation to prevent it absorbing phosphate in the gut

43
Q

why is FGF-23 production triggered?

A

when there is low Ca, PTH is secreted so more absorption of calcium occurs at the gut. There is also absorption of phosphate that occurs. This phosphate triggers osteoblasts to produce FGF-23 to switch off phosphate reabsorption and also switch of calcitriol production (which has the aim of increasing calcium too)

44
Q

what are the times of “isolated” hypophosphataemia?

A

Diseases that enable high FGF-23

o X-linked hypophosphatemia Rickets:

  • 1: 20,000.
  • Mutations in PHEX (breaks down FGF-23)  HIGH levels of FGF-23.
  • Toddlers with leg deformity, enthesopathy, dentin abnormalities.

o Autosomal dominant hypophosphatemia rickets (ADRR):

  • Variable age of onset.
  • Cleavage site of FGF-23 mutated–> high FGF-23.

o Oncogenic osteomalacia:
- Mesenchymal tumours autonomously produce FGF-23.

45
Q

what are the cause of PCT damage that also lead to hypophosphataemia and phosphaturia?

A 
o	Fanconi syndrome.
o	Multiple myeloma.
o	Heavy metal poisoning.
o	Drugs e.g. tenofovir, gentamycin.
o	Congenital disease e.g. Wilson’s, glycogen storage disease.
46
Q

why is biochemistry involved in osteoporosis diagnosis?

A

to exclude other causes, it should be normal in osteoporosis

  • Vit D def is checked
  • secondary endocrine causes are checked e.g. primary hyperparathyroidism, primary hyperthyroidism, hypogonadism
  • exclude multiple myeloma
  • high urine calcium checked
47
Q

what is the main tool used to assess osteoporosis?

A

BMD (represents 70% of total risk of fracture)

used in the FRAX (Fracture Risk Assessment Tool)

48
Q

what scan is used to determine BMD?

A

DEXA
measure the difference in densities between two materials

vertebral and hip BMDs are measured, the two most common areas for fractures . These areas respond fastest to treatment

49
Q

what is the definition of osteoporosis according to BMD?

A

a T score less than or equal to -2.5

1 SD reduction is a 2.5x increase in fracture risk

T score = measured BMD- young adult mean BMD/young adult SD

50
Q

what are the bone markers used to diagnose osteoporosis?

A 
formation markers (P1NP)
resorption markers
51
Q

what is a marker of bone formation used to diagnose?

A

P1NP (procollagen type 1 N-terminal propeptide)

in the production of collagen, this is cleaved, indicating the process of bone formation

52
Q

what are the resorption markers used to diagnose osteoporosis?

A

o Serum CTX – Cross-linked C-telopeptides.
o Urine NTX – Cross-linked N-telopeptides.

3 hydroxylysine molecules condense out to form a pyridinium ring linkage on resorption of bone.

53
Q

what are resorption markers used for mainly? what are the difficulties using them?

A

mainly used to monitor osteoporosis treatment

problems:
- Hard to reproduce.
- Positive association with age anyway.
- Need to correct for creatinine.
- Diurnal variation in urine markers.

54
Q

what formation marker is commonly used and for the diagnosis/monitoring of which diseases?

A

ALP
• Paget’s disease of bone.
• Osteomalacia.
• Bony metastasis.

55
Q

what is bone specific alkaline phosphatase?

A

tissue-specific to bone, form of ALP essential for mineralisation of bone and regulates the concentrations of phosphate
has a half life of 40 hours

56
Q

how does bone specific alkaline phosphate change in MBD?

A

Increased in Paget’s, osteomalacia, bone metastasis, hyperparathyroidism and hyperthyroidism

younger people have more ALP

57
Q

what can P1NP be used for apart from diagnosis?

A

predictor of response to anabolic treatments e.g. PTH treatment

58
Q

what do skeletal remodelling disorders caused by CKD contribute to?

A

vascular calcifications

the disorders in mineral metabolism with CKD is the main reason for mortality in CKD

59
Q

what effect does remodelling disorders in CKD have on the skeleton?

A

impairs skeletal anabolism
decreases osteoblast function
decreases bone formation.

60
Q

what is the biochemistry in renal osteodystrophy?

A

increased phosphate
reduced calcitriol

(kidney failure means less calcitriol, and nephron loss means less phosphate filtered into urine)

61
Q

what is the pathway to hypercalcaemia in renal osteodystrophy?

A

1) secondary hyperparathyroidism develops to compensate
2) unsuccessful so hypocalcaemia
3) parathyroid become autonomous (tertiary hyperparathyroidism)
4) hypercalcaemia.

62
Q

how are extra-skeletal calcifications formed?

e.g. in renal disease where phosphate excretion has become poor

A
  • increased phosphate in the plasma
  • this can bind to free (active) calcium and forms crystals
  • this also exacerbates hypocalcaemia
63
Q

what are the 3 main effects of nephron loss in CKD causing the renal osteodystrophy?

A

1) phosphate retention
2) reduced calcitriol
3) acidosis

64
Q

what are the consequences of the effects of nephron loss?

A

1) acidosis–> demineralisation
2) reduced calcitriol–> osteomalacia and hypocalcaemia (secondary hyperparathyroidism–> bone resorption)
3) phosphate retention (hyperphosphataemia)–> hypocalcaemia and metastatic calcification

LCRS Musculoskeletal (11 decks)

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