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Musculoskeletal > Metabolic Bone Disease – Biochemistry > Flashcards

Metabolic Bone Disease – Biochemistry Flashcards

1
Q

What is metabolic bone disease?

A

A group of disease that cause a change in bone density and bone strength by increasing bone resorption, decreasing bone formation or altering bone structure

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2
Q

What are the five main metabolic bone disorders?

A
  1. Primary Hyperparathyroidism
  2. Osteomalacia/Rickets
  3. Osteporosis
  4. Renal Osteodystrophy
  5. Paget’s Disease
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3
Q

What are the main components of bone strength?

A

Mass
Material
Microarchitecture
Macroarchitectue

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4
Q

When is peak bone mass reached?

A

Around 25 years

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5
Q

When does bone mass begin to decline?

A

Around 40 years

NOTE: in women, the decline in bone mass accelerates after menopause

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6
Q

How are microfractures repaired?

A

Bone remodelling

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7
Q

Briefly describe 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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8
Q

What is the normal range for serum calcium concentration?

A

2.15-2.56 mmol/L

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9
Q

Describe the distribution of calcium.

A

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

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10
Q

What is the ‘corrected’ calcium level?

A
  • considers the calcium bound to albumin

Corrected calcium = [Ca2+] + 0.02(45-[albumin])

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11
Q

Describe the effect of metabolic alkalosis on calcium distribution.

A

It makes more calcium bind to plasma proteins thus reducing the free calcium levels
NOTE: venous stasis may elevate free calcium

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12
Q

What are the two main targets of PTH?

A

Kidneys

Bone

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13
Q

Describe the effects of PTH in:

a. Bone
b. Kidneys

A

a. Bone
Acute- release of available calcium (not stored in hydroxyapatite crystal form)
Chronic, increased osteoclast activity- catabolic

b. Kidneys  
Increased calcium reabsorption  
Increased phosphate excretion  
Bone resorption via RANK
Increased stimulation of 1-alpha hydroxylase (thus increasing calcitriol production)
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14
Q

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

A

DISTAL convoluted tubule via TRPV5/6

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15
Q

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

A

PROXIMAL convoluted tubule

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16
Q

How many amino acids make up PTH and which part of this is active?

A

84

Active: N1-34

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17
Q

What is PTH dependent on?

A

Magnesium

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18
Q

What is the half-life of PTH?

A

8 mins

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19
Q

What else can the PTH receptor be activated by other than PTH?

A

PTHrP (PTH related protein)

This is produced by some tumours

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20
Q

What does the parathyroid gland use to monitor serum calcium?

A

Calcium-sensing receptors

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21
Q

Describe the relationship between PTH level and calcium in vivo.

A

Steep inverse sigmoid function
NOTE: even at high Ca conc, there is a minimum level of PTH release (it can’t get below this even in the case of hypercalcaemia)

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22
Q

What are the causes of primary hyperparathyroidism?

A
  1. Parathyroid adenoma (80%)
  2. Parathyroid hyperplasia (20%)
  3. Parathyroid cancer
  4. Familial syndromes
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23
Q

What biochemical results are diagnostic of primary hyperparathyroidism?

A

Elevated total/ionised calcium
With PTH levels frankly elevated or in the upper half of the normal range (negative feedback should drop PTH if there is hypercalcaemia)

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24
Q

What are the clinical features of primary hyperparathyroidism?

A

Stones, Bones, Abdominal Groans and Psychic Moans

  1. Stones – renal colic, nephrocalcinosis, CRF
  2. Bones – osteitis fibrosa cystica
  3. Abdominal moans – dyspepsia (indigestion), pancreatitis, constipation
  4. Psychic groans – depression, impaired concentration

NOTE: patients may also suffer fractures secondary to the bone resorption
IMPORTANT NOTE: hypercalcaemia also causes diuresis (polyuria and polydipsia)

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25
Q

What is the main site of action of calcitriol and what effect does it have?

A

Small intestine – increases calcium and phosphate absorption

26
Q

Describe the effects of calcitriol on bone and in the kidneys.

A

Facilitates PTH effect on the DCT in the kidneys (increased calcium reabsorption)
Synergises with PTH in the bone to increase osteoclast activation/maturation

27
Q

Which receptors/proteins are involved in mediating the effects of calcitriol on the intestines?

A

TRPV6

Calbindin

28
Q

What parameter is used to determine whether a patient is vitamin D deficient?

A

no absolute value?
Deficient < 20 ng/M (50 nmol/L)
Normal > 30 ng/M (75 nmol/L)

29
Q

What is Rickets?

A

Inadequate vitamin D activity leads to defective mineralisation of the cartilaginous growth plate (before a low calcium)

30
Q

State some signs and symptoms of Rickets.

A 
Symptoms: 
1. Lack of play  
2. Bone pain and tenderness (axial) 
3. Muscle weakness (proximal) 
Sign: 
1. Age dependent deformity 
2. Myopathy 
3. Hypotonia  
4.  Short stature  
5. Tenderness on percussion 
plus CHVOSTEK and TROSSEAU signs
31
Q

State some Vitamin D related causes of Rickets/Osteomalacia.

A 
Dietary deficiency  
Malabsorptoin  (GI)
Drugs – e.g. enzyme inducers such as phenytoin 
Chronic renal failure  
Rare hereditary
32
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
Normal or Low

b. Phosphate
Normal or Low

c. Alkaline Phosphatase
High

d.25-OH cholecalciferol (Calcifediol)
Low

e. PTH
High

f. URINE phosphate
High

33
Q

Other than PTH, what else can cause increased phosphate excretion?

A

FGF23 (inhibits phosphate/Na co transporter)

34
Q

What effect does the FGF23 factor have that is unlike PTH?

A

It inhibits 1 alpha-hydroxylase, thus inhibiting calcitriol production (which is how it leads to osteomalacia)

35
Q

Which cells produce FGF23 factor?

A

Osteoblast lineage cells

36
Q

Other than Vitamin D deficiency, what else can cause Rickets/Osteomalacia?

A 
Phosphate deficiency
(so Vit D and Ca are normal but not enough phosphate causes)
37
Q

State some phosphate-related conditions that cause Rickets/Osteomalacia.

A
  • Isolated phosphataemia:
    1. X-linked Hypophosphataemic Rickets (mutation in Phex which breaks down FGF23 so get high levels of FGF23)
  1. Autosomal Dominant Hypophosphataemia Rickets
    (cleavage site of FG23 mutated so get high levels)
  2. Oncogenic Osteomalacia (mesenchymal tumours can produce FGF23)
38
Q

What can cause osteoporosis due to increased bone resorption and decreased bone formation?

A

Glucocorticoids

39
Q

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

A
  1. It increases the number of bone remodelling units

2. It causes an imbalance in bone remodelling with increased bone resorption compared to bone formation

40
Q

Describe the biochemistry of someone with osteoporosis.

A

Everything should be normal if the cause is primary

- this should exclude all other causes

41
Q

What is the single best predictor of fracture risk?

A

BMD

42
Q

What is used to measure BMD?

A

DEXA scans

43
Q

Which bones are used when measuring BMD and why?

A

Vertebral

  • Commonest fracture
  • Good measure of cancellous bone
  • It is a highly metabolically active bone so it is quick to respond to treatment

Hip – second commonest fracture
NOTE: fracture risk assessment tool (FRAX) uses hip BMD

44
Q

Which chains make up type 1 collagen?

A

2 x alpha 1

1 x alpha 2

45
Q

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

A

Procollagen type 1 N-terminal propeptide (P1NP)

  • in production of collagen extension peptide are cleaved which can be measured
46
Q

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

A
  1. C-terminal telopeptide (CTX) – serum
  2. N-terminal telopeptide (NTX) – urine

-3 hydroxylysine molecules on adjacent tropocollagen fibrils condense to form a pyridinium ring linkage
which can be used to measure bone resorption

47
Q

After how long do bone resorption markers fall?

A

4-6 weeks

48
Q

What are the problems with cross-linking collagen, with regards to measurement of bone markers?

A
  1. Reproducibility
  2. Positive association with age
  3. Need to correct for creatinine
  4. Diurnal variation in urine markers
49
Q

What bone formation marker is commonly in use?

A

Alkaline Phosphatase

50
Q

What is ALP used in the diagnosis and monitoring of?

A

Osteomalacia
Paget’s
Bone Metastases

51
Q

What is P1NP being used for now?

A

Used as a predictor of response to anabolic treatments

52
Q

What are the two forms of alkaline phosphatase?

A

Liver

Bone

53
Q

Which bone diseases will cause a rise in ALP?

A

Osteomalacia
Bone metastases
Also hyperparathyroidism and hyperthyroidism

54
Q

How does alkaline phosphatase change with age?

A

Increases markedly during puberty reaching its highest levels
Remains relatively constant following puberty (potential small rise after the age of 50)

55
Q

What biochemical changes occur in renal osteodystrophy?

A

Increased serum phosphate

Reduction in calcitriol

56
Q

Describe the sequelae of renal osteodystrophy.

A

Secondary hyperparathyroidism
This is unsuccessful and hypocalcaemia develops
This leads to excessive stimulation of the parathyroid glands, leading to parathyroid hyperplasia
The parathyroid cells begin to reduce expression of calcium-sensing receptors (CSR) and Vitamin D receptors (VDR) and become autonomous (tertiary)
This causes hypercalcaemia

57
Q

Describe the sexual dimorphism in bone growth

A

Men have appositional bone growth whilst women form new bone on the inside of the bone marrow

58
Q

In BMD, what does a 1 SD reduction imply?

A

2.5X increase in fracture risk

59
Q

In BMD, how is a T-score calculated?

A

measured BMD - young adult mean BMD

all divided by young adult SD

60
Q

What are the two types of rare hereditary rickets and what are their causes?

A
  1. Type 1 VitD-dependant rickets
    - deficiency of 1-alpha hydroxylase
  2. Type 2 VitD-dependant rickets
    - defcetive VitD- recpetor for calcitriol

Musculoskeletal (10 decks)

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