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Musculoskeletal > Bone disease - Biochemistry > Flashcards

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 
Primary Hyperparathyroidism 
Osteomalacia/Rickets 
Osteporosis 
Renal Osteodystrophy 
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

Microcrack crosses canaliculi, severing the osteocyte processes, inducing osteocyte apoptosis.

This signals the surface lining cells, which release factors to recruit cells from blood and marrow to remodelling compartment

Osteoclasts are generated locally and resorb the matrix and the mitrocrack

Then osteoblasts deposit new lamellar bone

Osteoblasts that become trapped n 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

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

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 bone and kidneys

A

Bone - Acute release of available calcium (not stored in hydroxyapatite crystal form) More chronically, increased osteoclast activity

Kidneys - Increased calcium reabsorption Increased phosphate excretion 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

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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: there is a minimum level of PTH release (it can’t get below this even in the case of hypercalcaemia)

22
Q

What are the causes of primary hyperparathyroidism?

A

Parathyroid adenoma (80%)
Parathyroid hyperplasia (20%)
Parathyroid cancer
Familial syndromes

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)

24
Q

What are the clinical features of primary hyperparathyroidism?

A

Stones, Bones, Abdominal Groans and Psychic Moans

Stones – renal colic, nephrocalcinosis
Bones – osteitis fibrosa cystica
Abdominal moans – dyspepsia, pancreatitis, constipation
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)

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

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

Signs: 
Age dependent deformity 
Myopathy 
Hypotonia 
Short stature 
Tenderness on percussion
31
Q

State some Vitamin D related causes of Rickets/ Osteomalacia.

A 
Dietary deficiency 
Malabsorptoin 
Drugs – e.g. enzyme inducers such as phenytoin 
Chronic renal failure 
Hereditary (Rare)
32
Q

For each of the following state whether it would be high, low or normal 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 - Low
e. PTH - High
f. URINE phosphate - High

33
Q

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

A

FGF23
(Fibroblast growth factor 23) produced by Osteoblast lineage cells

Note: It also inhibits 1 alpha-hydroxylase, thus inhibiting calcitriol production

34
Q

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

A

Phosphate deficiency

35
Q

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

A

X-linked Hypophosphataemic Rickets (mutation in Phex (this cleaves FGF23))

Autosomal Dominant Hypophosphataemia Rickets

Oncogenic Osteomalacia (mesenchymal tumours can produce FGF23)

36
Q

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

A

Glucocorticoids

37
Q

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

A

It increases the number of bone remodelling units It causes an imbalance in bone remodelling with increased bone resorption compared to bone formation

38
Q

Describe the biochemistry of someone with osteoporosis.

A

Everything should be normal if the cause is primary

39
Q

What is the single best predictor of fracture risk?

A

Bone mineral density (Measured via DEXA scans)

40
Q

Which bones are used when measuring BMD and why?

A

Vertebral bodies - Commonest fracture, Good measure of cancellous bone, It is a highly metabolically active bone so it is quick to respond to treatment

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

41
Q

Which chains make up type 1 collagen?

A

2 x alpha 1

1 x alpha 2

42
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)

43
Q

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

A

C-terminal telopeptide (CTX) – serum N-terminal telopeptide (NTX) – urine 3 hydroxylysine molecules on adjacent tropocollagen fibrils condense to form a pyridinium ring linkage These can be measured

44
Q

After how long do bone resorption markers fall?

A

4-6 Weeks

45
Q

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

A

Reproducibility
Positive association with age
Need to correct for creatinine
Diurnal variation in urine markers

46
Q

What bone formation marker is commonly in use?

A 
Alkaline Phosphatase (used to diagnose and monitior
Osteomalacia, Paget’s and Bone Metastases)
47
Q

What is P1NP being used for now?

A

Used as a predictor of response to anabolic treatments

48
Q

What are the two forms of alkaline phosphatase?

A

Liver

Bone

49
Q

Which bone diseases will cause a rise in ALP?

A

Osteomalacia
Bone metastases

(Also hyperparathyroidism and hyperthyroidism)

50
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)

51
Q

What biochemical changes occur in renal osteodystrophy?

A

Increased serum phosphate

Reduction in calcitriol

52
Q

Describe the sequelae of renal osteodystrophy.

A

Secondary hyperparathyroidism
This is unsuccessful and hypocalcaemia develops

This leads to excessive stimulation of parathyroids, 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

Musculoskeletal (8 decks)

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