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Y2 LCRS 2 - Musculoskeletal > 3. Metabolic Bone Disease - Biochemistry > Flashcards

3. 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

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

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

This compensates for changes in protein level (if proteins are high, itcompensates 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 falsely 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 and kidneys

A

a. Bone
acute release of available calcium (not stored in hydroxyapatite crystal form) More chronically, increased osteoclast activity
b. 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

84Active: 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)

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22
Q

What are the causes of primary hyperparathyroidism?

A

Parathyroid adenoma (80%) Parathyroid hyperplasia (20%) Parathyroid cancer 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).
    i. e. corrected calcium > 2.60 mmol/L with PTH>3.9 pmol/l
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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)

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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

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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

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27
Q

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

A

TRPV6

Calbindin

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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)

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29
Q

What is Rickets?

A

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

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30
Q

State some signs and symptoms of Rickets.

A

Symptoms:  Lack of play  Bone pain and tenderness (axial)  Muscle weakness (proximal) Sign:  Age dependent deformity  Myopathy  Hypotonia  Short stature  Tenderness on percussion

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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  
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. Calciumb. Phosphatec. Alkaline Phosphatased. 25-OH cholecalciferole. PTHf. URINE phosphate

A

a. Calcium Normal or Low b. Phosphate Normal or Low c. Alkaline Phosphatase Highd.25-OH cholecalciferol Lowe. PTH Highf. URINE phosphate High

33
Q

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

A

FGF23

34
Q

What effect does this factor have that is unlike PTH?

A

It inhibits 1 alpha-hydroxylase, thus inhibiting calcitriol production

35
Q

Which cells produce this factor?

A

Osteoblast lineage cells

36
Q

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

A

Phosphate deficiency

37
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)

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

It increases the number of bone remodelling units 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

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 bodies  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 tocollagen production?

A

Procollagen type 1 N-terminal propeptide (P1NP)

46
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

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

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

49
Q

What bone formation marker is commonly in use?

A

Alkaline Phosphatase

50
Q

What is it 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

How does growth and exercise change peak bone mass?

A
  • Change in bone dimensions- Change in bone shape- Change in trabecular volumetric BMD
58
Q

When does consolidation of bone mass occur in men and women?

A

28-42 years

59
Q

Describe biochemical investigations

(serum and urine) in bone disease.

A
  • serum
    bone profile (calcium, corrected calcium, albumin, phosphate, alkaline phosphatase)
    renal function (parathyroid hormone, 25-hydroxyVitD)
  • urine
    calcium/phosphate, NTx (N-terminal telopeptide)
60
Q

Describe the biochemical changes in osteoporosis.

Ca, P, Alk p, bone form, bone resorp

A
  • Bone form: increased or normal

- Bone resorp: large increase

61
Q

Describe the biochemical changes in osteomalacia.

Ca, P, Alk p, bone form, bone resorp

A
  • Ca: normal or decrease
  • P: decrease
  • Alk P: increase
62
Q

Describe the biochemical changes in Paget’s.

Ca, P, Alk p, bone form, bone resorp

A
  • Ca: normal or increase
  • P: normal
  • Alk P: large increase
  • bone form: large increase
63
Q

Describe the biochemical changes in primary HPT.

Ca, P, Alk p, bone form, bone resorp

A

Ca: increase
P: normal or decrease
Alk P: normal or increase
Bone resorp: large increase

64
Q

Describe the biochemical changes in renal osteodystrophy.

Ca, P, Alk p, bone form, bone resorp

A

Ca: decrease or normal
P: increase
Alk P: increase

65
Q

Describe the biochemical changes in metastases.

Ca, P, Alk p, bone form, bone resorp

A

Ca: increase
P: increase
Alk P: increase
Bone resorp: increase

66
Q

What are the 3 main systems of calcium balance?

A

Gut: 1g/daily intake
Kidney: Out
Bone (1kg of Ca): Flux, compensatory mechanism to ECF Ca

67
Q

How does high serum calcium causes diuresis?

A
  • Ca2+ effects in thick ascending LOH
  • Binds to basolateral membrane and stimulate PLA2 and arachidonic acid –> decrease cytochrome P450 –> decrease activity of Na/2Cl/K pump and K channels on apical
  • Na not reabsorbed
68
Q

Name all five biochemical findings of primary HPT.

A
  1. Increased serum Ca by absorption from bone/gut
  2. Decreased serum phosphate by renal excretion
  3. PTH high (could be normal)
  4. Increased urine Ca excretion
  5. Cr may be elevated
69
Q

What are the mechanisms of activated VitD increasing gut calcium absorption

A

Passive: paracellular, linear
Active: up to 40%, saturable, duodenum, 1,25 VitD

70
Q

Where is FGF-23 produced?

Explain its effects on kidneys?

A
  • 32KD protein produced by osteoblast lineage cells in long bones
  • Decreases NPT2a and NPT2c expression
  • Cause P loss at PCT
  • Inhibit activation of VitD by 1 alpha-hydroxylase
71
Q

Outline the effects of FGF-23

A
  1. Inhibit 1 alpha-hydroxylase

2. Inhibit NPT2c which inhibits reabsorption of PO4 (cause P loss)

72
Q

What is autosomal dominant hypophosphataemic rickets (ADRR)?

A

Cleavage site for FGF-23 mutated –> high FGF-23

Variable age of onset, may improve

73
Q

What is X-linked hypophosphataemic rickets?

A

Mutations in PHEX, leads to high levels of FGF-23

Toddlers with leg deformity, enthesopathy, dentin anomalies

74
Q

What is the half life of VitD binding protein?

A

3 days

filtered by the kidneys

75
Q

What are some causes of high turnover osteoporosis?

A 
Estrogen deficiency 
Hyperparathyroidism
Hyperthyroidism
Hypogonadism in young women and men
Heparin
76
Q

What are some causes of low turnover osteoporosis?

A

Liver disease (primarily primary biliary cirrhosis)
Heparin
Age above 50 years

Y2 LCRS 2 - Musculoskeletal (10 decks)

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