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Musculoskeletal Y2 > Metabolic Bone Disease: Biochemistry > Flashcards

Metabolic Bone Disease: Biochemistry Flashcards

1
Q

What is metabolic bone disease?
A group of diseases that cause a change in… (2)

by… (3)

A
  • Bone density
  • Bone strength

by

  • INCREASING bone resorption
  • DECREASING bone formation
  • Altering bone structure
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2
Q

5 common metabolic bone disorders?

A
  • Primary hyperparathyroidism
  • Rickets/ Osteomalacia
  • Osteoporosis
  • Paget’s Disease
  • Renal osteodystrophy
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3
Q

Metabolic symptoms of common metabolic bone disorders? (4, 2 really:/)

A
  • Hypocalcaemia
  • Hypercalcaemia
  • Hypo/ Hyperphosphataemia
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4
Q

Bone symptoms of common metabolic bone disorders? (3)

A
  • Bone pain
  • Deformity
  • Fractures
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5
Q

Bone stores calcium as…

A

inorganic hydroxyapatite

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6
Q

Some types of bone are very metabolically active, e.g. …

A

cancellous bone (particularly in vertebrae)

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7
Q

Bone remodelling requires a continuous exchange of …

A

ECF with bone fluid reserve.

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8
Q

What organs are involved in calcium homeostasis

A

Bone, small intestine, kidney

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9
Q

What % of calcium is free, bound (to what: carrier protein and the other 1)

A
  • 47% free ionised (active) Ca unbound
  • 46% protein bound to albumin
  • 7% complexed to PO4 + citrate
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10
Q

how does hyperventilating change serum calcium

A

get an alkalosis which causes more Ca to bind to the protein so that the free levels drop.

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11
Q

What calcium level promotes PTH

A

Low

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12
Q

PTH acts where? (2)

A

Bone, kidney

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13
Q

Effect of PTH on bone? (2 and also acute and then chronic)

A

helps to release Ca and PO4 from bone. There is an acute release of available Ca (not hydroxyapatite crystals). More chronically, there is increased osteoclast activity to resorb bone, releasing Ca and PO4.

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14
Q

Effect of PTH on kidney? (3)

A

increases absorption of Ca from the distal tubule in the kidney and increases PO4 excretion

also increases the production of Calcitriol in the kidneys via the stimulation of 1-hydroxylase, which will increase Ca absorption in the gut (this is the main effect of Vitamin D)

If there is an increase in PO4 from the bone and gut, this will need to excreted which is why PTH causes an increase in Ca and simultaneously causes PO4 to be excreted from the kidneys. PTH inhibits the Na/PO4 co-transporter in the PCT which allows the PO4 to be excreted.

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15
Q

Changes to serum phosphates and alkaline phosphatase in most metabolic bone disorders?

A

Increases, only doesn’t in osteomalacia where P goes down (Alk P is up)
and primary HPT where P goes down (Alk P is up)
And osteoporosis where its normal

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16
Q

Alkalosis changes serum calcium how?

A

More becomes bound to albumin

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17
Q

What ion is PTH dependent on?

A

Mg

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18
Q

Low Mg can impair which hormone leading to bone diseases?

A

PTH

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19
Q

how can a small cell carcinoma cause hypercalcaemia?

A

?PTHrP is produced by some tumours which activates PTH receptor and so hypercalcaemia

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20
Q

What else can activate the PTH receptor apart from PTH

A

PTHrP

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21
Q

What is the curve of PTH secretion to Ca level?

A

Sigmoidal

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22
Q

If there is super high Ca levels, what is the PTH level

A

There is always a baseline secretion

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23
Q

What is the SET-POINT in the curve of PTH secretion to Ca level?

A

Steepest point of the curve, 1/2 the maximal suppression

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24
Q

Where in the kidney does PTH act

A

Distal tubule

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25
Q

How does PTH absorb Ca in the distal tubule?

A

PTH binds to receptors which causes the activation of a transport protein for Ca to bind to to enter the cell (TPRV5)

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26
Q

Once Ca has entered the cell how does it get into the blood from the DCT cell? (2 ways)

A

Ca then binds to an intracellular protein, and is transported through the cell and is either excreted via CaATPase (by AT) or by the Na/Ca exchanger.

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27
Q

How does PTH causes activated osteoclasts (3 stages)

A

PTH acts on osteoblasts to signal to produce more osteoclasts.
More activated osteoclasts are produced through the RANK and RANKL pathway.
Osteoclast progenitors have a RANK receptor which binds to RANKL on the osteoblasts/ stromal cells to then produce activated osteoclasts.

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28
Q

How do osteoclast progenitors become osteoclasts

A

Osteoclast progenitors have a RANK receptor which binds to RANKL on the osteoblasts/ stromal cells to then produce activated osteoclasts.

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29
Q

Primary HPT is more common in men or women

A

Women

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30
Q

Causes of hyperparathyroidism?

A

Parathyroid adenoma 80%

Parathyroid hyperplasia 20%

Parathyroid CA <1%

Familial Syndromes
MEN 1 2%
MEN 2A rare
HPT-JT rare

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31
Q

Defining Diagnosis of Primary HPT?

A

an elevated total/ ionised Calcium with PTH levels frankly elevated or in the upper half of the normal range

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32
Q

If the Ca= high, PTH= should be….

A

suppressed to the very end of the normal range

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33
Q

Clinical features of primary HPT? (pneumonic, at least 5)

A

BONES, STONES, ABDOMINAL MOANS AND PSYCHIC GROANS.

  • Renal stones, nephrocalcinosis, (high Ca trying to excrete so get kidney stones- increased incidence to renal impairment)
  • Dyspepsia, pancreatitis (dyspepsia= increased acid secretions)
  • Constipation, nausea, anorexia (affects the gut- appetite is gone)
  • Depression, impaired concentration
  • Drowsy, coma (in elderly people, causes mental problems.
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34
Q

What do patients present and complain about when coming in with PHPT?

A

Get: thirst, polyuria, tiredness, fatigue, muscle weakness

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35
Q

How does high serum Ca cause diuresis

A

Na/K/Cl transporter in the Loop of Henle (ascending limb) shuts if down serum Ca is high so no reabsorption of Na/K/Cl, causing diuresis.

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36
Q

Why does the Na/K/Cl triple transporter in the ALOH shut down with high serum Ca

A

In order to maintain the potential difference (+ve lumen, -ve blood)

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37
Q

what does the drug frusemide do and what does it cause?

A

Loop diuretic, shuts down triple transporter in ALOH, causes diuresis

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38
Q

acute/ pulsed increase in PTH effect on bone?

A

it has an anabolic effect and helps to build bone.

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39
Q

chronically elevated PTH effect on bone? What can this lead to?

A

catabolic effect which affects the cortical bone. This leads to a fracture increase due to thin cortices.

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40
Q

Long term hypercalcaemia causes what in the vasculature?

A

calcification of the arteries and will develop to hypertension and an increased vascular risk in the long term.

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41
Q

Primary HPT Biochemical Findings for:

Serum Ca
Serum PO4
Serum PTH
Urine Ca
Cr
A
  • Increased serum Ca  by absorption from bone/ gut
  • Decreased serum PO4
  • PTH in the upper half of the normal range or elevated  renal excretion in PCT
  • Increased urine Ca excretion
  • Cr may be elevated
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42
Q

Describe how UV light results in vitD

A

UV light converts 7-dehydrocholesterol -> to cholecalciferol and then to 25-hydroxycholecalciferol in the liver -> 25OH form is activated in the kidney to -> 1,25 dihydroxy

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43
Q

1,25 dihydroxycholecalcifderol/calcitriol effects?

A

increases gut absorption of Ca and PO4.

kidneys, Ca is reabsorbed through Vitamin D facilitating PTH in distal tubule and phosphate excretion in PCT

In bone, increases PTH function producing osteoclasts and releasing Ca and PO4

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44
Q

What receptor protein and molecule is involved in absorbing Ca in the kidney

A
  • TPRV5 and Calbindin
45
Q

What receptor protein and molecule is involved in absorbing Ca in the gut

A
  • TPRV6 and Calbindin
46
Q

Vit D effect in the gut? What receptor and protein?

A
  • Vitamin D activates Ca and PO4 absorption in the duodenum via TRPV6 and Calbindin
47
Q

Calcitriol effect of PTH secretion?

A

Reduces it

48
Q

How is Ca absorbed in the gut, active or passive?

A

There is passive transport- paracellularly

There is active transport- up to 40% saturable and this will occur in the duodenum, usually via the action of Vitamin D.

49
Q

What is measured when testing for Vit D deficiency?

A

the 25-OHcholecalciferol bound to Vitamin D binding protein (DBP)

50
Q

Symptoms of rickets? (3)

A
  • Bone pain and tenderness (axial)
  • Muscle weakness (proximal)
  • Lack of play
51
Q

Signs of rickets/osteomalacia? (5)

A
  • Age dependent deformity
  • Myopathy
  • Hypotonia
  • Short stature
  • Tenderness on percussion
52
Q

Rickets/osteomalacia causes? (including 4 GI causes)

A 
o	Lack of sunlight
o	Decreased production with age
-	Dietary-	GI
o	Small bowel malabsorption/ bypass
o	Pancreatic insufficiency
o	Liver/ biliary disturbance
o	Drugs, phenytoin, phenobarbitone  increased CYP450 activity that inactivates Vit D 
-	Renal
o	Chronic renal failure
-	Rare hereditary
o	Vitamin D dependent rickets  Type 1: deficiency of 1-hydroxylase
53
Q

Hypocalcaemia effects on muscle?

A

muscle spasm and paresthesia. Can be at risk of seizures too.

54
Q

Vit D solubility?

A

Fat soluble

55
Q

Primary HPT Biochemical Findings for:

Serum Ca
Serum PO4
Serum PTH
serum alkaline phosphatase

A

Low PO4
Low Ca
High PTH
High alkaline phosphatase

56
Q

FGF 23 is secreted by what, in response to what and what is its functions

A

Secreted by osteocytes in response to elevated phosphate
decreases the reabsorption and increases excretion of phosphate. FGF23 may also suppress 1-alpha-hydroxylase, reducing its ability to activate vitamin D and subsequently impairing calcium absorption

57
Q

How does PTH effect phosphate absorption in the kidneys

A

There are PO4 transporters to coabsorb the PO4 and Na in the PCT, PTH removes these

58
Q

How does FGF23 effect phosphate absorption in the kidneys

A

Shuts down the PO4 Na cotransporter

59
Q

how does FGF23 and PTH prevent hypocalcaemia and avoid hyperphosphataemia

A

Low Ca -> PTH secretion -> Ca absorbed in gut with PO4 -> Ca switches off PTH so PO4 isn’t excreted -> bone senses excess PO4 -> produces FGF23 -> switches off PO4 absorption in the gut -> stops vit D production too

60
Q

What abnormally functioning hormone causes excess phosphate loss

A

FGF-23, the PO4 would be continuously lost.

61
Q

explain X-linked hypophosphataemic Rickets

A
  • Most common form of rickets in the USA- can’t break down FGF-23 so have high levels of it. Its due to mutations in PHEX.
62
Q

explain Autosomal Dominant Hypophosphataemic Rickets

A

is an autosomal dominant problem can’t cleave FGF-23 thus have high levels of it

63
Q

Explain oncogenic osteomalacia

A

Benign Mesenchymal tumors

- Produce FGF-23, causes phosphaturia and stops 1-OHlase.

64
Q

WHAT IS Fanconi syndrome

A

damage to the proximal tubule. This leads to leakage of PO4, glucose and there will be acid-base disturbance. This is because the proximal part is where the alkali is supposed to be reclaimed.
In urine- there will be abnormalities.

65
Q

CAUSES OF FANCONI SYNDROME? (4)

A

Multiple myeloma
Heavy metal poisoning: lead, mercury
-Drugs: tenofovir, gentamycin
Congenital disease: Wilson’s, glycogen storage diseases

66
Q

Main CAUSE OF FANCONI SYNDROME?

A

Gentamycin in gram -ve infections

67
Q

Osteoporosis is essentially …

A

LOW BONE DENSITY

68
Q

Osteoporosis shows loss of connections between XXX

A

the trabecular network.

69
Q

Causes of high turnover osteoporosis? (5)

A 
o	Oestrogen deficiency- primarily in postmenopausal women
o	Hyperparathyroidism
o	Hyperthyroidism
o	Hypogonadism in young women and men
o	Cyclosporine (?)
o	Heparin treatment
70
Q

Causes of low turnover osteoporosis? (3)

A

o Liver disease- primarily primary biliary cirrhosis (reduces the rate of new bone formation)
o Heparin
o Age above 50yrs

71
Q

What type of bone is highly metabolically active

A

Cancellous

72
Q

How often do we get a new skeleton

A

Every 5-7 years

73
Q

What makes bone strong? (4)

A

Mass
Material properties
Microarchitecture
Macroarchitecture

74
Q

How does material properties make a bone strong? (3)

A
  • Collagen fibrils which cross link.
    Woven versus lamellar
    mineralisation
75
Q

How does Microarchitecture make a bone strong? (3)

A

Trabecular thickness
Trabecular connectivity
Cortical porosity

76
Q

How does Macroarchitecture make a bone strong? (2)

A

Hip axis length

Diameter of bone

77
Q

4 ways Bone structure and function may be assessed ?

A
  • Bone histology
  • Biochemical tests
  • Bone mineral densitometry e.g. osteoporosis
  • Radiology
78
Q

when is peak bone mass reached and how long is it maintained, difference between men and women loss of bone mass?

A

The peak bone mass is around the mid 20’s. It is stable until around 40.
Men have a slow loss of mass. Women have a fast, early loss in early menopause

79
Q

How does oestrogen affect bone growth in puberty

A

oestrogen, lose the capacity to lay down bone outwards

Women put bone on the endocortical surface so bone remains a similar diameter.

80
Q

How does exercise change bone growth in puberty

A

More layers of bone put on the outside if this bone is stressed

81
Q

How does exercise change bone growth post puberty

A

Later in life, can only change things on the inside of the bone

82
Q

what process repairs microfratcures

A

Bone remodeling is the process by which these areas are repaired

83
Q

What represents a remodelling event of a microfracture

A

Each osteon

84
Q

Describe the remodelling cycle starting with a micro fracture

A

If a little crack occurs, this is picked up by osteocytes sitting in bone via their mechanoreceptors.
They send signals and so macrophages are activated and signal to make osteoclasts resorb the bone.
A constant stimulus for this is needed. After the bad bit of bone is taken out, the osteoblasts come and form bone marrow mesenchymal stem cells. If these osteoblasts get stuck in the middle, they form osteocytes

85
Q

What cell dies in bone as you get older

A

osteocytes

86
Q

Effect of oestrogen and how it causes menopausal bone loss

A

: Oestrogen increases the action of OPG, thus causing inhibition of the RANK pathway (usually activates osteoclasts).
Menopausal changes include a decrease in oestrogen reduced inhibition of the RANK pathway- increased osteoclast action.
Causes remodelling errors and
Trabecular perforation
Cortical excess excavation

87
Q

How does an osteocyte signal that a microcrack has occurred

A

A microcrack crosses canaliculi, so severing osteocyte processes causing osteocytic apoptosis.

88
Q

MoA of oestrogen to avoid osteoporosis?

A

Oestrogen increases the action of OPG, thus causing inhibition of the RANK pathway (usually activates osteoclasts)

89
Q

Which bone is rapidly lost in the first few years of menopause

A

Cancellous

90
Q

Biochemistry in Osteoporosis: serum levels of all things in normal osteoporosis?

A

Should be normal

91
Q

What biochemical tests do you do for osteoporosis? (4)

A

1) Check for Vitamin D deficiency
2) Check for Secondary endocrine causes.
3) Exclude multiple myeloma
4) May have high urine Ca

92
Q

What secondary endocrine causes do you test for in osteoporosis? (3)

A

Primary hyperparathyroidism  PTH is high
Primary hyperthyroidism  free T3 is high and TSH is suppressed.
Hypogonadism testosterone is low.

93
Q

What tests do you do to confirm osteoporosis? (4)

A

Dual Energy X-Ray Absorpiometry (DEXA)

94
Q

What areas are BD measured to check for osteoporosis

A

Vertebral measurements

Hip measurements

95
Q

What can be measured in serum to indicate collagen synthesis in bone formation

A

P1NP= Procollagen Type 1 N-terminal Propeptide.

96
Q

What can be measured to indicate collagen breakdown in bone resorption

A

measuring urine hydroxyproline or urine collagen cross-links

97
Q

measuring urine hydroxyproline or urine collagen cross-links gives us an idea of what…

A

osteoclast activity

98
Q

procollagen becomes –>

A

tropocollagen

99
Q

examples of bone markers: (3)

A 
urine hydroxyproline
urine collagen cross-links.
P1NP= Procollagen Type 1 N-terminal Propeptide.
Alkaline phosphatase
Osteocalcin
100
Q

Akaline Phosphatase purpose?

A

essential for mineralization of bone

- Regulates concentrations of phosphocompounds

101
Q

Osteocalcin purpose?

A

involved in limiting mineralization, it’s incorporated into bone so that fragments are released on resorption

102
Q

Alkaline phosphatase is increased in which diseases: (5)

A
  • Paget’s disease
  • Osteomalacia
  • Bone metastases
  • Hyperparathyroidism
  • Hyperthyroidism
103
Q

What is osteoid

A

osteoid is the unmineralized, organic portion of the bone matrix that forms prior to the maturation of bone tissue

104
Q

Renal osteodytrophy levels of:

Serum PO4
VitD

A

PO4 increased

Vit D decreased

105
Q

Renal osteodystrophy causes the development of XX to compensate which leads to Y which causes Z

After a while this causes ƒ which leads to Ω

A

Secondary hyperparathyroidism

hypocalcaemia

hyperphosphataemia

tertiary hyperparathyroidism

hypercalcaemia

106
Q

Parathyroid hyperplasia develops in tandem with the progressive XXXX

A

decline in renal function.

107
Q

How does parathyroid hyperplasia occur

A

Initially, the parathyroid glands respond by increasing the proportion of secretory (chief) cells within the gland and then by increasing the total number of cells, resulting in diffuse hyperplasia of the gland.
In diffuse hyperplasia, cell growth is polyclonal, but is accompanied by down-regulation of the Ca receptor and VDR.
As CKD progresses to Stage 5 (end-stage renal disease), the parathyroid hyperplasia evolves even further; monoclonal abnormalities lead to nodular hyperplasia of the glands. These grossly enlarged parathyroid glands are associated significantly with reduced expression of Ca receptors and VDRs.
Parathyroid glands with nodular hyperplasia, thus become less responsive to serum Ca levels and resistant to the medial treatment of Secondary HPT.

108
Q

What leads to metastatic calcification

A

hyperphophataemia

Musculoskeletal Y2 (11 decks)

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