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Biochemistry of metabolic bone disease Flashcards

1
Q

Define metabolic bone disease

A

A group of diseases that cause a change in

  • bone density
  • bone strength

by

  1. INCREASING bone resorption
  2. DECREASING bone formation
  3. Altering bone structure

(may be associated with disturbances in mineral metabolism)

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2
Q

Outline the metabolic and bone specific symptoms in metabolic bone disease

A

METABOLIC
Hypocalacaemia
Hypercalcaemia
Hypo/Hyperphosphataemia

BONE-SPECIFIC
Bone pain
Deformity
Fracture

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3
Q

How many calcium and phosphates in hydroxyapatite

A

10 Ca2+

6 PO43-

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4
Q

What percentage of bone is remodelling at a time

A

5%

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5
Q

How often is the entire skeleton replaced

A

7 years

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6
Q

What makes a bone strong

and outline each part

A

Mass

Material properties

Microarchitecture

Macroarchitecture

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7
Q

Outline material properties as a factor of bone strength

A

Collagen cross linking? (like CXH)

mineralisation,

woven/lamellar (disorganised, where lamellae not organised along stress lines i.e acute healing or pagets_,

microcracks (stress in mortar lines during exercise)

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8
Q

Outline microarchitecture properties as a factor of bone strength

A

Trabecular thickness, trabecular connectivity and cortical porosity

i.e. in spine post menopause lose thickness and connection in trabecular bone, which cannot be reformed

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9
Q

Outline macroarchitecture properties as a factor of bone strength

A

Genetic but can be improved by sport.

Hip axis length and diameter

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10
Q

How can bone structure and function be assessed

A

Bone histology
Biochemical tests
Bone mineral densitometry, e.g. osteoporosis
Radiology

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11
Q

Outline age related changes in bone mass

A

Peak bone mass in mid 20s

Stable until around 40

Men slow loss

Women fast loss in early menopause

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12
Q

How does growth and exercise change peal bone mass

A

Increases:

Change in bone dimesion and shape

and

Change in trabecular volumetric bone mineral density

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13
Q

How can bone modelling be optimised during growth

A

In tibia, more bone placed anteriorly and posteriorly… optimise deposition so as not to waste mass

Increase in the bending strength ratio, which is the ration of the anteroposterior length: mediolateral

greater periosteal apposition?

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14
Q

Differentiate bone modelling and bone remodelling

A

During bone modeling (construction), bone
is deposited without prior resorption on the periosteal
surface, increasing its external diameter as occurs in
growth.(6,7) During bone remodeling (reconstruction), osteoclasts resorb a small volume of bone which is replaced by osteoblasts

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15
Q

What determines the external dimension and shape of bone and what determines the size of the medullary cavity

A

External dimension: deposition of
bone tissue on the periosteum

Medullar cavity size:endocortical resorption

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16
Q

Why is bone thicker during growth

A

periosteal apposition exceeds endocortical resorption so that the cortex thickens

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17
Q

What occurs during usual ageing

and then during post-menopause period

A

Normal ageing: adter ephiphysial closure, advancing
age is associated with a slowing of periosteal apposition and
endocortical resorption

during post menopause:
The periosteal bone formation is not that much impaired, but the endocortical bone resorption increases (because oestrogen causes osteoclast apoptosis but this reduces in menopause so resoprtion increases, an dis not compensated for by an increase in formation)

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18
Q

What does each osteon represent

A

A previous remodelling event

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19
Q

The accumulation of what could cause compromised bone strength

A

In every dya life, microfractures will occur between osteons, and these need to be repaired. This is essentially the remodelling process. Osteoclasts come in and remove the damaged bone and stimulate osteblasts to come in and lay down new bone

irreversible PLASTIC deformation does occur resulting in microfractures, which dissipate the excess energy, generally limited to the interstitial bone between osteons .

If these accumulate bone strength will be compromised.

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20
Q

Outline how osteoclasts receive signal in bone remodelling

A

microcrack crosses canaliculi, so severing osteocyte processes causing osteocytic apoptosis. This is thought to act as a signal to the connected surface lining cells , which along with the osteocytes release local factors that attract cells from blood and marrow into the remodeling compartment

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21
Q

Lining cells are of what lineage

A

Osteoblast

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22
Q

What must occur in order for resorption to take place

A

Osteoclasts must be generated, which occurs due to local factors

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23
Q

Outline the reversal and then formation stage of bone remodelling

A

Following osteoclastic resorption of matrix and the offending microcrack, then successive teams of osteoblasts deposit new lamellar bone. Osteoblasts that are trapped in the matrix become osteocytes; others die or form new, flattened osteoblast lining cells.

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24
Q

Outline the stages of the bone remodelling cycle

A

Activation, resorption, reversal, formation

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25
Q

Which biochemical investigations can be poerofrmed in bone disease

A

Bone profile:
calcium,corrected calcium (albumin), phosphate, alkaline phosphatase

Renal function:
creatinine
PTH
25-hydroxy vitamin D

Urine:
Calcium/ Phosphate
NTX ( biochemical marker of bone metabolism and the most sensitive and specific indicator of bone resorption)

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26
Q

State the biochemical changes in osteoporosis

Ca2+, phosphate, Alk P, bone formation and resorptin

A 
Normal Ca2+
Normal phosphate 
Normal Alk P 
Increased/normal bone formation 
Increased bone resorption
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27
Q

State the biochemical changes in osteomalacia … calcium phosphate and alk P

A

Ca2+ low (or normal if corrected by increased PTH)

P low (increased excretion due to PTH)

Alk P increased a bit

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28
Q

State the biochemical changes in pagets

Ca, P, Alk P, Bone formation/resorption

A

Ca2+ normal (maybe slightly increased), P normal, Alk P increased a lot! Bone formation increased a lot

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29
Q

State the biochemical changes in primary HPT

Ca, P, Alk P, Bone formation/resorption

A

Ca2+ high, P normal/low, Alk P high or normal, bone resorption greatly increased

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30
Q

Outline biochemical changes in renal osteodystrophy

Ca2+, P and Alk P

A

Ca2+= low or normal
P= increased
Alk P= high

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31
Q

Outline biochemical changes in metastases

A

Ca2+ high, P high, Alk P high and bone resorption high

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32
Q

Mass of calcium in the body

A

1kg

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33
Q

How much calcium usually ingested and excreted a day

A

1gm in, 850mg out (through GI), 150mg out (through urine)…

look at diagram slide 19

bone is compensatory mechanism

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34
Q

What does total calcium comprise

A

Protein bound (46%), free/ionised (47%)and complexed (7%)

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35
Q

What can calcium be complexed to

A

Phosphate and citrate

You can remember this as when phosphate increases is renal osteodystrophy, calcium binds to it, reducing free Ca2+ (but it’s the fact that the kidney cannot hang on to Ca2+ that actually causes the biochemical change)

36
Q

What does corrected calcium mean

A

the corrected calcium a lab gives you compensates for the protein level; if protein levels are HIGH they compensate down; o.o2 for each g/l of albumin

37
Q

What occurs in alkalosis and to what consequence

A

Free/ionised –> protein bound…. free levels drop and tingling results

38
Q

What could falsely elevate calcium levels

A

Venous stasis

39
Q

How does PTH regulate Ca+2

A

PTH increases Ca2+ reabsorption from the kidney, and increases phosphate excretion

PTH increases bone resoprtion, liberating Ca2+ and phosphate

PTH increases the activity of 1a-hydroxylase which converts 25 cholecalfiverol to 1,25 cholecalciferol (calcitriol, active vit D)

NOTICE, not the gut

40
Q

T/F… PTH secretion occurs within seconds of reduced plasma calcium

A

T, due to preformed stores

41
Q

T/F PTH can release Ca2+ from the hydorxyapatite crystals of bone in an acute process

A

F Bone acute release of available calcium; not in hydroxyapatite crystals more chronically INCREASED osteoclast activiyty to re-absorb bone

42
Q

Where within the kidney will PTH increases Ca2+ reabsorption

A

the distal conv tubule; the only site where ca re-absorption is under active hormonal control

43
Q

How does PTH increase gut absorption of Ca2+

A

NOT DIRECTLY…. by increased Vit D

44
Q

How does PTH increase phosphate excretion

A

by inhibiting the NAP cotransporter in the proximal tubule

45
Q

What type of hormone is PTH

A

PEPTIDE:

84 AA but only N1-34 active

46
Q

PTH is dependent on what. When could this be a problem

A

Mg

Alcoholics may have hypomagnaesia

47
Q

Half life of PTH and the clinical relavance

A

t1/2= 8 mins….

allows intraoperative sampling

48
Q

T/F PTH receptors on the cell membrane is linked to cAMP, and is activated exclusively by PTH

A

TRUE- it is cAMP linked

BUT

Can also be activated by PTH related peptide (PTHrp cis produced by some tuours, and so hypercalcaemia may be first presenting feature ie small cell ca lung)

49
Q

How does PTH correspond to Ca2+ levels in the blood

A

Steep inverse sigmoidal function
relates PTH levels and Cao2+ in vivo.

Calcium sensing receptor on the PTH glands

Low Ca2+= high PTH
High Ca2+=low PTH

BUT STILL BASELINE PTH secretion even if Ca2+ is really high (e.g. in hypercalcaemia of malignancy, PTH detectable, in lower half of normal range )

50
Q

What would PTH be like in primary HPT

A

Does not have to be high, could just be upper half of normal…. with raised Ca2+, PTH should be at baseline, so even upper half of normal, is abnormal in this situation

51
Q

What is the set point of PTH secretion?

A

point of half maximal
suppression of PTH

Small perturbation causes large change PTH

usually around 0.9mM

52
Q

How does PTH work on the kidney

A

PTH drives active calcium absorption in the distal tubule of the kidney

???

53
Q

How does PTH/Vitamin D3 work on bone

What is OPG

A

They act on osteoblasts to increase expression of RANKL. Also increases M-CSF

this activates osteoclast progenitors which causes then to proliferate and differentiate into pre-fusion osteoclasts

pre-fusion osteoclasts fuse to form activated osteoclasts

OPG (Osteoprotegerin) is the body’s inhibitor of the RANKL to prevent osteoclast differentiation and proliferation

54
Q

Typical age of primary HPT and sex ration

A

50s, female 3:1 male

2% post menopausal develop

55
Q

Causes of primary HPT

A

Parathyroid adenoma (80%)

Parathyroid hyperplasia (20%)

Paraythroid CA (<1%)

Familial syndromes MEN 1 (2%), MEN 2A, HPT-JT

56
Q

How is primary HPT diagnosed

A

High Ca2+ with PTH frankly elevated or in the upper half of normal range IMPORTANT TO REMEMBER UPPER HALF

Corrected Calcium > 2.60 mmol/l with PTH > 3.9 pmol/l (nr 1.0 - 6.8)

57
Q

What are the clinical features of primary HPT

A

Mainly due to HYPERCALCAEMIA

Thirst, polyuria
Tiredness, fatigue, muscle weakness

Stones, abdominal moans and psychic groans”

Renal colic, nephrocalcinosis, CRF

Dyspepsia, pancreatitis
Constipation, nausea, anorexia

Depression, impaired concentration, Drowsy, coma

FRACTURES SECONDARY TO BONE RESORPTION

58
Q

Why does high calcium cause a diuresis

A

It basically shuts down the triple transporter and the channel which allows K+ to go from the ascending limb cell to the urine…… more solute in the filtrate causes diuresis

hypercalciuruia …. leading to increased stone risk

59
Q

Hypercalcaemia can be likened to which drug

A

Loop diuretic e.g. frusemide

60
Q

Short term eevated PTH increases stone risk

A

F: chronically elevated

61
Q

Elevated PTH causes increased bone reoption of which type of bone

A

Cortical>cancellous

62
Q

Metabolic effect of acutely raised PTH and chronically raised PTH

A

Acute/ pulsed PTH : anabolic

Chronic: catabolic

63
Q

T/f Chronically elevated PTH increases fracture risk

A

T

64
Q

Biochemical findings in primary HPT

A
  1. Raised serum Ca2+
  2. Upper half of normal/frnakly elevated PTH
  3. Low serum phosphate (renal excretion in the PCT)
  4. High calcium in the urine
  5. Cr may be elevated
65
Q

Action of vitamin D

A
  1. Intestine- 1,25(OH)2Vitamin D activates Ca and P absorption
  2. Bone- synergises with PTH to increase osteoclastic osteolysis….. differentiation agent for osteoclast precursors.

also Increases osteoblast differentiation and bone formation

  1. Kidney-facilitates PTH action in distal t. to increase Ca reabsorption (TRPV 5 , calbindin)
66
Q

In what case might you get high levels of vitamin D

A

Toxicosis (too many supplements rare)

Granulomatous disease e.g. sarcoid/TB leads to excess 1OH hydroxylase

67
Q

How is vit D absorbed in the gut

A

Passive: paracellular linear

Active: up to 40%….. saturable, in the duodenum. Stimulated by 1,25 vitD (TRPV6, calbindin)

68
Q

What percentage of Ca+2 is absorbed in each part of gut

Panopto?

A

20 – 60% load
Duodenum/jejenum

Also colon

69
Q

On which channels does vitamin D act and where

A

On TRPV channels, TRPV5 in kidney and TRPV6 in gut

70
Q

How does vitamin d feedback

A

parathyroid directly to reduce PTH secretion

bone to increase FGF-23 production

71
Q

How does vit D change calcium absorption in the gut

A

Increases ACTIVE calcium transport

72
Q

When would PTH rise

A

When 25 OH D less than 30ng/ml…

gut Ca absorption can increase up to 80nmol/l

73
Q

Define rickets

A

inadequate Vitamin D activity leads to defective mineralisation
of the cartilagenous growth plate (before a low calcium)

74
Q

Symptoms of rickets

A

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

75
Q

Signs of rickets

A 
Age dependent deformity
	Myopathy
	Hypotonia
	Short stature
	Tenderness on percussion
76
Q

Causes of rickets/osteomalacia

A

VIT. D related:

Dietary

GI: Small bowel malabsorption/ bypass, Pancreatic insufficiency (remember ADEK are fat soluble so need bile to be absorbed), Liver/biliary disturbance drugs/coeliac/gastrectomy

Renal: chronic renal failure

Rare hereditary: vit. D dependent rickets

77
Q

Which drugs could cause vit. D defic. and why

A

phenytoin, phenobarbitone

INCREASE P450 cyctochrome activty which nactites vt D

78
Q

Outline types of hereditary vit D

A

type I deficiency of 1 α hydroxylase

type II defective VDR for calcitriol

79
Q

T.F production of vit D decreases w age

A

T

80
Q

Outline the biochemistry in rickets

A 
Ca- N/low 
Phosphate- N/low 
Alk P-high 
25(OH)vit D- low 
PTH- high (secondary HPT in compensation)

Urine- high phosphate,

glycosuria, aminiaciduria, high pH, proteinuria

81
Q

Which molecules act to reduce reabsoprtion of phosphate in the PCT

A

PTH (inhibits NaP cotransporter)

FGF-23 also does this

82
Q

How is FGF-23 similar to and different from PTH

A

LIKE PTH causes P loss

UNLIKE PTH inhibits
activation of Vit D by
1 α OH ase

83
Q

Where is FGF-23 produced

A

Produced by osteoblast

lineage cells, long bones

84
Q

When is FGF-23 helpful

A

When bone is being resorbed…. increase in phosphate release and calcium release….

this phosphate is excreted by PTH, and this actionis backed up by FGF-23

85
Q

Outline the biochemistry of renal osteodystrophyn

A

Due to problem with kidney:
Increasing serum phosphate
Reduction in 1,25 Vit D (calcitriol)

SO
Secondary Hyperparathyroidism develops to compensate

BUT
unsuccessful and HYPOCALCAEMIA develops

LATER
Parathyroids AUTONOMOUS (tertiary HPT)
causing HYPERCALCAEMIA

Musc (12 decks)

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