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Year 2 musc mine > Metabolic bone disease: biochemistry > Flashcards

Metabolic bone disease: biochemistry Flashcards

1
Q

what is 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

And may be associated with disturbances in mineral metabolism

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2
Q

What are the 5 common metabolic bone disorders?

A

Primary hyperparathyroidism

Rickets/ Osteomalacia

Osteoporosis

Paget’s Disease

Renal osteodystrophy

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3
Q

symptoms in these disease:

  • metabolic
  • specific to bone
A

Metabolic

  • Hypocalacaemia
  • Hypercalcaemia
  • Hypo/Hyperphosphataemia

Specific to bone

  • Bone Pain
  • Deformity
  • Fractures
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4
Q

what does the bone calcium do?

A

-hydroxyapatite
-cancellous bone metabolically active
remodelling
continuous exchange of ECF with bone fluid reserve

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5
Q

What makes a bone strong?

-the 4 Ms

A

Mass

Material properties (matrix and mineral)

  • collagen
  • woven versus lamellar
  • mineralisation
  • microcracks

microarchitecture

  • trabecular thickness
  • trabecular connectivity
  • cortical porosity

microarchitecture

  • hip axis length
  • diameter
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6
Q

what might be used to assess bone structure and function?

A

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

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7
Q

what is the age related changes in bone mass like?

A

Men have greater bone mass than women
bone mass increases, no increase from 27 to 42 (called consolidation), then decreases. For women there is a sharp drop in bone mass during menopause

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8
Q

how can growth and exercise change peak bone mass?

A

change in bone dimensions
change in bone shape
change in trabecular volumetric BMD

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9
Q

what is bone remodelling

A

bone has a structure designed to absorb energy
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.

Bone remodeling is the process by which these areas are repaired, each osteon essentially represents a previous remodelling event.

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10
Q

describe the bone remodelling cycle

A

Bone remodelling occurs in the basic multicellular unit, seen here.

Activation occurs
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 are osteoblast lineage), which along with the osteocytes release local factors that attract cells from blood and marrow into the remodeling compartment. For the resorption phase to start osteoclasts are generated locally and resorb 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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11
Q

what are the biochemical investigations that can be used in bone disease?

A 
Serum
Bone profile		
-calcium
- corrected calcium (albumin
-phosphate
-alkaline phosphatase

Renal function

  • creatinine
  • parathyroid hormone
  • 25-hydroxy vitamin D

Urine

  • Calcium/ Phosphate
  • NTX
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12
Q

biochemical changes table

A

see ppt

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13
Q

calcium balance systems

A

Calcium is most abundant mineral in body; 1kg

Mainly in BONE
Huge fluxws in /out of bone; it is not a metabolicaaly inert tissue
Cancellous bone has a huge blood supply; respiratory physiologists tell you the alveolar surface area for gas exchange is TENNIS court; bone is many times greater.

Thinking about calcium is easy

GUT whats comig in; 1g day recommended intake

Kidney whats going out

BONE flux; your compensatory mechanism

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14
Q

how do serum calcium measurements need correction?

A

We measure in serum is a TOTAL calcium
free; the active form
complexed; to P and citraate
protein-bound to ALBUMIN

So 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

PROBLEMS occur in acid-base disturbance

If HYPERVENTILATE; get alkalosis which causes more ca to bind to prtotein so that free levels drop; all experienced this;tingling

venous stasis may falsely elevate LEVELS

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15
Q

How does PTH regulate serum calcium levels?

A

If plasma calcium drops within seconds have secretion of PTH from pre-formed stores

Acts on 2 systems

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

  1. Kidney Increased ca re-absorption in the distal conv tubule; the only site where ca re-absorption is under active hormonal controlStimulation of 1alpha Ohase activity , so increasing actiavated vit D production, which leads to increased gut re-abs of ca;
    Decreases 24 oh ase activityIncreases p excretion by inhibiting the NAP cotransporter in the proximal tubule
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16
Q

clinically relevant points about PTH

A
  1. 84 amino acid peptide
    but N1-34 active
  2. Mg dependent
  3. T 1/2 8 min
  4. PTH receptor is activated
    also by PTHrP
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17
Q

how does the parathyroid gland monitor serum Ca through the calcium-sensing receptor?

A

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

MINIMUM: even at high calcium levels
there is base-line PTH secretion

SET-POINT: point of half maximal
suppression of PTH; steep part of slope;
Small perturbation causes large change PTH

**MINIMUM This is important in diagnosis.
Even in Hyperacalcaemia of malig PTH will be detectable; lower half normal rangs

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18
Q

PTH drives active calcium absorption in

A

the distal tubule of the kidney

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19
Q

how does PTH cause bone resorption?

A

RANK system

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20
Q

how is primary HPT diagnosed?

A

Primary hyperparathyroidism is diagnosed by

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

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

Subjects with hypercalcaemia and a PTH in the upper half of the normal range are physiologically not normal

It is important to note that such ‘non-suppressed’ concentrations are entirely compatible with the diagnosis of Primary HPT

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21
Q

clinical features of primary HPT

A

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

Patients may also suffer fractures secondary to bone resorption

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22
Q

high serum calcium causes a diuresis

A

frusemide

diuresis results in hypercalciuruia

23
Q

Chronically elevated PTH causes:

A

Chronically elevated PTH causes increased cortical bone resorption

Increased bone turnover

Acute/ pulsed PTH : anabolic

Chronic: catabolic

Cortical > cancellous

24
Q

biochemical findings in primary HPT

A
  1. Increased serum calcium by absorption from bone/gut
    1. Decreased serum phosphate renal excretion in proximal tubule
    2. PTH in the upper half of the normal range or elevated
  2. Increased urine calcium excretion
  3. Cr may be elevated
25
Q

how is VIT D metabolised?

A

Discuss metabolism

Action

INTESTINE 1,25(OH)2Vitamin D activates Ca and P absorption;

Bone synergises with PTH to increase osteoclastic osteolysis
differentiation agent for osteoclast precursors

Kidney facilitates PTH action in distal t. to increase Ca reabsorption

Excess 1oh ase occurs in granulomatoud disesae ie sarcoid, TB

26
Q

Vit D binding protein half life

A

Vit D binding protein (DBP): t 1/2 3 days, filtered by kidney

27
Q

activated Vitamin D increases ?

A

activated Vitamin D increases gut calcium absorption

28
Q

VIT D actions on:

  • intestine
  • bone
  • kidney
  • feedback
A

INTESTINE 1,25(OH)2Vitamin D activates Ca and P absorption
duodenum (TRPV6, calbindin)

Vit D increases active calcium transport in gut

Bone Synergises with PTH, acting on osteoblasts to increase
formation of osteoclasts through RANKL

	Increases osteoblast differentiation and bone formation

Kidney facilitates PTH action to increase Ca reabsorption
in distal tubule (inducing TRPV5, calbindin)

Feedback: parathyroid directly to reduce PTH secretion
bone to increase FGF-23 production

29
Q

Rickets:

  • define
  • symptoms
  • signs
A

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

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

Signs
	Age dependent deformity
	Myopathy
	Hypotonia
	Short stature
	Tenderness on percussion
30
Q

causes of rickets/osteomalacia:

A 
Vitamin D related
Dietary
Gastrointestinal		Small bowel malabsorption/ bypass
						Pancreatic insufficiency
						Liver/biliary disturbance
						Drugs- phenytoin, phenobarbitone

Renal Chronic renal failure

Rare hereditary Vitamin D dependent rickets:
type I deficiency of 1 α hydroxylase
type II defective VDR for calcitriol

Dietary
Factors lack of sunlight
decreased production with age
not added to foods xcept USA

GI v common in gastrectomies
now coeliac ,

DRUGS increase p450 cytochrome activity that inactivates vitD

31
Q

FGF-23 cause what?

A

FGF-23 cause PCT phosphate loss, aswell as PTH

FGF-23

32KD protein

Produced by osteoblast
lineage cells, long bones

LIKE PTH causes P loss

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

32
Q

PTH action on phosphate generated in Ca resorption is?

A

PTH action on phosphate generated in Ca resorption is backed up by FGF-23

33
Q

even when calcium and vit D levels are normal, osteomalacia and phosphate can also get:

A

can also get with renal phosphate loss, when calcium and
Vitamin D levels are usually normal’

Kidney forced to lose phosphate

‘isolated’ hypophosphataemia
	X-linked hypophosphataemic Rickets
		1;20,000
		mutations in PHEX; high levels of FGF-23
		toddlers with leg deformity, enthesopathy, dentin anomalies

	Autosomal dominant hypophosphataemic rickets (ADRR)
		variable age of onset; may improve
		cleavage site for FGF-23 mutated, so high FGF-2

oncogenic osteomalacia
		mesenchymal tumours
		produce FGF-23, causes phosphaturia and stops 1α OHase
34
Q

FGF-23 excess can cause

A

FGF-23 excess can cause rickets/osteomalacia

35
Q

Kidney proximal tubule damaged causes

A

Kidney proximal tubule damaged

causes phosphaturia and stops 1α hydroxylation of Vit D

36
Q

Fanconi Syndrome

leads to

A 
Fanconi Syndrome
			multiple myeloma
			heavy metal poisoning: lead, mercury
			drugs: tenofovir, gentamycin
			congenital disease: Wilsons, glycogen storage diseases
37
Q

osteoporosis is due to:

A

low bone density

38
Q

osteoporosis causes

A

high turnover- increased bone resorption greater than bone formation

low turnover- decreased bone formation more pronounced than decreased bone resorption

increased bone resorption and decreased bone formation

39
Q

what does estrogen deficiency do to bone?

A

Increases the number of remodelling units
Causes remodelling imbalance with increased bone resorption (90%) compared to bone formation (45%) Enhanced osteoclast survival and activity
Remodelling errors. Deeper and more resorption pits
lead to Trabecular perforation
Cortical excess excavation
Decreased osteocyte sensing

40
Q

biochemistry in osteoporosis is used to exclude other causes

A

Serum biochemistry should all be normal if primary

Check for Vit D deficiency
Check for secondary endocrine causes

Primary hyperparathyroidism		PTH high
Primary hyperthyroidism				free T3 high
										TSH suppressed
Hypogonadism						Testosterone low
  1. Exclude multiple myeloma
  2. May have high urine calcium
41
Q

what is the main tool to assess osteoporosis

A

Bone Density (BMD) is the main tool to assess for osteoporosis

Dual energy X-ray absorptiometry- current method

Measures transmission through the body of X-rays of two different photon energies

Enables densities of two different tissues to be inferred, i.e. bone mineral, soft tissue

42
Q

define osteoporosis based on BMD:

A

T-score = (measured BMD – young adult mean BMD) / young adult standard deviation

T-score = -2.5 OSTEOPOROSIS
-1 to -2.5 OSTEOPAENIA
> -1 NORMAL

43
Q

why central measurements?

A 
Vertebral
	Commonest fracture
	Increasing incidence after aged 60
Measure of cancellous bone
	Metabolic bone; quickest response to treatment

Hip
2nd commonest #, > 70, costs and mortality

Fracture Risk Assessment Tool (FRAX) uses hip BMD

44
Q

why are bone markers useful

A

Markers of bone formation and resorption give us
insight into activity

Unlike BMD they are DYNAMIC

Divided into markers of FORMATION
RESORPTION

45
Q

describe collagen synthesis 1

A

2 ‘Alpha 1’ and 1 ‘Alpha 2’ chain of type I collagen
produced by the osteoblast join

Extension peptides cut off
these propeptides can be measured in blood
P1NP = Procollagen type 1 N-terminal Propeptide

46
Q

describe collagen synthesis 2

A

3 hydroxylysine molecules on adjacent tropocollagen fibrils condense
to form a PYRIDINIUM ring linkage

These can be used to measure bone resorption; serum CTX, urine NTX

47
Q

Bone resorption markers are used in monitoring osteoporosis treatment- HOW

A

Monitoring of response to treatment with anti- resorptive drugs (BMD change 18mnths)

bone resorption markers fall in 4-6 weeks

expect a 50% drop of urine NTx by 3 months
48
Q

what are the problems with cross links?

A
  1. Reproducibility: CV 20%
  2. Positive association with age
  3. Need to correct for Cr
  4. Diurnal variation in urine markers
49
Q

what is the clinical use of bone formation markers

A

Only one in common usage is ALKALINE PHOSPHATASE

Use in diagnosis and monitoring of
Pagets
Osteomalacia
Boney metastases (prostate with PSA)

NOW P1NP is being use as a predictor of response to ANABOLIC
treatments
PTH treatment rises to peak in 3 months;
predicts response

50
Q

BSAP

  • types
  • role
  • uses
A 
Types
	tissue-specific form; liver vs bone
	intestine, germ cell, placental forms
Role
	essential for mineralisation
	regulates concentrations of phosphocompounds
Uses	
	Consistent within an individual; t ½ 40 hours
	Increased in	Paget’s disease
					Osteomalacia
					Bone metastases
			Hyperparathyroidism
			Hyperthyroidism
51
Q

what is Chronic Kidney Disease Mineral Bone Disorder

A

Skeletal remodeling disorders caused by CKD contribute
directly to to heterotopic calcification , especially vascular

The disorders in mineral metabolism that accompany CKD
are key factors in the excess mortality caused by CKD

CKD impairs skeletal anabolism, decreasing osteoblast 
      function and bone formation rates
52
Q

renal osteodystrophy:

  • biochemistry
  • so what occurs?
A

Biochemistry

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)
causing HYPERCALCAEMIA

53
Q

progression of secondary HPT

A

Parathyroid hyperplasia develops in tandem with the progressive decline in renal function.
The constantly increasing functional demand on parathyroid glands (mainly as a result of hypocalcaemia) drives cell proliferation.
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.1
In diffuse hyperplasia, cell growth is polyclonal, but is accompanied by down-regulation of the CaR and VDR.1
As CKD progresses to stage 5 (end-stage renal disease [ESRD]), parathyroid hyperplasia evolves even further; monoclonal abnormalities lead to nodular hyperplasia of the glands.2,3 These grossly enlarged parathyroid glands are associated with significantly reduced expression of CaRs and VDRs.4,5
Parathyroid glands with nodular hyperplasia therefore become less responsive to serum calcium levels6,7 and resistant to the medical treatment of SHPT.6,8

Year 2 musc mine (3 decks)

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