Metabolic Bone Disease - Biochemical (13.01.2020) Flashcards

1
Q

What are the 5 common metabolic bone disorders?

A
  • Primary hyperparathyroidism
  • Rickets/ Osteomalacia
  • Osteoporosis
  • Paget’s Disease
  • Renal osteodystrophy
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2
Q

Symptoms of these diseases

A

Metabolic

  • Hypocalacaemia
  • Hypercalcaemia
  • Hypo/Hyperphosphataemia

Specific to bone

  • Bone Pain
  • Deformity
  • Fractures
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3
Q

What makes bone strong?

A

4 M’s:

  • mass
  • material properties
  • microarchitecture
  • microarchitecture
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4
Q

Ways to asses structure and function of bone?

A
  • Bone histology
  • Biochemical tests
  • Bone mineral densitometry, e.g. osteoporosis
  • Radiology
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5
Q

Exercise and bone

A
  • can increase bone mass
  • can increase bone density
  • in young age
  • changes shape and bone dimensions depending in where strength is needed
  • change in trabecular volumetric BMD
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6
Q

Sexual dimorphism in bone growth

A
  • Men: bigger bones under the influence of testosterone
  • Women: lower bone mass than men
  • steroids and IGF-1 play a role here.
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7
Q

life spans of osteoclasts and osteoblasts

A

c: weeks
b: months

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8
Q

Biochemical investigations in bone disease

A
  1. Serum

Bone profile

  • calcium
  • corrected calcium (albumin)
  • phosphate
  • alkaline phosphatase

Renal function

  • creatinine
  • parathyroid hormone
  • 25-hydroxy vitamin D
  1. Urine
    - Calcium/ Phosphate
    - NTX
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9
Q

Alkalosis and calcium levels

A

alkalosis makes more calcium bind to albumin

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10
Q

Clinical feature of 1* HPT

A
  • Thirst, polyuria (hypercalcaemia causes diuresis)
  • 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 (Chronically elevated PTH causes increased cortical bone resorption cortical>cancellous)

  • Acute/ pulsed PTH : anabolic
  • Chronic: catabolic
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11
Q

Biochemical findings in PHT

A
  1. Increased serum calcium by absorption from bone/gut
  2. Decreased serum phosphate renal excretion in proximal tubule
  3. PTH in the upper half of the normal range or elevated
  4. Increased urine calcium excretion
  5. Cr may be elevated
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12
Q

Where in the gut is calcium reabsorbed under the actions of vitamin D3?

A

20-60% in duodenum, jejunum and colon

Passive: Paracellular
linear

Active: up to 40%
saturable
duodenum
1,25 Vit D

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13
Q

Dangers of rickets becoming severe

A
  • bronchospasm
    seizures
    echopic calcification in basal gangla -> PD
  • dementia
  • cataracts
  • muscle twithcing
  • NM irritability (e.g. chvosteks sign, trousseaus sign -> spasm after BP cuff put on for a few minutes)
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14
Q

What are the causes of Ricktes/osteomalacia?

A
  • dietary
  • GI
    • Small bowel malabsorption/ bypass (very common in gastrectomies; coeliac)
    • Pancreatic insufficiency
    • Liver/biliary disturbance
    • Drugs- phenytoin, phenobarbitone
  • Renal (chronic renal failure)
  • Rare hereditary
    • vitamin D dependant rickets
      • T1: deficiency of 1 alpha hydroxylase
      • T2: defective VDR for calcitriol

Lack of sunlight!
Not added to foods except in USA.
Decreased production with age.

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15
Q

FGF 23

A
  • 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

-> decreases levels of P043-

Can cause rickets or osteomalacia

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16
Q

What are phosphate wasting hormones?

A

PTH and FGF-23

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17
Q

Fanconi syndrome - causes

A
  • multiple myeloma
    heavy metal poisoning: lead, mercury
    drugs: tenofovir, gentamycin
    congenital disease: Wilsons, glycogen storage diseases
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18
Q

Commonest causes of phosphate related osteomalacia

A

Kidney proximal tubule damaged -> causes phosphaturia and stops 1α hydroxylation of Vit D

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19
Q

Osteoporosis - causes

A

High Turnover

  • oestrogen deficiency
  • hyperthyroidism
  • HPT
  • Heparin
  • cyclosporine?
  • hypogonadism in young women and in men

Low turnover

  • liver disease - primarily primary biliary cirrhosis
  • heparin
  • age above 50

Increased bone resorption and decreased bone formation:
- glucocorticoids

20
Q

How much bone is lost in menopause?

A

30% of trabecular bone
50% of women have a post-menopausal fracture

Oestrogen deficiency:
- 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

21
Q

BMD in osteoporosis

A
  • Single best predictor of fracture risk
  • BMD represents 70% of total risk
  • T-score: how many SDs are you away from a 25 year old
  • Z-score is in the same age group
22
Q

Correlation of fracture risk with BMD

A

1 SD reduction = 2.5 increase in risk of fracture

23
Q

Bone markers

A
  • not widely used
  • divided into markers of FORMATION and markers of RESORPTION
  • as you are forming bone molecules are released because you are cutting ends off of Procollagen
24
Q

Alkaline phosphatase

A

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

25
Q

BSAP

A
  • increased in anything causing increased bone turnover
  • very high when you are growing
    = bone specific alkaline phosphatase
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
26
Q

Heterotopic calcification

A
  • calcification of BVs

- doe of a vascular event

27
Q

Renal osteodystrophy

A

GFR below 60 ->

  1. increases serum phospahte
  2. decrease in calcitriol

so: 2* HPT to compensate

BUT: unsuccessful and hypocalcameia develops

Later: autonomous PTG and this causes 3* HPT

PTH enlargement, nodular parathyroids

28
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
29
Q

When do we reach peak bone mass? How does it change throughout life?

A
  • in our 20s
  • stable until ~40
  • Men slow loss
  • Women fast loss in early menopause (can lose up to 30% of cancellous bone; there is a slow and fast pahse of post menopausal bone loss)
30
Q

What is the most abundant mineral in the body?

A

Calcium (1kg)

constant flux, metabolically active (GIT, kidneys, Bone, soft tissue)

31
Q

Why do serum calcium levels need correction?

A
  • Total calcium 2.15-2.56 mmol/L
  • total calcium contains:
    • free calcium (47%)
    • calcium bound to albumin (46%)
    • complexed calcium (7%) -> to P or citrate
  • in alkalosis there is a shift from free to protein bound calcium (e.g. hyperventilation -> alkalosis -> more ca binds to albumin -> less free calcium -> tingling)
  • Corrected calcium = [calcium] + 0.02( 45 – [albumin])
  • the corrected calcium a lab gives you compensates for the protein level; if protein levels are HIGH they compensate down; 0.02 for each g/l of albumin
  • e.g. if they have less albumin, their real calcium amount is actually higher than the free blood result.

=> to account for albumin bound calcium

32
Q

Facts 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)
  • SET-POINT: point of half maximal
    suppression of PTH; steep part of slope;
    Small perturbation causes large change PTH
  • Even at high levels of Ca there is still some baseline PTH
33
Q

What does hypomagnesemia lead to?

A
  • PTH is Mg dependant

- low Mg will decrease PTH and cause hypocalcemia

34
Q

In which people is 1* HPT common? What are the common causes?

A

Age : 50s, female 3:1 male; 2% post menopausal develop

Causes
Parathyroid adenoma 80%

	Parathyroid hyperplasia 	20%

	Parathyroid CA 		<1%

	Familial Syndromes
		MEN 1 		 2%  
		MEN 2A 		 rare
		HPT-JT		 rare
35
Q

Diagnosis of 1* HPT

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
36
Q

Where does vitamin D feed back to?

A
  • parathyroid directly to reduce PTH secretion

- bone to increase FGF-23 production

37
Q

What is the definition of vitamin D deficiency?

A
  • no absolute consensus
  • many US/EU people are vitamin D deficient
  • The preferred level for 25(OH)D is now recommended by many experts to be >30 ng/mL (75nmol/l).
  • upper limit questionable as levels can be higher if someone is in the sun a lot.
  • On the basis of the literature, it appears that vitamin D intoxication does not occur until blood levels are >150–200 ng/mL (375nmol/l)
38
Q

What is rickets?

A

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

Symptoms
Bone pain and tenderness (axial e.g. on percussion)
Muscle weakness (proximal)
Lack of play (The children don’t play, they want to stay in, they have bone pain)

Signs
	Age dependent deformity
	Myopathy
	Hypotonia
	Short stature
	Tenderness on percussion
39
Q

Biochemistry of rickets/osteomalacia

A
Serum
	Calcium		N/low
	Phosphate		N/low
	Alk phos		High 
	25(OH)Vit D	Low
	PTH			High (secondarily to compensate)

Urine
Phosphate High
?Glycosuria, aminoaciduria, high pH, proteinuria

40
Q

Osteomalacia and phosphate

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

=> genetic or oncogenic! also damage to pct

41
Q

How can FGF cause osteomalacia?

A
  • though low PO43-

- either because it is not deactivated or because tumour cells make too much of it

42
Q

Biochemistry in osteoporosis

A
  • > used to exclude other causes
    1. Serum biochemistry should all be normal if primary Check for Vit D deficiency
  1. Check for secondary endocrine causes
    - Primary HPT: PTH high
    - Primary hyperthyroidism: free T3 high; TSH suppressed;
    - Hypogonadism: Testosterone low
  2. Exclude multiple myeloma
  3. May have high urine calcium
43
Q

Examples of bone markers

A

Bone formation collagen synthesis:
- 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

Bone formation; collagen synthesis II

  • 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

Used to monitor osteoporosis treatment:
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

Problems with cross links:

  1. Reproducibility: CV 20%
  2. Positive association with age
  3. Need to correct for Cr
  4. Diurnal variation in urine markers
44
Q

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
45
Q

How does alkaline phosphatase change with age?

A
  • Bone alk P represents about 75% of serum levels pre-puberty
  • Increases markedly with growth
  • Is about 1:1 with liver in adults
  • Increases> age 50; esp menopausal women ; levels up by 75%;
  • But not used as marker in osteoporosis
  • Placental isoform increases during pregnancy
    gradually first two trimesters
    rapidly last trimester
  • labs don’t standardly give isoforms
46
Q

CKD-MBD

A

CKD mineral bone disorder
- 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

47
Q

Biochemistry of renal osteodystrophy

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

also: acidosis causes demineralisation