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Year 2 LCRS - Musculoskeletal > Metabolic Bone Disease - Biochemistry > Flashcards

Metabolic Bone Disease - Biochemistry Flashcards

1
Q

What is metabolic bone disease?

A

a group of diseases that causes 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 common metabolic bone disorders?

What are some symptoms of these?

A
  • primary hyperparathyroidism
  • rickets/osteomalacia
  • osteoporosis
  • Paget’s disease
    Renal osteodystrophy
symptoms:
metabolic
- hypocalcaemia
- hypercalcaemia
- hypo/hyperphosphataemia

specific to bone:

  • bone pain
  • deformity
  • fractures
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3
Q

What makes bone strong?

A
  1. mass
  2. material properties
    - collagen, cross-linking
    - woven vs lamellar
    - mineralisation
  3. microarchitecture
    - trabecular thickness and connectivity
    - cortical porosity
  4. macroarchitecture
    - hip axis legnth
    - diameter
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4
Q

Describe age related changes to bone?

A

Men and women tend to reach the “consolidation” stage at 28yo and the lose bone mass past 42yo

Menopause makes women pass the fracture threshold whilst many men never go below it

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5
Q

What are microfractures?

A

Cracks occur between osteons which is the reason for constant bone remodelling (5% at any one time)

  1. Osteoclasts reabsorb damage
  2. Osteoblasts lay down new bone
  3. Osteoblasts absorbed in laying down bone,act as mechanoreceptors for future fractures
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6
Q

Describe the sexual dismorphism of bone growth?

A

men have appositional bone growth whilst women form new bone on the inside of the bone marrow

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7
Q

How can you investigate primary hyperparathyroidism?

A

Serum:

  • Bone profile –calcium, corrected calcium (albumin), phosphate, ALP
  • Renal function –creatinine, PTH, 25-OH VitD

Urine:
- Calcium/Phosphate, NTX

  • Calcium balance involves the GI tract, the kidneys and the bone –3 MAIN SYSTEMS

** The corrected calcium considers the calcium binded to the albumin
Corrected Ca2+= [calcium] + 0.02(45-[albumin]).
I.e. correct 0.02 for every albumin off normal range.

A blood alkalosis forces calcium to bind to albumin –e.g. a hyperventilating patient will have alkalotic blood and this less free calcium.

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8
Q

What are the biochemical changes in bone diseases?

A

osteoprorosis:

  • calcium: N
  • phosphate: N
  • alk p: N
  • bone formation: +/ same
  • bone resorption: ++

osteomalacia:

  • calcium: N / -
  • phosphate: -
  • alk p: +
  • bone formation:
  • bone resorption:

Pagets:

  • calcium: N / +
  • phosphate: N
  • alk p: +++
  • bone formation: ++
  • bone resorption:

Primary HPT :

  • calcium: +
  • phosphate: N/ -
  • alk p: N/ +
  • bone formation:
  • bone resorption: ++

Renal osteodystrophy:

  • calcium: -/N
  • phosphate: +
  • alk p: +
  • bone formation:
  • bone resorption:

Metastases:

  • calcium: +
  • phosphate: +
  • alk p: +
  • bone formation:
  • bone resorption: +
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9
Q

What is the role of PTH?

A

minute-by-minute regulation of [Ca2+]

makes kidneys retain more calcium, makes bones release calcium (via osteoclasts using RANK system), regulate activation of vitamin D in kidneys leading to increased reabsorbtion of calcium in gut

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10
Q

What is PTH dependent on?

A

Mg2+

* t 1/2 = 8 minutes
84aa peptide (only N1-34 are active)
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11
Q

Describe the PTH suppression graph

What is the minimum and set point?

A

sigmoid

  • Minimum –even at high [Ca2+], there is still a base-line PTH secretion
  • Set-point (Ca2+) –the point of HALF-maximal suppression of PTH. So, small changes in [Ca2+] precipitate large PTH changes

*some people have a physiologically high minimum etc.

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12
Q

What are the causes of primary hyperparathyroidism?

A

Parathyroid adenoma - 80% (normally just one gland)
Parathyroid hyperplasia - 20%
Parathyroid cancer - <1%
Familial syndromes -MEN1 ->2%, MEN 2A and HPT-JT -> rare

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13
Q

How do you diagnose primary HPT?

A

elevated total/ionised calcium with PTH levels frankly elevated or in the upper normal range

  • Subjects with hypercalcaemia with a PTH in the upper normal range is not physiologically normal

** Primary HPT results in HIGH serum calcium and LOW serum phosphate (excreted in PCT); creatinine may also be elevated

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14
Q

What are the clinical features of primary HPT?

A

stones, moans and abdominal groans (also fractures due to bone reabsorption)

  • Renal colic -> Nephrocalcinosis -> CRF
  • Dyspepsia, pancreatitis, constipation, nausea, anorexia
  • Depression, impaired concentration, coma
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15
Q

How does high [Ca2+] lead to dehydration?

A

High [Ca2+] shuts down the K-channels as potassium is recycled to reabsorb calcium normally via paracellular reabsorption

This results in a dehydration as less Na reabsorbed

  • Frusemide has the same mechanism of action of inhibiting the potassium channels. (Loop diuretic –Triple transporter inhibitor)
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16
Q

What are the consequences of chronically high PTH?

A

increased cortical bone resorption -> increased bone turnover -> increased fracture risk

acute/pulsed PTH : anabolic

chronic : catabolic

17
Q

How is calcium reabsorbed?

A

TRPV6 is activated by 1, 25(OH)Vit-D to reabsorb calcium

Reabsorption via channel or paracellular

20-60% via the duodenum, jejunum and colon.oMostly passive but up to 40% active transport.

18
Q

What are the actions of vitamin D?

A

(main action on gut)

Reabsorb calcium and phosphate in the gut–TRPV6, calbindin

Acts on osteoblasts to increase formation of clasts through RANKL

Increase osteoblast differentiation

Facilitate PTH action in DCT–TRPV5, calbindin. oFeedbacks on parathyroid to reduce PTH secretion

19
Q

What is vitamin D deficiency?

A

muscle function optimal at >70nmol/L (experts say >75nmol/L) so less than 50nmol/L is defined as deficient

30-50% of European and US citizens are vitamin D deficient

20
Q

What is rickets?

What are the signs, symptoms and biochemistry?

A

Rickets –defective mineralisation of the cartilaginous growth plate (before a low calcium) due to vitamin D deficiency:

Symptoms :

  • (axial) bone pain
  • proximal myopathy

Signs:

  • age-dependant deformity
  • myopathy
  • Hypotonia
  • shortstature
  • tenderness on percussion

Chvostek’s and Trousseau’s signs on inspection

Biochemistry:

Serum –N/LOW calcium, N/LOW phosphate, HIGH ALP, LOW calcitriol, HIGH PTH (compensatory)

Urine –HIGH phosphate,glycosuria, aminoaciduria, high pH, proteinuria.

21
Q

What are causes of vitamin D deficiency?

A
  • dietary
  • GI (malabsorption, pancreatic/liver disturbance, drugs (phenytoin, phenobarbitone, orlistat))
  • renal (CRF)
  • rare hereditary (VitD-dependant rickets)
  • Type1 VitD-dependant rickets –deficiency of 1-alpha-hydroxylase
    Type 2 VitD-dependant rickets –defective VitD-R for calcitriol
22
Q

What does FGF-23 do?

A

FGF-23 and PTH inhibit the phosphate/Na co-transporters and so result in phosphate loss

FGF-23 inhibits NPT2a and NPT2c

Phosphate is fully filtered and only reabsorbed in the PCT

FGF-23 is produced by osteoblasts and causes phosphate loss BUT also INHIBITS activation of VitD by 1-alpha-hydroxylase -> switches off calcium formation

23
Q

How do the actions of FGF-23 differ from those of PTH?

A

PTH = phosphate loss

FGF-23 = phosphate loss, inhibits calcitriol formation

FGF-23 inhibits NPT2a and NPT2c

PTH inhibits NPT2a

24
Q

What are the types of hypophosphatemia?

A

“Isolated” Hypophosphatemia:
- X-linked hypophosphatemia Rickets:
>1: 20,000
> Mutations in PHEX (breaks down FGF-23) -> HIGH levels of FGF-23
> Toddlers with leg deformity, enthesopathy, dentin abnormalities
- Autosomal dominant hypophosphatemia rickets (ADRR):
> Variable age of onset
> Cleavage site of FGF-23 mutated -> high FGF-23
- Oncogenic osteomalacia:
> Mesenchymal tumours autonomously produce FGF-23

Kidney proximal tubules damage can lead to hypophosphatemia and phosphaturia

25
Q

What are some examples of PCT damage?

A 
Fanconi syndrome
Multiple myeloma
Heavy metal poisoning
Drugs –e.g. tenofovir, gentamycin
Congenital disease –e.g. Wilson’s, glycogen storage disease
26
Q

What is osteoporosis?

What causes it?

A

Low bone density

Causes:

  • high turnover (e.g. oestrogen deficiency)
  • low turnover (e.g. liver disease)
  • increased resorption
  • decreased formation (e.g. glucocorticoids)
27
Q

What does oestrogen deficiency from menopause cause?

A
  • Increased number of remodelling units
  • Causes remodelling imbalance –increased resorption compared to formation
  • Remodelling errors (deeper and more resorption pits) lead to trabecular perforation and cortical excess excavation
  • Decreased osteocyte sensing
28
Q

How do you diagnose osteoporosis?

A

Biochemistry is used to EXCLUDE other causes –serum biochemistry should all be normal if osteoporosis:

  • Check for VitD deficiency
  • Check for secondary endocrine causes –e.g. P-HPT (PTH high), P-HT (T3 high),hypogonadism
  • Exclude multiple myeloma
  • Check for high urine calcium

BMD is the MAIN tool used to assess osteoporosis –BMD represents 70% of total risk of fracture
- DEXA scans –measures differences in densities between 2 different materials
- Definition of osteoporosis is based on BMD –T-score: <=-2.5= osteoporosis
> 1 S.D. reduction = 2.5x increase in fracture risk
- We measure vertebral (commonest fractures, measures cancellous bone which is metabolic bone so responds fastest to treatment) and hip (second most common) BMDs
- FRAX –Fracture Risk Assessment Tool –uses BMD

t score = [(measured BMI) - (young adult mean BMD)] / (young adult SD)

29
Q

What are the different types of bone markers?

A

Unlike BMD, bone markers are dynamic

Formation markers:

  • P1NP –Procollagen type 1 N-terminal Propeptide
  • In production of collagen (2a11a2), extension polypeptides (P1NP) are cleaved

Resorption markers:

  • Serum CTX –Cross-linked C-telopeptides.oUrine NTX –Cross-linked N-telopeptides
  • 3 hydroxylysine molecules condense out to form a pyridinium ring linkage on resorption of bone.
30
Q

What are the bone markers used for?

A

Resorption markers are used to monitor osteoporosis treatment

  • Bone reabsorption markers fall in 4-6 weeks
  • Expect a 50% drop of urine NTx by 3 months.
    • Problems though:
  • Hard to reproduce
  • Positive association with age anyway
  • Need to correct for creatinine
  • Diurnal variation in urine markers

Formation markers:
- Only one formation marker is in common use –ALP
- Used in diagnosis/monitoring of:
> Paget’s disease of bone
> Osteomalacia
> Bony metastasis
- BSAP –Bone-Specific Alkaline Phosphatase:
> Types –tissue-specific(bone)form of ALP
> Roles –essential for mineralisation of bone and regulates concentrations of phosphate
> Uses –T1/240 hours. Increased in Paget’s, osteomalacia, bone metastasis, HPT, HT

  • ALP varies with age (younger people have more)

** P1NP is being used as a predictor of response to anabolic treatments –e.g. PTH treatment.

31
Q

What happens in CKD?

A

Skeletal remodelling disorders caused by CKD contribute to vascular calcification (extra-skeletal deposition)

The disorders in mineral metabolism with CKD are a main reason to mortality from CKD

Pathophysiology –impairs skeletal anabolism, decreases osteoblast function, decreases bone formation

32
Q

What happens in renal osteodystrophy?

A

Biochemistry –increased [phosphate], reduced calcitriol

  • kidney failure so less calcitriol and nephron loss so less phosphate filtrated into urine

Pathway –secondary hyperparathyroidism develops to compensate -> unsuccessful so hypocalcaemia -> parathyroid become autonomous (tertiary hyperparathyroidism) -> hypercalcaemia

There is a progressive hyperplasia of the parathyroids

33
Q

What are the consequences of CKD and renal osteodystrophy?

A

Nephron loss via CKD

Phosphate binds calcium in serum
- Calcium phosphate crystals are deposited causing extra-skeletal calcifications

Acidosis causes demineralisation

In renal osteodystrophy, you can get heterotopic calcification –bone formation at an abnormal anatomical site, usually in soft tissue - I.E. in MCP joints

*** Renal osteodystrophy is a CONSEQUENCE of CKD; the results of CKD cause the symptoms of osteodystrophy such as heterotopic calcification

Year 2 LCRS - Musculoskeletal (10 decks)

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