Metabolic Bone Disease – Biochemistry Flashcards Preview

Y2 LCRS 2 - Musculoskeletal - Laz COPY > Metabolic Bone Disease – Biochemistry > Flashcards

Flashcards in Metabolic Bone Disease – Biochemistry Deck (54)
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1
Q

What is metabolic bone disease?

A

A group of disease that cause a change in bone density and bone strength by increasing bone resorption, decreasing bone formation or altering bone structure

2
Q

What are the five main metabolic bone disorders?

A
  1. Primary Hyperparathyroidism
  2. Osteomalacia/Rickets
  3. Osteoporosis
  4. Renal Osteodystrophy
  5. Paget’s Disease
3
Q

What are the main components of bone strength?

A
  • Mass
  • Material
  • Microarchitecture
  • Macroarchitectue
4
Q

When is peak bone mass reached?

A

Around 25 years

5
Q

When does bone mass begin to decline?

A

Around 40 years NOTE: in women, the decline in bone mass accelerates after menopause

6
Q

How are microfractures repaired?

A

Bone remodelling

7
Q

Briefly describe the bone remodelling cycle in response to microcracks

A
  1. A microcrack crosses the canaliculi and severs the osteocyte processes, inducing osteocyte apoptosis
  2. This signals to the surface lining cells, which release factors to recruit cells from the blood and marrow to the remodelling compartment
  3. Osteoclasts are generated locally and resorb the matrix and the microcrack
  4. Then osteoblasts deposit new lamellar bone
  5. Osteoblasts that become trapped in the matrix become osteocytes
8
Q

What is the normal range for serum calcium concentration?

A
  • 2.15-2.56 mmol/L
9
Q

Describe the distribution of calcium

A
  • 46% plasma protein bound (albumin)
  • 47% free calcium
  • 7% complexes (with phosphate or citrate)
10
Q

What is the ‘corrected’ calcium level?

A
  • This compensates for changes in protein level (if proteins are high, itcompensates down)
  • Corrected calcium = [Ca2+] + 0.02(45-[albumin])
11
Q

Describe the effect of metabolic alkalosis on calcium distribution

A
  • It makes more calcium bind to plasma proteins thus reducing the free calcium levels
  • NOTE: venous stasis may elevate free calcium
12
Q

What are the two main targets organs of PTH?

A
  1. Kidneys
  2. Bone
13
Q

Describe the effects of PTH in:

1) Bone
2) Kidneys

A

1) Bone

  • Acute release of available calcium (not stored in hydroxyapatite crystal form)
  • More chronically, increased osteoclast activity

2) Kidneys

  • Increased calcium reabsorption qnd Increased phosphate excretion.
  • Increased stimulation of 1-alpha hydroxylase (thus increasing calcitriol production)
14
Q

Where does the PTH-mediated increase in calcium reabsorption take place in the nephron?

A

DISTAL convoluted tubule

15
Q

Where does the PTH-mediated increase in phosphate excretion take place in the nephron?

A

PROXIMAL convoluted tubule

16
Q

How many amino acids make up PTH and which part of this is active?

A

84 Active: N1-34

17
Q

What is PTH dependent on?

A

Magnesium

18
Q

What is the half-life of PTH?

A

8 mins - i.e. very short

19
Q

What else can the PTH receptor be activated by other than PTH?

A
  • PTHrP (PTH related protein)
  • This is produced by some tumours
20
Q

What does the parathyroid gland use to monitor serum calcium?

A

Calcium-sensing receptors

21
Q

Describe the relationship between PTH level and calcium in vivo.

A
  • Steep inverse sigmoid function
  • NOTE: there is a minimum level of PTH release (it can’t get below this even in the case of hypercalcaemia)
22
Q

What are the causes of primary hyperparathyroidism?

A
  • Parathyroid adenoma (80%)
  • Parathyroid hyperplasia (20%)
  • Parathyroid cancer
  • Familial syndromes
23
Q

What biochemical results are diagnostic of primary hyperparathyroidism?

A
  • Elevated total/ionised calcium
  • With PTH levels frankly elevated or in the upper half of the normal range (negative feedback should drop PTH if there is hypercalcaemia)
24
Q

What are the clinical features of primary hyperparathyroidism?

A
  • Stones, Bones, Abdominal Groans and Psychic Moans
  1. Stones – renal colic, nephrocalcinosis
  2. Bones – osteitis fibrosa cystica
  3. Abdominal moans – dyspepsia, pancreatitis, constipation
  4. Psychic groans – depression, impaired concentration
  • NOTE: patients may also suffer fractures secondary to the bone resorption
  • IMPORTANT NOTE: hypercalcaemia also causes diuresis (polyuria and polydipsia)
25
Q

What is the main site of action of calcitriol and what effect does it have?

A

Small intestine – increases calcium and phosphate absorption

26
Q

Describe the effects of calcitriol on bone and in the kidneys

A
  • Facilitates PTH effect on the DCT in the kidneys (increased calcium reabsorption)
  • Synergises with PTH in the bone to increase osteoclast activation/maturation
27
Q

Which receptors/proteins are involved in mediating the effects of calcitriol on the intestines?

A

TRPV6 Calbindin

28
Q

What parameter is used to determine whether a patient is vitamin D deficient?

A

Deficient < 20 ng/M (50 nmol/L) Normal > 30 ng/M (75 nmol/L)

29
Q

What is Rickets?

A

Vitamin-D deficiency leading to defective mineralisation of the cartilaginous growth plate (=OSTEOMALACIA) in children (before a low calcium)

30
Q

State some signs and symptoms of Rickets

A

Symptoms:

  • Bone pain and tenderness (axial)
  • Muscle weakness (proximal)

Sign:

  • Age dependent deformity
  • Myopathy
  • Hypotonia
  • Short stature
  • Tenderness on percussion
31
Q

State some Vitamin-D related causes of Rickets/Osteomalacia

A
  • Dietary deficiency
  • Malabsorption
  • Drugs – e.g. enzyme inducers such as phenytoin
  • Chronic renal failure
  • Rare hereditary
32
Q

For each of the following state whether it would be high, low or normal in the serum of a Rickets patient: a. Calcium b. Phosphate c. Alkaline Phosphatase d. 25-OH cholecalciferol e. PTH f. URINE phosphate

A

a. Calcium Normal or Low b. Phosphate Normal or Low c. Alkaline Phosphatase High d.25-OH cholecalciferol Low e. PTH High f. URINE phosphate High

33
Q

1) Other than PTH, what else can cause increased phosphate excretion?
2) What effect does this factor have that is unlike PTH?
3) Which cells produce this factor?

A

1) FGF23

2)

  • It inhibits 1 alpha-hydroxylase, thus inhibiting calcitriol production

3)

  • Osteoblast lineage cells
34
Q

Other than Vitamin D deficiency, what else can cause Rickets/Osteomalacia?

A
  • Phosphate deficiency
35
Q

State some phosphate-related conditions that cause Rickets/Osteomalacia

A
  • X-linked Hypophosphataemic Rickets (mutation in Phex (this cleaves FGF23))
  • Autosomal Dominant Hypophosphataemia Rickets
  • Oncogenic Osteomalacia (mesenchymal tumours can produce FGF23)
36
Q

What can cause osteoporosis due to increased bone resorption and decreased bone formation?

A

Glucocorticoids

37
Q

How does oestrogen deficiency lead to a decrease in bone mineral density?

A
  • It increases the number of bone remodelling units
  • It causes an imbalance in bone remodelling with increased bone resorption compared to bone formation
38
Q

Describe the biochemistry of someone with osteoporosis

A

Everything should be normal if the cause is primary

39
Q

What is the single best predictor of fracture risk?

A

BMD

40
Q

What is used to measure BMD?

A

DEXA scans

41
Q

Which bones are used when measuring BMD and why?

A
  • Vertebral bodies
    • Commonest fracture
    • Good measure of cancellous bone
    • It is a highly metabolically active bone so it is quick to respond to treatment
  • Hip
    • Second commonest fracture site
  • NOTE: fracture risk assessment tool (FRAX) uses hip BMD
42
Q

Which chains make up type 1 collagen?

A
  • 2 x alpha
  • 1 1 x alpha 2
43
Q

What can be used as a marker of bone formation that is linked to collagen production?

A

Procollagen type 1 N-terminal propeptide (P1NP)

44
Q

What can be used as a measure of bone resorption that is linked to collagen production?

A
  • C-terminal telopeptide (CTX) – serum N-terminal telopeptide (NTX) – urine 3 hydroxylysine molecules on adjacent tropocollagen fibrils condense to form a pyridinium ring linkage
  • These can be measured
45
Q

After how long do bone resorption markers fall?

A

4-6 weeks

46
Q

What are the problems with cross-linking collagen, with regards to measurement of bone markers?

A
  • Reproducibility
  • Positive association with age
  • Need to correct for creatinine
  • Diurnal variation in urine markers
47
Q

What bone formation marker is commonly in use?

A

Alkaline Phosphatase

48
Q

What is it used in the diagnosis and monitoring of?

A

Osteomalacia Paget’s Bone Metastases

49
Q

What is P1NP being used for now?

A

Used as a predictor of response to anabolic treatments

50
Q

What are the two forms of alkaline phosphatase?

A
  1. Liver
  2. Bone
51
Q

Which bone diseases will cause a rise in ALP?

A
  1. Osteomalacia
  2. Bone metastases
  3. Hyperparathyroidism and hyperthyroidism
52
Q

How does alkaline phosphatase change with age?

A
  • Increases markedly during puberty reaching its highest levels
  • Remains relatively constant following puberty (potential small rise after the age of 50)
53
Q

What biochemical changes occur in renal osteodystrophy?

A
  • Increased serum phosphate
  • Reduction in calcitriol
54
Q

Describe the sequelae of renal osteodystrophy

A
  • Secondary hyperparathyroidism
  • This is unsuccessful and hypocalcaemia develops
  • This leads to excessive stimulation of the parathyroid glands, leading to parathyroid hyperplasia
  • The parathyroid cells begin to reduce expression of calcium-sensing receptors (CSR) and Vitamin D receptors (VDR) and become autonomous (tertiary hyperparathyroidism)
  • This causes hypercalcaemia