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Endocrine Bone Disorders Flashcards

1
Q

What is the most important vitamin D metabolite?

A

1, 25-dihydroxycholecalciferol (calcitriol)

-active form

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2
Q

What is the principle effect of calcitriol?

A

Intestinal absorption of calcium, magnesium and phosphate

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3
Q

What are the renal effects of calcitriol?

A
  1. Increased reabsorption of calcium and
  2. Decreased phosphate reabsorption in the kidneys
    (via FGF23)
    Stimulates osteoclast formation from precursors
    Stimulates osteoblasts to make osteoclast-activating factors (OAFs e.g. RANKL)
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4
Q

What does vitamin D deficiency cause? State some symptoms.

A 
Lack of bone mineralisation  
Softening of bone (can lead to bowing of the legs) 
Bone deformities  
Bone pain 
Severe proximal myopathy
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5
Q

What are the different names for vitamin D deficiency in children and adults?

A

Children – Rickets

Adults – Osteomalacia

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6
Q

State some causes of vitamin D deficiency.

A
  1. Diet
  2. Lack of sunlight
  3. GI malabsorption
    - eg coeliac disease, inflammatory bowel disease,
  4. Renal failure (2nd hydroxylation)
  5. Liver failure (1st hydroxylation)
  6. Vitamin D receptor defects (autosomal recessive, rare, resistant to vitamin D treatment)
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7
Q

Which step, in vitamin D metabolism, required UV light?

A

The conversion of 7-dehydrocholesterol in the skin to cholecalciferol (vitamin D3) requires UV light

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8
Q

Describe the two hydroxylation reactions in vitamin D metabolism.

A
  1. Cholecalciferol is firstly hydroxylated to form 25-hydroxycholecalciferol in the LIVER
  2. It then goes to the KIDNEYS where it undergoes its next hydroxylation (by 1-hydroxylase) to form 1, 25-dihydroxycholecalciferol -calcitriol
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9
Q

What can stimulate 1-hydroxylase in the kidneys?

A

Parathyroid Hormone (PTH)

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10
Q

How can lack of sunlight cause vitamin D deficiency?

A

It will mean that less 7-dehydrocholesterol is being converted to cholecalciferol

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11
Q

How can liver disease cause vitamin D deficiency?

A

The liver is where the first hydroxylation takes place and where 25-hydroxycholecalciferol is stored so liver disease can interfere with this step in vitamin D metabolism

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12
Q

How can renal failure cause vitamin D deficiency?

A

The second hydroxylation step takes place in the kidneys (via 1-alpha-hydroxylase) so renal failure can interfere with 1-alpha-hydroxylase activity

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13
Q

What is usually measured to gage the level of calcitriol? What condition must be fulfilled for this to be a good measure of calcitriol?

A

25-hydroxycholecalciferol

This is only a good measure in the case of normal renal function

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14
Q

Describe how you would diagnose vitamin D deficiency.

A
  1. Plasma [25(OH)D3]- Calcifediol (aka 25-hydroxycholecalciferol) usually low
  2. Plasma Ca2+ = LOW
  3. Plasma [PO43-] low (reduced gut absorption)
  4. [PTH] high (2o hyperparathyroidism stimulated by the hypocalcaemia)
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15
Q

What would you expect the plasma phosphate level to be in someone with renal failure and why?

A

HIGH – because there is a decrease in plasma excretion via the kidneys

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16
Q

What would you expect the plasma calcium level to be in someone with renal failure and why?

A

LOW – because they are not producing as much calcitriol (due to renalfailure interfering with 1-alpha hydroxylase) so there is less calcium absorption in the small intestines

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17
Q

What are the consequences of hypocalcaemia caused by renal failure?

A

There is a decrease in bone mineralisation and an increase in bone resorption (because of an increase in PTH) leading to osteitis fibrosa cystica
The imbalance in calcium and phosphate can also lead to the formation of salts that can be deposited in extra-skeletal tissue causing extra-skeletal calcification

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18
Q

What can vitamin D excess lead to?

A

Hypercalcaemia and hypercalciuria (due to increased intestinal absorption of calcium)

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19
Q

What can vitamin D excess result from?

A
  1. Excessive treatment with active metabolites of vitamin D, as in patients with chronic renal failure
  2. Granulomatous disease – granulomatous tissue has 1-hydroxylase so it can be a source of ectopic calcitriol
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20
Q

What is Paget’s disease?

A

-Accelerated, localised but disorganised bone remodelling
-Excessive bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts)
-New bone formed = WOVEN bone
structurally disorganised, mechanically weaker than normal adult lamellar bone

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21
Q

What is Paget’s disease characterised by histologically?

A

Abnormal, large osteoclasts

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22
Q

State some symptoms of Paget’s disease.

A
  1. Increased vascularity (warmth over affected bone)
  2. Increased osteoblast/osteoclast activity
  3. Most commonly affected bones are: pelvis, femur, tibia, skull, and thoracolumbar spine
    Increased incidence of fracture
  4. Bone pain
  5. Deafness – cochlear involvement
  6. Radiculopathy – due to nerve compression
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23
Q

Describe how you would diagnose Paget’s disease.

A
  1. Plasma calcium = NORMAL
  2. Plasma ALP (alkaline phosphatase) = HIGH
  3. Radiological findings: plain X ray shows
    - Lytic lesions (early)
    - thickened, enlarged, deformed bones (later)
    - Radioisotope (technetium) scanning can be performed to indicate areas of involvement
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24
Q

What are the two components of bone in which 95% of the body’s calcium is stored?

A

Inorganic mineral component –65%
- Stored as calcium hydroxyapatite crystals between the collagen fibrils

Organic (osteoid) component –35%
- Collagen fibres (95%)

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25
What is the normal plasma calcium range?
2.2-2.6 mmol/L
26
State 2 hormones that increase plasma calcium concentration.
Calcitriol | PTH
27
State a hormone that decreases plasma calcium concentration.
Calcitonin
28
What are the 2 direct effects of PTH?
Causes bone to release calcium and phosphates | Increased calcium reabsorption in the kidneys and stimulation of 1a-hydroxylase
29
What are the 2 direct effects of calcitriol?
Increased calcium absorption from the small intestine | Increased mobilisation of calcium in bone
30
What can stimulate PTH release?
Hypocalcaemia
31
State 4 signs of hypocalcaemia.
PCAT (too much excitability) 1. Parasthesia (e.g tingling, prickling, numb, burning - abnormal dermal sensation ) 2. Arrhythmias 3. Convulsions 4. Tetany
32
What effect does hypocalcaemia have on excitable tissues?
It sensitises excitable tissue --> neuromuscular excitability
33
State 2 clinical signs of neuromuscular irritability due to hypocalcaemia.
Chvostek’s Sign - Tap the facial nerve just below the zygomatic arch - Positive = twitching of facial muscles Trousseau’s Sign - Pump the blood pressure cuff for several minutes - Induces carpopedal spasm
34
State 4 causes of hypocalcaemia.
1. Low PTH levels = Hypoparathyroidism - surgical - autoimmune - magnesium deficiency 2. Vitamin D deficiency 3. PTH resistance e.g Pseudohypoparathyroidism 4. Renal failure (impaired 1-alpha hydroxylase)
35
Describe the effect of hypercalcaemia on neuronal excitability.
It reduces neuronal excitability and you get atonal muscles
36
What are the main signs and symptoms of hypercalcaemia?
Stones, abdominal moans and psychic groans 1. Stones – renal effects - Polyuria + polydipsia - Nephrocalcinosis = deposition of calcium in the kidneys (can cause renal colic) 2. Abdominal moans – GI effects - Anorexia, nausea, constipation, pancreatitis, dyspepsia 3. Psychic groans – CNS effects - Fatigue, depression, impaired concentration, altered mentation, coma
37
What are the two main causes of hypercalcaemia?
1. Primary Hyperparathyroidism (e.g. parathyroid adenoma) | 2. Malignancy (tumours can also produce PTH-like peptide)
38
State 2 other causes of hypercalcaemia.
1. Paget's disease (condition w high bone turnover) | 2. Vitamin D excess
39
Describe how you would differentiate between primary hyperparathyroidism and malignancy causing hypercalcaemia.
In primary hyperparathyroidism there is no negative feedback because the parathyroid adenoma will be producing PTH autonomously - Plasma Calcium = HIGH - PTH = HIGH In malignancy, the negative feedback will be intact as it is due to increased bone turnover due to bony metastases - Plasma Calcium = HIGH - PTH = LOW
40
Describe the treatment of vitamin D deficiency in the case of normal renal function.
Give 25-hydroxy vitamin D (kidney hydroxylates further) This can be in the form of: 1. Ergocalciferol = 25-hydroxy vitamin D2 2. Cholecalciferol = 25-hydroxy vitamin D3
41
Describe the treatment of vitamin D deficiency in the case of renal failure.
Alfacalcidol = 1-hydroxycholecalciferol | ready hydroxylated Vitamin D
42
What do osteocytes produce?
Type 1 collagen and other extracellular matrix components
43
What is RANK ligand?
An osteoclast-activating factor – it increases the activation of osteoclasts It stimulates the maturation of osteoclasts from osteoclast precursors If there are more mature osteoclasts, you get more bone resorption
44
Define osteoporosis.
- bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average for young healthy adults (usually referred to as a T-score of -2.5 or lower)
45
State some predisposing conditions for osteoporosis.
1. Post-menopausal oestrogen deficiency 2. Age-related deficiency of bone homeostasis 3. Hypogonadism in young people 4. Endocrine conditions (e.g. Cushing’s syndrome, hyperthyroidism, primary hyperparathyroidism) 5. Iatrogenic (e.g. prolonged use of glucocorticoids, heparin)
46
What are the benefits of oestrogen HRT to prevent osteoporosis in post-menopausal women?
It has an anti-resorptive effect in bone and, hence, prevents bone loss
47
What are some cautions and risks of oestrogen replacement?
In patients with a uterus (i.e. not had a hysterectomy), you must give additional progestogen to prevent endometrial hyperplasia and reduce the risk of endometrial carcinoma Risks: 1. Breast cancer 2. Venous thromboembolism
48
Name 2 selective oestrogen receptor modulators (SERM) and their effects.
Selective oestrogen receptor ANTAGONISTS – Tamoxifen  Antagonises ERs in the breast  Oestrogenic activity in bone  But, oestrogenic activity in uterus, which limits its use in osteoporosis Selective oestrogen receptor AGONIST – Raloxifene  Oestrogenic in bone  Anti-oestrogenic in breast and uterus  But there is a risk of stroke and venous thromboembolism
49
What are the 1st, 2nd and 3rd line treatments for osteoporosis?
Bisphosphonates Denusomab Teriparatide
50
What are bisphonates analogues of?
Pyrophosphate
51
Give 2 examples of bisphosphonates.
Alendronate | Sodium etidronate
52
Describe how bisphosphonates work.
They bind avidly to hydroxyapatite crystals in the bone and are ingested by osteoclasts They impair the ability of osteoclasts to resorb bone It also decreases the maturation of osteoclasts and promotes osteoclast apoptosis
53
State some uses of bisphosphonates.
1. Osteoporosis 2. Malignancy – reduces bony pain 3. Paget’s disease – reduces bony pain Severe hypercalcaemic emergency -I.V. saline to rehydrate - - Then bisphosphonates
54
Describe the pharmacokinetics of bisphosphonates.
They are orally active but poorly absorbed Must be taken on an empty stomach Accumulates at the site of bone mineralisation and remains a part of the bone until it is resorbed
55
State 4 unwanted actions of bisphosphonates.
1. Oesophagitis 2. Osteonecrosis of the jaw (greatest risk in cancer patients receiving IV bisphosphonates) 3. Atypical fractures (due to over-suppression of bone remodelling)
56
What is denusomab and how often does it need to be given?
It s a human monoclonal antibody It binds to RANKL and inhibits osteoclast formation and activity It is given subcutaneously every 6-12 months
57
What is teriparatide and how often does it need to be given?
Recombinant fragment of PTH Increases bone resorption and formation – but formation exceeds resorption Daily subcutaneous injections EXPENSIVE
58
What is the difference between primary and secondary hyperparathyroidism?
Primary- autonomous PTH production due to adenoma -produces a hypercalcaemia Secondary- no Calcitriol so lower Ca2+ so more PTH production to try normalise serum Ca2+ - not a hypercalcaemia though
59
How do changes in EC calcium affect nerve and skeletal muscle excitability?
To generate an AP in nerves/skeletal muscle requires Na+ influx across cell membrane - HIGH ec calcium (HYPERcalcaemia) = Ca2+ blocks Na+ influx, so LESS membrane excitability - LOW ec calcium (HYPOcalcaemia) = enables GREATER Na+ influx, so MORE membrane excitability
60
How is BMD measured?
BMD is measured using Dual Energy X-ray Absorptiometry (DEXA)
61
What does BMD predict?
Future fracture risk
62
How would you treat Paget's disease of bone?
Bisphosphonates reduce bone pain and disease activity
63
Describe Paget's disease of bone in terms of gender and cause
Affects men and women equally Genetic component SQSTM1 and RANK on chromosome 5 and 6 Possible viral origin
64
What us Osteoprotegrin and what does it do?
OPG acts as a competitive inhibitor for RANKL | so RANKL stimulates osteoclast activity whilst OPG inhibits it
65
How do you treat Hyperparathyroid bone disease?
AKA ostetitis fibrosa cystica 1. hyperphosphataemia - low phosphate diet - Phosphate binders 2. Alphacalcidol – ie calcitriol analogues 3. Parathyroidectomy in 3o hyperparathyroidism Indicated for hypercalcaemia &/or hyperparathyroid bone disease

Endocrinology (18 decks)

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