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Year 2 - endocrinology > Endocrine and metabolic bone disorders > Flashcards

Endocrine and metabolic bone disorders Flashcards

1
Q

What does bone contain a large store of?

A

calcium (more than 95

% of body’s store)

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2
Q

What are the 2 components of bone?

A
  1. Osteoid (organic component – unmineralised bone made up of type 1 collagen). 35%
  2. Calcium hydroxyapatite crystals (inorganic component, fill the space between collagen fibrils). 65%
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3
Q

What are osteoblasts?

A

They synthesise bone (osteoid)

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4
Q

What are osteoclasts?

A

They release lysosomal enzymes which break down bone

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5
Q

How does PTH activate osteoclasts?

A

PTH stimulates osteoblasts to produce osteoclasts activating factors. One of these is called RANKL - it binds to the RANK receptor on the osteoclast to stimulate bone resorption.

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6
Q

How does PTH affect osteoblasts (direct or indirect)?

A

Direct effect by binding to osteoblasts

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7
Q

Describe the interaction between osteoblasts and osteoclasts during osteoclast differentiation

A

Osteoblasts express RANKL which binds to a receptor on the osteoclast precursor. Once it binds this stimulates osteoclast activity.

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8
Q

Which receptors can be found on osteoblasts?

A

Receptors for PTH & calcitriol (1,25 (OH)2 vitamin D)

THEY REGULATE BALANCE BETWEEN BONE FORMATION AND RESORPTION

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9
Q

What are the different types of bone?

A

lamellar:
hard, cortical bone
spongy, trabecular bone

woven bone

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10
Q

How is bone organised?

A
  • Bone is formed in a lamellar pattern
  • This means that collagen fibrils are laid down in altering orientations
  • This gives the most mechanical strength possible
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11
Q

What is woven bone?

A
  • It is weak bone

- This is because it doesn’t have the same organisation of collagen fibrils (fibrils laid quite randomly)

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12
Q

What does vitamin D deficiency lead to?

A

Inadequate mineralisation of newly formed bone matrix (osteoid)

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13
Q

What is rickets?

A
  • Affects children
  • Affects the cartilage of epiphysial growth plates and bones
  • Skeletal abnormalities causes e.g. tibia bows, pain, growth retardation, increased fracture risk
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14
Q

What is osteomalacia?

A
  • Affects adults
  • After epiphysial closure so affects bones
  • Skeletal pain, increased fracture risk, proximal myopathy
  • No bony deformities as in rickets
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15
Q

What is the effect of vitamin D deficiency on bone?

A
  • There are typical fracture sites for severe vitamin D deficiency
  • Normally in places where there is a lot of bone loading
  • Normal stresses (e.g. weight bearing) on abnormal bone cause insufficiency fractures at looser zones e.g. the pelvis
  • Patients may walk with a ‘waddling gait’ due to pain from abnormal pelvis fractures
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16
Q

What is primary hyperparathyroidism?

A

Adenoma which secretes too much PTH. Because of the autonomous secretion of PTH here, patients have a high serum calcium and high PTH

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17
Q

What is secondary hyperparathyroidism?

A

There is a normal physiological response to low calcium because of either renal failure or vitamin D deficiency -> increased release of PTH

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18
Q

What is tertiary hyperparathyroidism?

A

Seen in chronic renal failure, there is chronically low calcium because calcitriol cannot be made. PTH increases to try and drive calcium increase.

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19
Q

What happens if the kidneys fail?

A
  • Calcitriol cannot be made, so calcium isn’t absorbed from the gut very well -> hypocalcaemia
  • The kidneys excrete phosphate, so less excretion results in increased serum phosphate. Phosphate binds to calcium, further decreasing bioavailable serum calcium
  • This results in inadequate bone mineralisation (-> osteitis fibrosa cystica), and increased PTH release
  • Increased PTH increases bone resorption, which also leads to osteitis fibrosa cystica
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20
Q

What do patients with renal failure have to ensure?

A
  • Need to manage their diet very strictly to reduce phosphate intake
21
Q

What is a problem with having high phosphate?

A

Vascular calcification

22
Q

What is osteitis fibrosa cystica?

A
  • Rare, hyperparathyroid bone disease
  • Seen in people with very high PTH
  • Seen in renal failure
23
Q

What is the mechanism behind osteitis fibrosa cystica?

A
  • In renal failure there is not enough calcium hence

High PTH -> osteoclast stimulation -> increased bone resorption

24
Q

What is seen in radiography in osteitis fibrosa cystica?

A

The areas of radiolucency on the x-rays show where bones are so thin because of the over-activity of osteoclasts. We see a pepper-pot skull. ‘Brown tumours’ – radiolucent bone lesions where bone has been broken down.

25
Q

What is the treatment of osteitis fibrosa cystica?

A

Hyperphosphataemia:
Low phosphate diet (can be hard)
Phosphate binders – reduce GI phosphate absorption by collating phosphate in the gut

Alphacalcidol – i.e. calcitriol analogues – you have to give patients active vitamin D (can’t convert into active form as their kidneys are failing)

Parathyroidectomy in tertiary hyperparathyroidism

Indicated for hypercalcaemia &or hyperparathyroid bone disease

26
Q

What is osteoporosis and who does it affect?

A
  • Increased risk of fracture
  • reduction in bone mass
  • particularly a problem in post menopausal women, but everyone loses bone mass with age
27
Q

What is a measure of osteoporosis?

A
  • Bone mineral density – it predicts fracture risk
  • Bone mineral density (BMD) > 2.5 standard deviations below the average value for young healthy adults (usually referred to as a T-score of -2.5 or lower)
  • A DEXA scan can give a T-score
28
Q

How is bone mineral density measured?

What is scanned?

A
  • BMD is measured using a DEXA scan (dual energy x-ray absorptiometry)
  • The femoral neck and lumbar spine are scanned
  • The scan looks at the mineral (calcium) content of bone
  • The more mineral, the greater the bone density (bone mass)
29
Q

What is the difference between osteomalacia and osteoporosis?

A

Both predispose to fractures but osteomalacia is caused by insufficiency of mineralised bone due to vitamin D deficiency whilst osteoporosis is decreased bone mass

30
Q

What happens in osteomalacia?

A
  • Vitamin D deficiency (adults) causing inadequately mineralised bone
  • Serum biochemistry is abnormal (low 25(OH) vitamin D, low Ca2+, high PTH (secondary hyperparathyroidism)
31
Q

What happens in osteoporosis?

A
  • Bone reabsorption exceeds formation
  • Decreased bone mass
  • Serum biochemistry normal
  • Diagnosis via DEXA scan
32
Q

What are some predisposing conditions for osteoporosis?

A

Postmenopausal oestrogen deficiency
- Oestrogen deficiency leads to a loss of bone matrix, subsequent increased risk of fracture

Age-related deficiency in bone homeostasis (men and women) e.g. osteoblast senescence

Hypogonadism in young women and in men

Endocrine conditions

  • Cushing’s syndrome
  • Hyperthyroidism
  • Primary hyperparathyroidism

Iatrogenic

Prolonged use of glucocorticoids

o Heparin

33
Q

What are the treatment options for osteoporosis?

A
  • Oestrogen/Selective Oestrogen Receptor Modulators
  • Bisphosphonates
  • Denosumab
  • Teriparatide
34
Q

How does oestrogen therapy work?

A
  • Treatment of post-menopausal women with pharmacological doses of oestrogen
  • Anti-resorptive effects on the skeleton
  • Prevents bone loss
35
Q

What are some precautions that must be taken when giving oestrogen HRT?

A
  • Women with an intact uterus need additional progestogen to prevent endometrial hyperplasia/cancer
  • Use limited largely due to concerns with increased risk of breast cancer and venous thromboembolism
36
Q

What are selective oestrogen receptor modulators (SERMS)?

raloxifen and tamoxifen and describe their effects on bone, endometrium and breast

A
  1. Tissue selective ER antagonists/anti-estrogens e.g. tamoxifen
    - Antagonises ERs in breast but has oestrogenic activity in bone
    - Oestrogenic effects on endometrium limit its use in osteoporosis management
  2. Tissue selective ER agonist raloxifene has been further developed for its selectivity on bone
    - Oestrogenic activity in bone, and anti-oestrogenic at breast and uterus
    - Reduces breast cancer risk (anti-oestrogen) but increases risk of venous thromboembolism
37
Q

What are bisphosphonates - how do they work?

A
  • Bind to hydroxyapatite and ingested by osteoclasts – impair ability of osteoclasts to reabsorb bone
  • Decrease osteoclast progenitor development and recruitment
  • Promote osteoclast apoptosis
  • Net result = reduced bone turnover
38
Q

When are bisphosphonates used?

A
  1. Osteoporosis – first line treatment
  2. Malignancy (associated hypercalcaemia, reduce bone pain from metastase)
  3. Paget’s disease – reduce bony pain
  4. Severe hypercalcaemic emergency – i.v. Initially (+++ re-hydration first)
39
Q

Describe the pharmacokinetics of bisphosphonates

A
  • Orally active but poorly absorbed; take on an empty stomach (food, especially milk, reduces drug absorption generally) – so these tablets are a pain to take
  • Accumulates at site of bone mineralisation and remains part of bone until it is resorbed – months, year
40
Q

What are some unwanted actions of bisphosphonates?

A
  • Oesophagitis (heart burn): may require switch from an oral to an intravenous preparation
  • Osteonecrosis of the jaw: greatest risk in cancer patients receiving intravenous bisphosphonates
  • Atypical fractures: may reflect over-suppression of bone remodelling in prolonged bisphosphonate use
  • Patients are given bisphosphonate holiday so that bones can recover from this treatment
41
Q

What is denosumab?

A
  • Human monoclonal antibody
  • Denosumab binds RANKL, inhibiting osteoclast formation and activity
  • Hence inhibits osteoclast-mediated bone resorption -> helpful treatment for osteoporosis
42
Q

How is denosumab administered?

Is it the 1st line of treatment for osteoporosis and why?

A
  • Subcutaneous injection every 6 months

- 2nd line to bisphosphonates (largely because of price

43
Q

What is teriparatide?

A
  • Recombinant parathyroid hormone fragment – amino-terminal 34 amino acids of native PTH
  • Increases bone formation and bone resorption, but formation outweighs resorption
44
Q

How is teriparatide administered?

Is it the 1st line of treatment for osteoporosis and why?

A
  • 3rd line treatment for osteoporosis
  • Daily subcutaneous injection
  • Very expensive
45
Q

What is paget’s disease?

A
  • Accelerated, localised but disorganised bone remodelling
  • Excessive bone resorption (osteoclastic over activity) followed by a compensatory increase in bone formation (osteoblasts), but the new bone formed is woven bone
  • This bone is structurally disorganised, mechanically weaker than normal adult lamellar bone, frail, bone deformity and hypertrophy
  • Most patients are asymptomatic
  • Characterised by abnormal, large osteoclasts – excessive in number
46
Q

Describe the familial link of paget’s disease, its prevalence, epidemiology

A
  • Often positive family history (possible genetic cause)
  • There is evidence for viral origin (e.g. measles virus)
  • Highest in UK, N America, Australia and NZ
  • Lowest in Asian and Scandinavia
  • Men and women affected equally
  • Disease usually not apparent in people younger than 50 years
47
Q

What are the clinical features of paget’s disease?

A
  • Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected
  • Arthritis
  • Fracture
  • Pain
  • Bone deformity
  • Increased vascularity (warmth over affected bone)
  • Deafness – if cochlear involvement
  • Radiculopathy – pinched nerve in spinal column due to nerve compression
  • Bowing of tibia
48
Q

How is paget’s disease diagnosed?

A
  • Plasma [Ca2+] is normal
  • Plasma alkaline phosphatase is usually increased
  • Plain x rays = Lytic lesions (early), thickened, enlarged, deformed bones (later)
  • Radionuclide bone scan demonstrates extent of skeletal involvement
49
Q

How is paget’s disease treated?

A
  • Bisphosphonates – very helpful for reducing bony pain and disease activity
  • Simple analgesia

Year 2 - endocrinology (18 decks)

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