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LCRS Year 2 - Endocrinology > Endocrine and Metabolic Bone Disorders > Flashcards

Endocrine and Metabolic Bone Disorders Flashcards

1
Q

How much of the body’s Ca2+ do the bones store?

A

> 95%

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2
Q

Is bone remodelling a linear or dynamic process and what does this mean?

A

Bone remodelling is a constant dynamic process. Because bones store so much of the body’s calcium, they are constantly broken down to raise serum calcium or being built to reduce serum calcium.

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3
Q

What are the two types of cell involved in bone remodelling?

A

Osteoblasts (formation of bone, Build)

Osteoclasts (break down bone, destruCtion)

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4
Q

What do osteoblasts contain and release, and how are they involved in the bone remodelling equilibrium?

A 
Synthesises osteoid (organic components of bone) and participate in mineralisation/calcification of osteoid
- overall manages bone formation and deposition of calcium in bone
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5
Q

What do osteoclasts contain and release, and how are they involved in the bone remodelling equilibrium?

A

Releases lysosomal enzymes which break down bone

- overall manages bone resorption and extraction of calcium from bone

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6
Q

How do osteoblasts interact with the maturation of osteoclasts?

A

Osteoclasts cannot mature without an osteoblast

  • osteoblasts express RANKL on their cell surface
  • RANKL binds to RANK-receptor to stimulate osteoclast maturation, formation and activity
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7
Q

What hormones do osteoblasts have receptors for and what does this allow?

A

PTH and calcitriol

- allows for regulation of balance between bone formation and bone resorption

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8
Q

What are the 2 main types of bone?

A

Cortical (hard) bone

Trabecular (spongy or trabecular) bone

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9
Q

What type of patten are both cortical and trabecular bone made up of, how are the collagen fibrils laid down and how strong is this pattern/and resulting bone?

A

LAMELLAR pattern

  • collagen fibrils laid down in alternating orientations
  • mechanically strong
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10
Q

What is the 3rd type of bone, how are its collagen fibres organised and how strong is it relative to cortical/trabecular bone?

A

Woven bone

  • disorganised collagen fibrils
  • weaker - the collagen is chaotically distributed, doesn’t allow much strength
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11
Q

What are the effects of vitamin D deficiency on bone in children and adults?

A

Inadequate mineralisation of the newly formed bone matrix (osteoid)

Children - Rickets

  • affects cartilage of epiphyseal growth plates and bone (makes bones ‘soft’, get ‘bendy’ bones)
  • skeletal abnormalities (bendy or ‘bowed’ legs) and pain, growth retardation, increased fracture risk

Adults

  • epiphyseal growth plates have closed so no alteration in shape of bone but still certainly affects and weakens bone
  • skeletal pain, increased fracture risk, proximal myopathy
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12
Q

What are ‘looser zones’?

A

Areas of bone where, usually in cases of vitamin D deficiency, the abnormal bone has been weakened such that normal stresses now causes stress fractures or insufficiency fractures

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13
Q

What is typical in vitamin D deficient (rickets/osteomalacia) patients regarding their walking?

A

Waddling gait

- attempt to avoid pain in femurs and hip due to weakened bones

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14
Q

What happens in primary, secondary, and tertiary hyperparathyroidism? (good slide in presentation explaining this, try drawing this as a diagram)

A

Primary - adenoma in the parathyroid gland, overactive parathyroid gland. Lots of PTH produced autonomously meaning Ca2+ negative feedback is ineffective so Ca2+ is also high

Secondary - low Ca2+ from vitamin D deficiency/renal failure, no negative feedback on PTH production so PTH increases and Ca2+ reaches low or normal levels

Tertiary - chronically low plasma Ca2+ because they haven’t been able to produce active vitamin D leads to PTH rising up and up until PTH production becomes autonomous so Ca2+ negative feedback is ineffective

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15
Q

Generally, does renal failure positively or negatively affect bones and what is the main reason?

A

Negatively

- main reason is inability to produce active vitamin D

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16
Q

What does renal failure lead to?

A

Inability to make active vitamin D

  • no calcitriol means reduced or no Ca2+ reabsorption in the kidneys or the gut
  • leads to HYPOCALCAEMIA

Inability to excrete phosphate

  • increases serum phosphate
  • phosphate binds to free calcium reducing free calcium leading to HYPOCALCAEMIA
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17
Q

What does the hypocalcaemia resulting from renal failure cause?

A
  • Reduced bone mineralisation (formation)
  • Increased PTH
  • Thus increased bone resorption (breakdown)
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18
Q

Which cells does hypocalcaemia super-activate and which hormone activates this?

A

Osteoclasts - breakdown bone to release calcium to raise serum calcium
- PTH causes this

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19
Q

What are the two bone disorders that can result from untreated hypocalcaemia?

A

Osteitis fibrosa cystica

Vascular calcification

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20
Q

What happens in osteitis fibrosa cystica?

A

Excess osteoclastic bone resorption secondary to high PTH

Cysts appear where overactive osteoclasts have broken down large chunks of bone in an attempt to restore normal serum calcium levels

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21
Q

What happens in vascular calcification and what causes it?

A

Blood vessels become calcified, have reduced ability to expand and contract due to build of up calcium in the walls
- caused by phosphate (probably by binding to free calcium and leading to deposition in the walls similar to atherosclerosis)

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22
Q

What are ‘Brown tumours” and where are they seen?

A

Radiolucent bone lesions

- seen in x-rays of patients with osteitis fibrosa cystica (hyperparathyroid bone disease)

23
Q

How is osteitis fibrosa cystica (hyperparathyroid bone disease) treated?

A

Hyperphosphataemia

  • low phosphate diet
  • phosphate binders, reduces GI phosphate absorption

Alphacalcidol - calcitiol (active form) analogues

Parathyroidectomy in cases of tertiary hyperparathyroidism

24
Q

What is osteoporosis?

A

Loss of bony trabeculae (lattices in bone)

  • reduced bone mass
  • weaker bone predisposed to fracture after minimal trauma
25
Q

How is osteoporosis diagnosed?

A

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 below)
- we take this because it predicts future fracture risk as this is the commonest clinical problem that results from osteoporosis

26
Q

How is Bone Mineral Density (BMD) measured?

A

Dual Energy X-ray Absorptiometry (DEXA scan) on the femoral neck and lumbar spine
- mineral (calcium) content of bone measured, the more mineral, the greater the bone density (bone mass)

27
Q

What is the region of bone mineral density between healthy and osteoporotic called? (lecturer referred to it as the ‘bus journey to osteoporosis’ if you’re in this region)

A

Osteopenia

28
Q

What is the similarity between osteomalacia and osteoporosis?

A

Both predispose to fracture

29
Q

Both osteomalacia and osteoporosis cause similar problems in predisposing the patient to fracture, what are the distinguishing differences between the two disorders?

A

Osteomalacia

  • Vitamin D deficiency (adults) causing inadequately mineralised bone
  • Serum biochemistry abnormal (low calcidriol, low vit D, low Ca2+, high PTH, secondary hyperparathyroidism)
  • Diagnosis by serum biochemistry abnormalities

Osteoporosis

  • Rate of bone resorption exceeds rate of bone formation
  • Decreased bone MASS not mineralisation
  • Serum biochemistry normal (IMPORTANT difference)
  • Diagnosis via DEXA scan
30
Q

How does postmenopausal oestrogen deficiency predispose women to osteoporosis?

A
  • oestrogen deficiency leads to loss of bone matrix

- subsequent increased risk of fracture

31
Q

What are pre-disposing conditions for osteoporosis?

A

Postmenopausal oestrogen deficiency

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

Hypogonadism in young women (oestrogen deficiency) and in men (testosterone deficiency)

Endocrine conditions

  • Cushing’s syndrome
  • Hyperthyroidism
  • Primary hyperparathyroidism

Iatrogenic

  • Prolonged use of glucocorticoids
  • Heparin
32
Q

(Informative card) What are the % of patients that were 1) unable to carry out at least one independent activity of daily living, 2) unable to walk independently, 3) permanent disability, 4) death within one year, at one year after hip fracture?

A

1) Unable to carry out at least one independent activity of daily living - 80%
2) Unable to walk independently - 40%
3) Permanent disability - 30%
4) Death within one year - 20%

Emphasises why osteoporosis and fracture risk is so important clinically

33
Q

What are the treatment options for osteoporosis?

A
  • Oestrogen
  • Bisphosphonates
  • Denosumab
  • Teriparatide
34
Q

How can oestrogen, as HRT, be used to treat osteoporosis but what must it be administered with in women with an intact uterus?

A
  • Treatment of post-menopausal women with pharmacological doses of oestrogen
  • anti-resorptive effects on the skeleton
  • prevents further bone loss, slows osteoclast activity

Must be administered with additional progestogen to prevent endometrial hyperplasia/cancer

35
Q

Why is the use of oestrogen HRT limited?

A

Concerns over:

  • Increased risk of breast cancer
  • Venous thromboembolism (clots)
36
Q

How do bisphosphonates help treat osteoporosis?

A
  • Bind avidly to hydroxyapatite and ingested by osteoclasts - sort of ‘stuns’ the osteoclast impairing its ability to reabsorb and break down bone
  • Decrease osteoclast progenitor development and recruitment
  • Promote osteoclast apoptosis

Net result = reduced bone turnover
- first line treatment for osteoporosis

37
Q

What are the uses of bisphosphonates?

A

Osteoporosis - first line treatment as not hormonal or affected by hormones

Malignancy

  • treats associated hypercalcaemia
  • reduce bone pain from metastases

Paget’s disease - reduces bony pain

Severe hypercalcaemic emergency - i.v. initially (hydration first!)

38
Q

The pharmacokinetics of bisphosphonates; what form are these drugs active in, how well absorbed are they, and what are the conditions you have to take them on?

A
  • Orally active
  • Poorly absorbed
  • Take on an empty stomach (food, especially milk, reduces drug absorption)
39
Q

The pharmacokinetics of bisphosphonates; where do these drug molecules accumulate, what do they remain a part of, when do they become released again, and what sort of time-scale do these drugs remain in the body for?

A
  • Accumulate at site of bone mineralisation,
  • Remains a part of the bone matrix
  • Remains there until that part of the bone is resorbed
  • Can remain for months even years until finally resorbed and excreted (can lead to concern over whether to treat young patients with this because they last so long)
40
Q

What are the unwanted effects of bisphosphonates?

A

Oesophagitis - inflammation of oesophageal lining by reflux of stomach acid

Indigestion (dyspepsia)

Osteonecrosis of the jaw

  • greatest risk in cancer patients receiving iv bisphosphonates
  • prevents bone turnover to a degree sufficient to cause the bone to harden and die (osteonecrosis)

Atypical fractures
- may reflect over-suppression of bone remodelling in prolonged bisphosphonate use (patients given bisphosphonate ‘holidays’ to allow the bones to begin remodelling again)

41
Q

What is denosumab and how is it useful in treating osteoporosis?

A

Human monoclonal antibody

  • binds RANKL, inhibiting osteoclast formation and activity as they require binding to RANKL to begin maturation
  • hence inhibits osteoclast-mediated bone resorption
42
Q

How is DENOSUMAB administered and how often is it administered?

A

Subcutaneous injection
6-monthly
2nd line to bisphosphonates
- Expense limits current use

43
Q

What is TERIPARATIDE and how is it useful in treating osteoporosis?

A
  • Recombinant PTH 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 and how often is it administered?

A

Daily subcutaneous injection

  • 3rd line treatment for osteoporosis
  • Hugely expensive again limiting use
45
Q

What is Paget’s disease (of bone)?

A

Accelerated, localised but very disorganised bone remodelling
- excessive bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts)

46
Q

What new type of bone is formed in Paget’s disease?

A

WOVEN bone

  • structurally disorganised
  • mechanically weaker than normal adult lamellar bone
47
Q

What does Paget’s disease lead to?

A
  • Bone frailty - increased fracture risk

- Bone hypertrophy and deformity

48
Q

What causes Paget’s disease?

A

The causes of Paget’s disease are fairly unknown. Sometimes there is a family history suggesting a genetic cause and some evidence for viral origin based on its areas of prevalance, high in UK, USA, Australia and NZ, low in Asia and Scandinavia
Men and women are affected equally

49
Q

When do symptoms present and do most patients see symptoms or not?

A

Disease is not usually apparent under 50yrs

Most patients are asymptomatic

50
Q

What is Paget’s disease characterised by, on a microscopic level?

A

Abnormal, large osteoclasts - excessive in number since activity is through the roof

51
Q

Which areas are most commonly affected by Paget’s disease?

A

Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affect

52
Q

What are the clinical features of Paget’s disease?

A

Main features:
- Bone pain
- Bone deformity
- Increased fracture risk
Peripheral features:
- Arthritis
- Increased vascularity (warm over affected bone due to increased activity)
- Deafness if small bones of the ear are involved
- Radiculopathy (pinched nerve) due to nerve compression

53
Q

What metrics would provide a diagnosis of Paget’s disease?

A
  • Plasma Ca2+ normal
  • Plasma alkaline phosphatase usually increased
  • Plain x-rays = lytic lesions (early), thickened, enlarged, deformed bones (later)
  • Radionuclide bone scan demonstrates extent of skeletal involvement (radioactive isotope taken up by highly active areas of bone showing up on the scan where the bones are most active)
54
Q

What are the treatment options for Paget’s disease?

A

Bisphosphonates - very helpful for reducing bony pain and disease activity
- Simple analgesia can also be given to reduce pain

LCRS Year 2 - Endocrinology (21 decks)

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