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

Endocrine and Metabolic Bone Disorders Flashcards

1
Q

What proportion of the body’s calcium does bone store?

A

> 95%

and is also a reservoir of phosphate

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2
Q

Composition of bone

A
  • 35% bone mass organic (type 1collagen fibers)
  • 65% bone mass inorganic mineral component (calcium hydroxyapatite crystals filling the space in-between collagen fibrils)
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3
Q

What are the cell types in bone?

A

Osteoblasts
-> synthesise osteoid and participate in mineralisation/calcification of osteoid(bone formation)

Osteoclasts
-> release lysosomal enzymes which break down bone(bone resorption)

  • osteocytes
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4
Q

Bone resorption

A
  • osteoclasts release lysosomal enzymes which break down bone (bone resorption)
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5
Q

Bone remodelling

A
  • DYNAMIC process involving bone resorption and bone formation
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6
Q

Osteoclast differentiation

A
  • involves osteoblasts
  • RANKL expressed on osteoblast surface
  • RANKL binds to RANK-R to stimulate osteoclast formation and activity
  • Osteoblasts express receptors for PTH & calcitriol (1,25 (OH)2 vit D) –> regulate balance between bone formation & resorption
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7
Q

What are the structural types of bone?

A
  • Cortical (hard) bone
  • Trabecular (spongy or trabecular) bone; meshwork of bony bars (trabeculae)
  • Both formed in a lamellar pattern = collagen fibrils laid down in alternating orientations, mechanically strong
  • Woven bone – disorganised collagen fibrils, weaker (woven bone is immature)
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8
Q

What are the effects of vitamin D deficiency on bone?

A
  • Inadequate mineralisation of newly formed bone matrix (osteoid)
  • Vitamin D is needed to mineralise newly formed bone
  • Children – RICKETS
    • > affects cartilage of epiphysial growth plates and bone
    • > skeletal abnormalities and pain, growth retardation, increased fracture risk. There is a lot of deformity and also short stature in rickets.
  • Adults – OSTEOMALACIA
    • > after epiphyseal closure, affects bone
    • > skeletal pain, increased fracture risk, proximal myopathy
    • > Adults don’t have rickets because they don’t grow anymore, the growth plates have closed.
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9
Q

What might you observe in vitamin D deficiency?

A
  • Normal stresses on abnormal bone cause insufficiency fractures - Looser zones
  • Waddling gait - typical
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10
Q

Looser zones

A
  • stress fractures / insufficiency fractures
  • pseudo structures
  • caused by normal stress on abnormal bone
  • bone is weak
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11
Q

What are the effects of hyperparathyroidism on bone?

A
  • check!!!!!!
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12
Q

What are the 3 types of hyperparathyroidism?

A
  • 1° HPT: PT-gland adenoma producing PTH (not regulated PTH secretion leads to high PTH and consequently high serum calcium.
  • 2° HPT: increased PTH secondary to renal disease or vitamin D deficiency causing low calcium. PTH is high as a physiological response. The calcium is low or normal.
  • 3° HPT: The PT-glands become autonomous and increase in size as a result of chronic hypocalcaemia due to renal disease. They secrete lots of PTH but this isn’t capable of increasing calcium much because of kidney disease.
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13
Q

Renal failure and bone disease

A
  • Renal function leads to:
    a) decrease in calcitriol -> decreased calcium absorption
    b) decreased PO43- excretion -> high serum PO43- AND increase in vascular calcification Phosphate rises in CKD which also binds to calcium and calcium drops in the blood)
  • this leads to hypocalcaemia -> leads to:
    a) decreased bone demineralisation -> osteitis fibrosa cystica
    b) increase in PTH -> increased bone resorption -> osteitis fibrosa cystica

Decreased bone mineralisation, increased PTH, can lead to tertiary, phosphate causes calcification in e.g. blood vessels, cysts in bone called brown tumours due to extremely high PTH.

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14
Q

Brown Tumours

A
  • radiolucent bone lesions
  • also known as osteitis fibrosa cystica and rarely as osteoclastoma
  • one of the manifestations of hyperparathyroisim
  • reparative cellular process, rather than a neoplastic process
  • Well-defined, purely lytic lesions that provoke little reactive bone. The cortex may be thinned and expanded, but will not be penetrated.
  • XR: dark areas in bone
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15
Q

Osteitis fibrosa cystica

A
  • hyperparathyroid bone disease
  • rare
  • excess osteoclastic bone resorption secondary to high PTH
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16
Q

TREATMENT OF OSTEITIS FIBROSA CYSTICA (HYPERPARATHYROID BONE DISEASE)

A

Hyperphosphataemia

  • Low phosphate diet
  • Phosphate binders – reduce GI phosphate absorption

Alphacalcidol – ie calcitriol analogues (They cannot hydroxylase vit D so you have to give them the active form)

Parathyroidectomy in tertiary hyperparathyroidism
- Indicated for hypercalcaemia &/or hyperparathyroid bone disease

17
Q

Osteoporosis

A
  • Loss of bony trabeculae, reduced bone mass, weaker bone predisposed to fracture after minimal trauma
  • With age, everyone has a reduction in bone mass.
  • In women, there is a fast drop in bone mass in menopause if not on HRT (can even be 30%)
  • increased risk of fractures
18
Q

What is the structural feature of bone in osteoporosis? What is the visible defect?

A
  • fewer trabeculae

- also thinner?

19
Q

Diagnosis definition of osteoporosis

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 lower)
  • BMD predicts future fracture risk
  • FRAX tool is also useful
20
Q

How do you measure bone density?

A
  • Dual Energy X-ray Absorptiometry (DEXA) - femoral neck and lumbar spine
  • Mineral (calcium) content of bone measured, the more mineral, the greater the bone density (bone mass)
  • Involves radiation
  • Measure two areas (femoral neck and lumbar spine)
  • Machine measures calcium density in bone
  • Plot the patients T-score on the graph.
21
Q

What is a T-score? What is a z-score?

A
  • T-score compares to the bone of a 20/25 year old

- z-score is a comparison for the age matched normal

22
Q

What are the similarities and differences in osteoporosis and osteomalacia?

A
  • Both predispose to fracture!!

OSTEOMALACIA

  • Vitamin D deficiency (adults) causing inadequately mineralised bone
  • Serum biochemistry ABNORMAL (low 25(OH) vit D, low/low N Ca2+, high PTH (2o hyperparathyroidism)

OSTEOPOROSIS

  • Bone reabsorption exceeds formation
  • osteoclasts are more active than osteoblasts, you’re not making enough bone (can be high or low turnover)
  • Decreased bone MASS
  • Serum biochemistry NORMAL
  • Diagnosis via DEXA scan
  • no pain in osteoporosis
23
Q

PRE-DISPOSING 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) eg osteoblast senescence
- as we age, osteoblasts become more active

Hypogonadism in young women and in men

Endocrine conditions

  • Cushing’s syndrome
  • Hyperthyroidism
  • Primary hyperparathyroidism

Iatrogenic

  • Prolonged use of glucocorticoids (Steroids can predispose you to reduction of bone density)
  • Heparin
24
Q

What are the consequences of hip fractures?

A
  • have a major impact on life
  • e.g. permanent disabiilty
  • e.g. inability to carry out at least one daily activity
  • e.g. unable to walk independently
  • e.g. death within 1 year (20%)
25
Q

Treatment options for osteoporosis

A
  • Oestrogen/Selective Oestrogen Receptor Modulators
  • Bisphosphonates
  • Denosumab
  • Teriparatide
  • HRT in menopausal women
26
Q

OESTROGEN (HRT) as treatment of osteoporosis

A

Treatment of post-menopausal women with pharmacological doses of oestrogen

  • Anti-resorptive effects on the skeleton
  • Prevents bone loss

Women with an intact uterus need additional progestogen to prevent endometrial hyperplasia/cancer

Use limited largely due to concerns re:

  • Increased risk of breast cancer
  • Venous thromboembolism
  • not a long term option
  • You can give it for a few years but not too long because of increased risk of breast cancer
  • Not a long term solution for post-menopausal osteoporosis
27
Q

BISPHOSPHONATES as a treatment of osteoporosis

A
  • Bind avidly to hydroxyapatite and ingested by osteoclasts – impair ability of osteoclasts to reabsorb bone
  • Decrease osteoclast progenitor development and recruitment
  • Promote osteoclast apoptosis (programmed cell death) -> osteoclasts are paralysed which is good because we want to tip the balance towards bone formation.
    Net result = reduced bone turnover
28
Q

In what conditions are bisohosphonates used?

A
  • Osteoporosis – first line treatment
  • Malignancy
    - Associated hypercalcaemia
    - Reduce bone pain from metastases
    - Helps with pain from bone metastases which are very painful and they can make the calcium levels normal again.
  • Paget’s disease – reduce bony pain
  • Severe hypercalcaemic emergency – i.v. initially (+++ re-hydration first)
29
Q

Pharmacokinetics of bisphosphonates

A
  • Orally active but poorly absorbed; take on an empty stomach (food, especially milk, reduces drug absorption generally)
  • Accumulates at site of bone mineralisation and remains part of bone until it is resorbed - months, years
  • > sometimes compliance is not great
  • Causes dyspepsia,
  • Too effective? Can paralyse osteoclasts for years. In younger patients – what does that do?
30
Q

UNWANTED ACTIONS OF BISPHOSPHONATES

A

Oesophagitis
- may require switch from oral to iv preparation

Osteonecrosis of the jaw
- greatest risk in cancer patients receiving iv bisphosphonates

Atypical fractures
- may reflect over-suppression of bone remodelling in prolonged bisphosphonate use

  • Makes bone adynamic
  • Small risk of necrosis of bone
  • Ask about dental surgery, get that done first before they are started on bisphosphonates
31
Q

DENOSUMAB

A
  • Human monoclonal antibody
  • Binds RANKL, inhibiting osteoclast formation and activity
  • Hence inhibits osteoclast-mediated bone resorption
  • SC injection 6/12ly
  • 2nd line to bisphosphonates
32
Q

What is the difference in how denosumab and bisphosphonates work?

A
  • denosumab: inhibits activation of osteoclasts by binding RANKL
  • bisphosphonates kills (promotes apoptosis) of osteoclasts
33
Q

TERIPARATIDE as osteoporosis treatment

A
  • Recombinant PTH fragment - amino-terminal 34 amino acids of native PTH
  • Increases bone formation and bone resorption, but formation outweighs resorption
  • 3rd line treatment for osteoporosis
  • Daily s.c. injection
  • very expensive!!!

=> balance is tipped in favour of bone formation

34
Q

Paget’s disease of bone

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
  • > BONE FRAILTY
  • > BONE HYPERTROPHY & DEFORMITY
  • usually affects one bone
  • There are some very busy osteoclasts
  • Bone looks abnormal and it is mechanically weak (not mechanically strong, cannot withhold stress)
35
Q

Etymology of Paget’s disease of bone

A
  • Often positive family history – ? genetic cause
  • ?Evidence for viral origin (e.g. measles virus)
  • Prevalence
    • Highest in UK, N America, Australia and NZ
    • Lowest in Asian and Scandinavia
    • unequal prevalence in the world
    • Men and women affected equally
  • Disease usually not apparent under age 50y (in general it is a disease of the elderly)
  • Most patients are ASYMPTOMATIC!!!
  • Characterised by abnormal, large osteoclasts – excessive in number
36
Q

Clinical features of Paget’s disease of bone

A
  • Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected
  • Arthritis
  • Fracture (bone is not mechanically strong)
  • Pain
  • Bone deformity
  • Increased vascularity (warmth over affected bone)
  • Deafness – cochlear involvement
  • Radiculopathy – due to nerve compression, nerve root (pinched nerve)
37
Q

How do you diagnose Paget’s disease of bone?

A
  • normal plasma calcium
  • alkaline phosphatase is usually increased
  • plain x-rays: Lytic lesions (early), thickened, enlarged, deformed bones (later)
  • Radionuclide bone scan demonstrates extent of skeletal involvement
  • ALKALINE PHOSPHATASE high bone enzyme, busy in remodelling -> EXAM relevant.
38
Q

Alkaline phosphatase in bone

A

ALKALINE PHOSPHATASE high bone enzyme, busy in remodelling -> EXAM relevant.

39
Q

What are the treatment options in Paget’s disease of bone?

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

Year 2 - LCRS - Endocrinology (18 decks)

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