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Endocrinology > 13. Endocrine and metabolic bone disorders > Flashcards

13. Endocrine and metabolic bone disorders Flashcards

1
Q

What are the two components to bone?

A
  • Osteoid - organic component, unmineralised bone, type 1 collagen
  • Calcium hydroxyapatite crystals - inorganic component, fills the space between collagen fibrils
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2
Q

What are osteoblasts and osteoclasts?

A
  • Osteoblasts - synthesise bone, mineralisation of osteoid

* Osteoclasts - bone resorption, release lysosomal enzymes to break down bone

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3
Q

How does PTH act on bone?

A

(indirect effect on osteoclasts)

  • PTH stimulates osteoblasts to produce various osteoclast activating factors (OAFs) e.g. RANKL
  • OAFs move to the the osteoclasts and stimulate the breakdown of bone matrix
  • Release of Ca
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4
Q

How does the osteoblast activate the osteoclast with regards to RANK?

A
  • RANK ligand (RANKL) expressed on osteoblast surface
  • RANKL binds to RANK receptor (RANK-R) on osteoclast precursor
  • Osteoclast becomes activated
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5
Q

What do osteoblasts express receptors for apart from those for PTH?

A

Receptors for calcitriol (1,25(OH)2D3)

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6
Q

How is the outside of bone different to the inside?

A
  • Outside - hard, cortical bone

* Inside - spongy, trabecular bone

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7
Q

What pattern is bone formed in?

A
  • Lamellar pattern
  • Collagen fibrils laid down in altering orientation
  • Most mechanical strength possible
  • ‘Woven bone’ is also a type, but it is weaker
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8
Q

Compare rickets to osteomalacia

A

Rickets
• Affects cartilage of epiphysial growth plates and bone
• Skeletal abnormalities (tibia bowing)
• Skeletal pain, growth retardation, increased fracture risk

Osteomalacia
• After epiphyseal closure, affects bone
• Skeletal pain, increased fracture risk, proximal myopathy
• Don’t get the same bony deformities seen in rickets

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9
Q

What are the typical bone effects of severe vitamin D deficiency?

A
  • Normally where there it is a lot of bone loading
  • Insufficiency fractures at looser zones
  • ‘Waddling gait’ due to pain from abnormal pelvis fractures
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10
Q

How does kidney failure affect the bones?

A
  • Calcitriol cannot be made - calcium isn’t absorbed from the gut well = hypocalcaemia
  • Kidneys can’t excrete phosphate - increased serum phosphate - phosphate binds to calcium = decreased bioavailable serum calcium
  • Inadequate bone mineralisation = osteitis fibrosa cystica (rare disease)
  • Increased PTH release as a response to low calcium - this increases bone resorption (breakdown) = osteitis fibrosa cystica
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11
Q

What affect can high serum phosphate have on blood vessels?

A

• Vascular calcificaiton

• high rate of macrovascular disease in kidney failure, partly due to phosphate that can’t be excreted

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12
Q

How can osteitis fibrosa cystica be treated?

A
  • Treat hyperphosphataemia - low phosphate diet, phosphate binders (reduce GI phosphate absorption by collating phosphate on the gut)
  • Alphacalcidol - calcitriol analogues (must be active vitamin D)
  • Parathyroidectomy (in 3°)
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13
Q

What is osteoporosis?

A
  • Reduction in bone mass
  • Loss of bony trabeculae - weaker bone - predisposed to fracture after minimal trauma
  • Everyone becomes osteoporotic with age
  • Problem especially in post-menopausal women
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14
Q

How do you measure if someone has osteoporosis?

A
  • Measure bone mineral density (predicts fracture risk)
  • Use DEXA scan (dual energy x-ray absorptiometry)
  • Scan the femoral neck and lumbar spine
  • Looks at mineral (calcium) content of bone
  • BMD of >2.5 SD below the average (T-score) shows osteoporosis
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15
Q

How is osteoporosis different to osteomalacia?

A
  • Unbalanced bone formation in osteoporosis, inadequate mineralisation due to serum biochemistry in osteomalacia
  • Serum biochemistry is normal in osteoporosis
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16
Q

What are the pre-disposing conditions for osteoporosis?

A
  • Post-menopausal oestrogen deficiency (loss of bone matrix)
  • Age-related deficiency in bone homeostasis e.g. osteoblast senescence
  • Hypogonadism
  • Endocrine conditions e.g. Cushing’s
  • Iatrogenic - prolonged use of glucocorticoids, heparin
17
Q

How can osteoporosis be treated?

A
  • Oestrogen/selective receptor modulators
  • Bisphosphonates
  • Denosumab
  • Teriparatide
18
Q

What is the effect of oestrogen (HRT) on women?

A
  • Anti-resorptive effects on bone - prevents bone loss
  • Women with an intact uterus need additional progesterone to prevent endometrial hyperplasia/cancer
  • Use limited due to increased risk of breast cancer and VTE
19
Q

How are selective oestrogen receptor modulators (SERMS) used in treating osteoporosis?

A

1) Tissue selective ER antagonist 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 e.g. raloxifene (further developed)
• Oestrogenic activity in bone, and anti-oestrogenic at breast and uterus
• Reduces breast cancer risk but still increased risk of VTE

20
Q

How are bisphosphonates used in treating osteoporosis?

A
  • First line treatment
  • Bind to hydroxyapaptite and ingested by osteoclasts - impair ability of osteoclasts to resorb bone
  • Decrease osteoclast progenitor development and recruitment
  • Promote osteoclast apoptosis
  • Also stop osteoclasts from forming a ruffled border / secreting enzymes to resorb bone
  • Net result = reduced bone turnover
21
Q

What can bisphosphonates be used for apart from osteoporosis?

A
  • Malignancy associated with hypercalcaemia (reduces bone pain)
  • Paget’s disease - reduces bone pain
  • Severe hypercalcaemic emergency (but after re-hydration)
22
Q

Why should you take bisphosphonates on an empty stomach?

A

Even though they are orally active - poorly absorbed

23
Q

How long can bisphosphonates remain at the site of bone mineralisation?

A
  • Stay until resorbed

* Can be months, years

24
Q

What are the unwanted actions of bisphosphonates?

A

• Oesophagitis (heart burn)
• Osteonecrosis of the jaw - greatest risk in cancer patients receiving IV
• Atypical fractures - over-suppression of bone remodelling
- make bone more brittle
- prevents microfractures from being repaired

Patients can be given a ‘bisphosphonate holiday’ for recovery from treatment

25
Q

What is denosumab and how does it work?

A

• Human monoclonal antibody
• Binds RANKL, inhibiting osteoclast activity
- inhibited bone resorption
• Subcutaneous injection every 6 months
• 2nd line to bisphosphonates (mainly due to price)

26
Q

What is teriparatide and how does it work?

A
  • Recombinant parathyroid hormone fragment - amino-terminal 34 amino acids of native PTH
  • Increases bone formation and resorption, but formation outweighs resorption
  • Daily subcutaneous injection
  • 3rd line treatment
  • Very expensive
27
Q

What is Paget’s disease, and outline the cause and prevalence?

A

• Accelerated, localised but disorganised bone remodelling
• Excessive bone resorption (osteoclastic over-activity) followed by a compensatory increase in bone formation
- woven, disorganised, weak
• Evidence for viral origin
• Most patients are asymptomatic
• Characterised by abnormal, large osteoclasts

28
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
  • Radiculopathy - due to nerve compression
29
Q

How can Paget’s disease be diagnosed?

A
  • Normal plasma [Ca2+]
  • Increased plasma [alkaline phosphatase] - bone isoenzymes
  • X-rays - early lytic lesions, later thickening, enlargement and deformities
  • Radionuclide bone scan can demonstrate extent of skeletal involvement
30
Q

How can Paget’s disease be treated?

A
  • Bisphosphonates

* Simple analgesia

Endocrinology (17 decks)

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