Endocrine and metabolic bone disorders

Question 1

What proportion of the body’s calcium is stored in the bone

Answer 1

> 95%

Question 2

What components is bone made of

Answer 2

Organic compound (35%) - osteoid, unmineralised bone 
Type 1 collagen - 95%

Inorganic compound (65%) -Calcium hydroxyapatite crystals fill the space between collagen fibrils

Question 3

Which cells are found in the bone

Answer 3

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

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

Question 4

What is bone remodelling

Answer 4

Osteoblasts -> osteoblasts

Dynamic process

Question 5

Describe the process of osteoclast differentiation

Answer 5

1. RANKL expressed on osteoblast surface
2. RANKL binds to RANK-R to situlate osteoclast formation and activity
3. Osteoblasts express PTH and calcitriol receptors to regulate between formation and resorption

Question 6

What are the types of bone

Answer 6

Cortical - hard

Trabecular - spongy or trabecular

Question 7

In which pattern is cortical and trabecular formed

Answer 7

Lamellar pattern - collagen fibrils laid down in alternating orientations
Mechanically strong

Question 8

Describe woven bone

Answer 8

Disorganised collagen fibrils

Weaker

Question 9

What are the effects of vit D deficiency on bone

Answer 9

Inadequate mineralisation of newly formed bone matrix (osteoid)
Normal stresses on abnormal bone cause insufficiency fractures - Looser zones
Waddling gait - typical

Question 10

What are the effects of vit D deficiency on bone in children

Answer 10

Rickets
affects cartilage of epiphysial growth plates and bone
skeletal abnormalities and pain, growth retardation, increased fracture risk

Question 11

What are the effects of vit D deficiency on bone in adults

Answer 11

Osteomalacia
after epiphyseal closure, affects bone
skeletal pain, increased fracture risk, prox myopathy

Question 12

What could cause the types of hyperparathyroidism

Answer 12

Primary - Adenoma

Secondary - Renal failure, vit D deficiency (low Ca)

Tertiary - autonomous parathyroids (chronic low plasma Ca)

Question 13

Draw a diagram to show how renal failure can cause bone disease

Answer 13

1. Reduce phosphate excretion leads to greater plasma levels -> Vascular calcification
2. Reduced calcitriol and Ca absorption
3. Hypocalcaemia
4. Increased PTH and reduced bone mineralisation
5. Bone resorption increase from PTH
6. osteitis fibrosa cystica

Question 14

Describe osteitis fibrosa cystica

Answer 14

Hyperparathyroid bone disease
Rare
XS osteoclastic bone resorption secondary to high PTH
Characteristic = brown tumours

Question 15

What is treatment for osteitis fibrosa cystica

Answer 15

Hyperphosphataemia
Low phosphate diet
Phosphate binders – reduce GI phosphate absorption

Alphacalcidol – ie calcitriol analogues

Parathyroidectomy in 3 hyperparathyroidism
Indicated for hypercalcaemia or hyperparathyroid bone disease

Question 16

Describe osteoporosis

Answer 16

Loss of bony trabeculae, reduced bone mass, weaker bone predisposed to fracture after minimal trauma

Question 17

What is the significance of BMD in osteoporosis

Answer 17

Bone mineral density (BMD) > 2.5 standard deviations below the average value for young healthy adults (T-score < -2.5)
BMD predicts future fracture risk

Question 18

How is BMD measured

Answer 18

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)

Question 19

Compare osteoporosis to osteomalacia

Answer 19

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
Decreased bone MASS
Serum biochemistry normal
Diagnosis via DEXA scan

Question 20

What are the pre-disposing conditions for osteoporosis

Answer 20

Postmenopausal oestrogen deficiency
Age-related deficiency in bone homeostasis (eg osteoblast senescence)
Hypogonadism in young women and in men
Endocrine conditions
Iatrogenic

Question 21

How does postmenopausal oestrogen deficiency lead to osteoporosis

Answer 21

Oestrogen deficiency leads to a loss of bone matrix

Subsequent increased risk of fracture

Question 22

Which endocrine disorders can lead to osteoporosis

Answer 22

Cushing’s syndrome
Hyperthyroidism
Primary hyperparathyroidism

Question 23

What are the latrogenic pre-disposing conditions for osteoporosis

Answer 23

Prolonged use of glucocorticoids

Heparin

Question 24

What are the treatment options for osteoporosis

Answer 24

Oestrogen/Selective Oestrogen Receptor Modulators
Bisphosphonates
Denosumab
Teriparatide

Question 25

What is the treatment in post-menopausal women for osteoporosis and what is required for women with an intact uterus

Answer 25

Oestrogen doses Anti-resorptive effects on the skeleton Prevents bone loss Intact uterus - additional progestogen to prevent endometrial hyperplasia/cancer

Question 26

Why is oestrogen use limited

Answer 26

Increased risk of breast cancer | Venous thromboembolism

Question 27

What is the mechanism of action for bisphosphonates

Answer 27

Binds avidly to hydroxyapatite and ingested by osteoclasts - impairs ability of osteoclasts to reabsorb bone Decrease osteoclast progenitor development and recruitment Promote osteoclast apoptosis Net result = reduced bone turnover.

Question 28

What are the uses of bisphosphonates

Answer 28

Osteoporosis – first line treatment Malignancy - Associated hypercalcaemia, reduce bone pain from metastases Paget’s disease – reduce bony pain Severe hypercalcaemic emergency – i.v. initially (+++ re-hydration first)

Question 29

Describe the pharmacokinetics of bisphosphonates

Answer 29

Orally active but poorly absorbed - take on an empty stomach Accumulates at site of bone mineralisation and remains part of bone until it is resorbed - months, years

Question 30

What are the unwanted actions of bisphosphoantes

Answer 30

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

Question 31

Describe denosumab

Answer 31

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

Question 32

Describe teriparatide

Answer 32

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 Expensive

Question 33

What is Paget's disease

Answer 33

Accelerated, localised but disorganised bone remodelling Excessive bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts) New bone = woven which is disorganised and weaker Leads to bone hypertrophy, deformity and frailty Characterised by abnormal, large osteoclasts

Question 34

Describe the epidemics of Paget's disease

Answer 34

``` Often family history positive Viral origin Highest in UK, N. America, Australia and NZ Lowest in Asian and Scandinavia Disease not apparent under 50 Asymptomatic ```

Question 35

What are the clinical features of Paget's disease

Answer 35

``` Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected Arthritis Fracture Pain Bone deformity Increased vascularity (warmth over affected bone) Deafness – cochlear involvement Radiculopathy – due to nerve compression ```

Question 36

How is Paget's disease diagnosed

Answer 36

Normal plasma Ca Plasma alkaline phosphatase increased Plain X-rays = lytic lesions (early) -> thickened enlarged deformed bones Radionucleotide bone scan demonstrates extend of skeletal movement

Question 37

What are the treatment options of Paget's disease

Answer 37

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