Endo 14: Endocrine and metaboic bone disorders

Question 1

Outline component of bone

Answer 1

Organic components
(osteoid – unmineralised bone)
(35% bone mass)

Inorganic mineral component
(65% bone mass)

Question 2

Outline composition of organic and inorganic component of bone

Answer 2

Organic: Type 1 collagen fibres (95%)

Inorganic: Calcium hydroxyapatite crystals
fill the space between collagen fibrils

Question 3

Function of osteoblast

Answer 3

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

Question 4

Function of osteoclast

Answer 4

Osteoclasts

release lysosomal enzymes
which break down bone
bone resorption

Question 5

How do you activate an osteoclast

Answer 5

The osteoclast must recognise RANKL expressed on osteoblast/stromal cell by its RANK receptor

Question 6

T/f Osteoclasts contain RANKL

Answer 6

False, osteoblasts do

Question 7

How do osteoblasts regulate balance between been formation and resorption

Answer 7

Osteoblasts express receptors for PTH & calcitriol (1,25 (OH)2 vit D) in response to which RANKL expression can be altered

Question 8

Differentiate type of bone

Answer 8

Cortical (hard) bone… around side

Trabecular (spongy or trabecular) bone

Question 9

Outline formation of normal bone

Answer 9

collagen fibrils laid down in alternating orientations, mechanically strong and then mineralisation occurs

Question 10

What is woven bone

Answer 10

Woven bone – disorganised collagen fibrils, weaker

Question 11

Effect of vitamin D deficiency on bone… in

Children
Adults

Answer 11

Inadequate mineralisation of newly formed bone matrix (osteoid)

Children: RICKETS:

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

Adults: OSTEOMALACIA

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

Question 12

What is a looser zone and where does this occur

Answer 12

Normal stresses on abnormal bone cause insufficiency fractures…..

femur and pelvis

Question 13

What is a symptom of vitamin D deficiency on bone

Answer 13

Waddling gait - typical

Looser zones

Question 14

Differentiate 1o, 2o and 3o hyperparathyroidism

Answer 14

1o- lack of -ve feedback

2o- vit D defic or renal failure

3o- parathyroids revved up due to kidney failure for example (because not enough vit D) and stay revved up even after kidney failure cured

Question 15

Effect of renal failure on bone disease

Answer 15

Can’t make calcitriol, not enough Ca2+ reabsorption, hypocalcaemia, less bone mineralisation

If kideys aren’t working, you can’t excrete phosphate, so increased phosphate (which binds calcium and reduces free calcium in blood) so hypocalcaemia, so high PTH so bone resoprtion of Ca2+ (active osteoclasts).

These 2 combined= OSTEITIS FIBROSA CYSTICA

Increased plasma PO43- leads to VASCULAR CALCIFICATION (bad for heart)

Question 16

What is Osteitis fibrosa cystica what is it caused by and what is seen radiologically

Answer 16

Due to hyperparathyroid bone disease

XS osteoclastic bone resorption secondary to high PTH- Peppered skull

‘Brown tumours’ = radiolucent bone lesions

Question 17

How is osteitis fibrosa cystica treated

Answer 17

Hyperphosphataemia

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

Alphacalcidol – ie calcitriol analogues

Parathyroidectomy in 3o hyperparathyroidism
-Indicated for hypercalcaemia and/or hyperparathyroid bone disease

Question 18

What is osteoporosis

Answer 18

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

Question 19

How is osteoporosis classified

Answer 19

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)

Question 20

What does bone mineral density predict

Answer 20

Fracture risk

Question 21

How is BMD measured

Answer 21

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 22

Differentiate osteomalacia and osteoporosis biochemistry

Answer 22

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 23

What predisposes you to osteoporosis

Answer 23

Postmenopausal oestrogen deficiency

• Oestrogen deficiency leads to a loss of bone matrix
• Subsequent increased risk of fracture

Question 24

Other pre-disposig conditions for osteoporosis

Answer 24

Postmenopausal oestrogen deficiency

Age-related deficiency in bone homeostasis (men and women) due to osteoblast senescence

Hypogonadism in young women and in men

Endocrine conditions

• Cushing’s syndrome
• Hyperthyroidism
• Primary hyperparathyroidism

Iatrogenic

• Prolonged use of glucocorticoids (i.e. not for replacement, for high GC dose for immunosupression i.e. rheumatoid)
• Heparin

Question 25

Treatment for osteoporosis

Answer 25

Oestrogen/Selective Estrogen Receptor Modulators (SERMs..... also used for contraceptive) Bisphosphonates Denosumab Teriparatide

Question 26

Outline treatment of oestrogen for osteoporosis

Answer 26

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

Question 27

Outline treatment of osteoporosis with bisphosphonates

Answer 27

Bind avidly to hydroxyapatite and ingested by osteoclasts – impair ability of osteoclasts to resorb bone Decrease osteoclast progenitor development and recruitment Promote osteoclast apoptosis (programmed cell death) Net result = reduced bone turnover.

Question 28

Use 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

Pharmacokinetics of bisphosphnates

Answer 29

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 Oral (or IV if oesophagitis)

Question 30

Unwanted action of bisphonates

Answer 30

Oesophagitis - may require switch from oral to iv preparation Osteonecrosis of the jaw - greatest risk in cancer patients receiving iv bisphosphonates to try to reduce their calcium Atypical fractures - may reflect over-suppression of bone remodelling in prolonged bisphosphonate use

Question 31

How does denosumab work

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

What is 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 £££

Question 33

What is pagets disease of bone

Answer 33

Accelerated, localised but disorganised bone remodelling Excessive bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts) .... but the new bone is woven bone

Question 34

Outline woven bone in paget's disease

Answer 34

structurally disorganised mechanically weaker than normal adult lamellar bone

Question 35

Effects of paget's disease on bone

Answer 35

BONE FRAILTY | BONE HYPERTROPHY & DEFORMITY (areas of resorbed bone next to areas of new, disorganised bone)

Question 36

What causes paget's

Answer 36

Maybe genetic..... men and women equally affected Most asymptomatic... characteriesed by absormal, large osteoclasts, excessive in number

Question 37

Clinical features of paget's disease of bone

Answer 37

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 38

Diagnosis of paget's disease

Answer 38

Plasma [Ca2+] normal (as the bone resorption is only in certain areas) *Plasma [alkaline phosphatase] usually increased (from bone not liver, different isoenzyme) Plain x rays = -Lytic lesions (early), thickened, enlarged, deformed bones (later) Radionuclide bone scan demonstrates extent of skeletal involvement

Question 39

Treatment of paget's

Answer 39

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