Endocrine and metabolic bone disorders

Question 1

What are the two components of bone?

Answer 1

Organic components, (osteoid – unmineralised bone)
(35% bone mass), Type 1 collagen fibres (95%)

Inorganic mineral component (65% bone mass), Calcium hydroxyapatite crystals fill the space between collagen fibrils

Question 2

Describe the two types of cell related to bone formation and resorption?

Answer 2

Osteoblasts- synthesise osteoid and participate in mineralisation/calcification of osteoid
Osteoclasts-release lysosomal enzymes which break down bone

Question 3

Describe how osteoclasts are activated?

Answer 3

Osteoblasts express RANK-L on their surface and this binds to RANK-R on osteoclasts to activate them.

Question 4

Describe 2 types of bones?

Answer 4

You have cortical bone which is hard bone found on the outside and trabecular bone which is spongy bone found on the inside. They both have lamellar patterns where collagen fibrils are laid down in and organised alternating orientation.

Question 5

Describe difference between rickets and osteomalisia.

Answer 5

Rickets is in children and affects cartilage of epiphysial growth plates and bone. Osteomalasia is in adults and arises after epiphyseal closure and affects bone.

Question 6

Describe symptoms of vitamin D deficiency state?

Answer 6

Rickets- skeletal abnormalities and pain, growth retardation, increased fracture risk.
Osteomalsia- skeletal pain, increased fracture risk, proximal myopathy
Looser zones are common to both- normal stresses on abnormal bone cause insufficiency fractures

Question 7

Describe the pathophysiology of the 3 types of hyperparathyroidism?

Answer 7

Primary due to parathyroid tumour driving PTH secretion, secondary due to low calcium levels prompting PTH secretion, tertiary when PTH levels have been elevated for so long due to low calcium when calcium is corrected PTH level remain autonomously high.

Question 8

Describe pathophysiology of osteitis fibrosa cystica?

Answer 8

Otherwise called hyperparathyroid disease…you get excess osteoclastic bone resorption 2o to high PTH.
Identified on X rays by translucent lesions called brown tumours.

Question 9

Describe treatment of OFC?

Answer 9

Low phosphate diet
Phosphate binders – reduce GI phosphate absorption
Alphacalcidol – ie calcitriol analogues
Parathyroidectomy in 3o hyperparathyroidism

Question 10

How is osteoporosis diagnosed?

Answer 10

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).
You do a DEXA scan which measures the mineral content of the neck and femoral spine.

Question 11

What are the differences between osteoporosis and osteomalcia?

Answer 11

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

Question 12

What are pre-disposing factors that put you at risk of developing osteoporosis?

Answer 12

Postmenopausal oestrogen deficiency
Age-related deficiency in bone homeostasis (men and women) eg osteoblast senescence
Hypogonadism in young women and in men
Cushing’s syndrome
Hyperthyroidism
Primary hyperparathyroidism
Prolonged use of glucocorticoids
Heparin

Question 13

Name 4 drugs used to treat osteoporosis?

Answer 13

Oestrogen
Bisphosphonates
Denosumab
Teriparatide

Question 14

Why is oestrogen used?

Answer 14

Treatment of post-menopausal women with pharmacological doses of oestrogen

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

Question 15

What are risk factors of using oestrogen?

Answer 15

• Increased risk of breast cancer
• Venous thromboembolism
• Endometrial hyperplasia-women put on progesterone to lessen this risk alongside.

Question 16

Describe bisphosphonates method of action?

Answer 16

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)
Net result = reduced bone turnover.

Question 17

Describe pharmacokinetics of bisphosphonates?

Answer 17

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

Question 18

Describe side effects of bisphosphonates?

Answer 18

Osteophagitis, osteonecrosis of the jaw, atypical fractures due to suppression of remodelling in prolonged use.

Question 19

Describe the method of action of Denosumab?

Answer 19

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 20

Describe method of action of Teriparatide?

Answer 20

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 21

Describe pathophysiology of Paget’s disease?

Answer 21

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

Question 22

Describe epidemiology of Paget’s disease?

Answer 22

Often positive family history
Evidence for viral origin (e.g. measles virus)
Highest in UK, N America, Australia and NZ
Lowest in Asian and Scandinavia
Men and women affected equally
Disease usually not apparent under age 50y
Most patients are asymptomatic

Question 23

Describe clinical features of Paget’s disease?

Answer 23

Arthritis
Fracture
Pain
Bone deformity
Increased vascularity  (warmth over affected bone) 
Deafness – cochlear involvement
Radiculopathy – due to nerve compression

Question 24

Describe diagnosis of Paget’s disease?

Answer 24

Plasma [Ca2+] normal
Plasma [alkaline phosphatase] usually increased
Plain x rays = you get Lytic lesion (thickened deformed bone)

Question 25

Describe treatment of Paget’s disease?

Answer 25

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