Endocrine + metabolic bone disorders

Question 1

How does renal dysfunction lead to bone disease?

Answer 1

• Decreased renal function
• Decreased calcitriol production + decreased phosphate excretion
• Decreased Ca absorption + increased plasma [phosphate]
• Both lead to hypocalcaemia
• Decreased bone mineralisation –> osteitis fibrosa cystica
• Increased [PTH] –> increased bone resorption
• Extra-skeletal calcification due to increased plasma [phosphate]

Question 2

What is osteoporosis?

Answer 2

Bone mineral density that is 2.5 SDs or more below the average value for young healthy adults
- Usually referred to as a T-score of -2.5 or lower

Question 3

What are the risk factors for osteoporosis?

Answer 3

1. Post-menopausal oestrogen deficiency
   - Leads to loss of bone matrix
2. Age-related deficiency in bone homeostasis
   - E.g. osteoblast senscence
3. Hypogonadism in men + young women
4. Endocrine conditions
   - Cushing’s syndrome
   - Hyperthyroidism
   - Primary hyperparathyroidism
5. Iatrogenic
   - Prolonged use of glucocorticoids
   - Heparin

Question 4

How can osteoporosis be treated?

Answer 4

• Oestrogen/SERMs
• Bisphosphonates
• Denusomab
• Teriparatide

Question 5

What is Paget’s disease?

Answer 5

• Accelerated, localised but disorganised bone remodelling

- Excessive bone resorption (osteoclast overactivity) followed by compensatory increase in bone formation (osteoblasts)

Question 6

What are the biochemical features of Paget’s disease?

Answer 6

• Normal plasma [Ca]

- Increased plasma [alkaline phosphate]

Question 7

What are the radiological features of Paget’s disease?

Answer 7

• Early - lytic lesions

- Later - thickened, enlarged, deformed bones

Question 8

How can Paget’s disease be treated?

Answer 8

• Bisphosphonates - reduce bony pain + disease activity

- Simple analgesia

Question 9

What are the clinical features of Paget’s disease?

Answer 9

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

Question 10

How does oestrogen (HRT) help treat osteoporosis?

Answer 10

• Treatment in post-menopausal women w/pharmacological doses of oestrogen
• Anti-resorptive effect on skeleton
• Prevents bone loss

Question 11

How do SERMs help treat osteoporosis?

Answer 11

Selective oestrogen receptor modulators

1. Tissue-selective ER antagonists/anti-oestrogens
   - Antagonise ERs in breast (bad)
   - Oestrogenic activity in bone (good)
   - Oestrogenic effects on endometrium (bad)
2. Tissue-selective ER agonists
   - Oestrogenic activity in bone (good)
   - Anti-oestrogenic activiyy in breast + uterus (good)

Question 12

How do bisphosphonates help treat osteoporosis?

Answer 12

1st line treatment

• Analogues of pyrophosphate
• Bind avidly to hydroxyapatite + ingested by osteoclasts
• Impairs ability of osteoclasts to resorb bone
• Decreased progenitor development + recruitment
• Promotes osteoclast apoptosis
• REDUCE BONE TURNOVER

Question 13

What is used as 1st line treatment for osteoporosis?

Answer 13

Bisphosphonates - reduce bone turnover

Question 14

How does denosumab help treat osteoporosis?

Answer 14

• Human monoclonal antibody
• Binds to RANKL + inhibits osteoclast formation + activity
• 2nd line treatment

Question 15

How does teriparatide help treat osteoporosis?

Answer 15

• Recombinant PTH fragment - terminal 34AAs of native PTH
• Increases bone formation + bone resorption, but formation outweighs resorption
• 3rd line