Endo 13 - Endocrine and Metabolic Bone disorders

Question 1

In primary HPT, there is high Ca and high PTH. Why?

Answer 1

No negative feedback (i.e. autonomous PTH secretion despite hypercalcaemia)

Removal of adenoma is how it is treated

Question 2

Describe how secondary HPT may arise

Answer 2

1. Low Ca (often due to Vit D deficiency)
2. PTH increases - to try to normalise serum Ca
3. Secondary HPT - marked by:

High PTH, low/normal Ca

Question 3

What are the biochemical findings in Vit D deficiency

Answer 3

1. Low plasma 25(OH)D3
2. Low plasma Ca (may be normal if secondary hyperparathyroidism developed)
3. Low plasma phosphate
4. High pTH

Question 4

How is vitamin D deficiency treated

Answer 4

Normal renal function:
1. Give 25-hydroxy vitamin D - will be converted into active Vit D via 1a hydroxylase in kidney.

e.g. Ergocalciferol, cholecalciferol

If renal failure:
1. Give alfacalcidol - 1ahydroxycholecalciferol

Question 5

When can Vit D excess occur as a result of?

Answer 5

1. Excessive treatment with active Vit D metabolites e.g. Alfacalcidol
2. Granulomatous diseases - e.g. sarcoidosis, leprosy and TB all have macrophages that produce 1a hydrolyase

Question 6

What can Vit D excess/intoxication lead to

Answer 6

1. Hypercalcaemia

2. Hypercalcuria

Question 7

How are osteoclast precursors stimulated to become activated osteoclasts

Answer 7

Osteoclast precursor must bind to RANKL - stimulates differentiation and fusion (RANKL expressed by osteoblasts/stromal cell)

Question 8

Osteoblasts contain receptors for?

Answer 8

1. PTH

2. Calcitriol (active Vit D)

Question 9

Cortical (hard) and trabecular (soft) bone are both formed in what pattern?

Answer 9

Lamellar pattern - collagen fibrils (type 1) laid in alternating orientations - mechanically strong

Question 10

What are the effects of Vit D deficiency on bone

Answer 10

Causes inadequate mineralisation of newly formed bone matrix (osteoid)

Children - rickets.

1. Cartilage of epiphyseal growth plates and bone
2. Skeletal abnormalities, pain, increased fracture risk, growth retardation

Adults - osteomalacia

1. Occurs after epiphyseal closure
2. Skeletal pain, increased fracture risk, proximal myopathy

Question 11

Normal stresses on abnormal bone can cause insufficiency fractures. What are these known as?

Answer 11

Loosers zones

Waddling gait is typical

Question 12

Tertiary HPT may occur when?

Answer 12

Chronic Kidney disease - low plasma Ca constantly

PT glands constantly producing PTH so they get revved up and start to hypertrophy

Question 13

How can impaired renal function contribute to bone disease

Answer 13

Decreased renal function causes both less active Vit D and also impaired phosphate excretion

Decreased Vit D –> less Ca absorption —> hypocalcaemia –> Less bone mineralisation —> Osteitis fibrosa cystica

Decreased phosphate excretion —> increased plasma phosphate (causes vascular calcification too) —> hypocalcaemia —> increased PTH —-> increased bone resorption —–> osteitis fibrosa cystica

Question 14

What are brown tumours

Answer 14

Radiolucent bone lesions - often as a result of osteitis fibrosa cystica (HPT bone disease)

Question 15

How is osteitis fibrosa cystica treated

Answer 15

1. Low phosphate diet and phosphate binders (reduce GI phosphate absorption) - to treat hyperphosphataemia
2. Alphacalcidol - calcitriol analogues
3. Parathyroidectomy in tertiary HPT

Question 16

Osteoporosis is a reduction in bone mass, weaker bone that is predisposed to fracture after minimal trauma. What type of bone is lost

Answer 16

Loss of bony trabeculae

Question 17

How is osteoporosis defined and diagnosed

Answer 17

<2.5 SD below avg value for young healthy adults on BMD

Question 18

Where is a DEXA scan usually used to measure BMD

Answer 18

Femoral neck and lumbar spine

Question 19

Distinguish between osteoporosis and osteomalacia

Answer 19

Both predispose to fracture

Osteomalacia = ABNORMAL serum biochemistry - it is how it is diagnosed (low 25-Vit-D, low/N calcium, high PTH)

Osteomalacia is caused by Vit D deficiency causing inadequately mineralised bone

Osteoporosis = Decreased bone mass, diagnosis via DEXA scan. NORMAL serum biochemistry. Bone resorption exceeds formation

Question 20

What are the predisposing conditions for osteoporosis

Answer 20

1. Postmenopausal oestrogen deficiency
2. Age related deficiency in bone homeostasis - e.g. osteoblast senescence
3. Hypogonadism
4. Endocrine conditions (e.g. Cushings, hyperthyroidism, primary HPT)
5. Iatrogenic - e.g. prolonged use of glucocorticoids, heparin

Question 21

What are the treatments for osteoporosis

Answer 21

1. Oestrogen
2. Bisphosphates
3. Denosumab
4. Teriparatide

Question 22

Describe the use of oestrogen (HRT) to treat osteoporosis

Answer 22

Has anti-resorptive effects on bone - less bone loss

BUT women with intact uterus need to be given progestogen to prevent endometrial hyperplasia/cancer

Limited use due to:
Increased risk of breast cancer and venous thromboembolism

Question 23

Describe the use of bisphosphonates to treat osteoporosis (main treatment - firstline)

Answer 23

They bind avidly to hydroxyapatite crystals - which are 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 24

What are the medical uses of bisphosphonates

Answer 24

1. Osteoporosis
2. Malignancy
3. Pagets disease
4. Severe hypercalcaemic emergency

Question 25

Describe the pharmacokinetics of bisphosphonates

Answer 25

1. Orally active but poorly absorbed - must be taken on empty stomach
2. Accumulates at site of bone mineralisation - remains part of bone until it is resorbed

Question 26

What are the unwanted actions of bisphosphonates

Answer 26

1. Oesophagitis (may require switch from oral to IV prep)
2. Osteonecrosis of the jaw
3. Atypical fractures due to unusual remodelling pattern

Question 27

Explain the use of denosumab (2nd line treatment for osteoporosis)

Answer 27

1. Human monoclonal antibody - binds to RANKL and inhibits osteoclast formation and activity
2. Therefore, bone resorption inhibited
3. Subcutaneous injection every 6 months

Question 28

Describe the use of teriparatide

Answer 28

1. Recombinant PTH fragment
2. Increases bone formation and bone resorption - but formation outweighs resorption
3. 3rd line treatment
4. Daily SC injection

Question 29

Explain Paget’s disease

Answer 29

Excessive bone resorption (osteoclastic overactivity) followed by compensatory increase in bone formation (osteoblast)

It is an accelerated, localised process, but disorganised bone remodelling

Woven bone formed instead of lamellar (lamellar = strong)

Woven bone is structurally disorganised and mechanically weaker than lamellar bone

Paget’s associated with bone frailty and hypertrophy / deformity

Question 30

What is Paget’s characterised by

Answer 30

Abnormal, large osteoclasts excessive in number (under microscope)

Question 31

What are the clinical features of Paget’s disease

Answer 31

Skull, thoracolumbar spine, pelvis, femur and tibia most affected

Can cause bone pain, bone fracture and bone deformity

May also cause warmth over affected area, deafness (if bones of ear), nerve compression

Question 32

What is the biochemical hallmark of Paget’s disease

Answer 32

Increased alkaline phosphatase

(plasma Ca normal)

Radionuclide bone scan very useful - demonstrates extent of skeletal involvement

Question 33

What are the treatment options for Pagets

Answer 33

1. Bisphosphonates - reduced bony pain and disease activity

2. Simple analgesia