Endocrinology and Disease of Bone

Question 1

How is vitamin D formed?

Answer 1

25-OH-D synthesized in skin from 7-dehydrocholesterol + UVB

(D3 Cholecalciferol and D2 Ergocalciferol from diet)

Calcidiol (25-OH-D) stored in liver

25-OH-D further hydroxylated in kidney forming

1,25(OH)2D (Active Vitamin D, Calcitriol)
Enzyme = 1 alpha hydroxylase

Question 2

What can stimulate 1-alpha hydroxylase in the kidneys?

Answer 2

PTH (Parathyroid hormone)

Question 3

What is the principle effect of calcitriol?

Answer 3

Increase calcium, magnesium and phosphate absorption in the small intestines

Question 4

What are the other effects of calcitriol?

Answer 4

Increased reabsorption of calcium and decreased phosphate reabsorption in the kidneys (via FGF23)

Stimulates osteoclast formation from precursors

Stimulates osteoblasts to make osteoclast-activating factors (OAFs e.g. RANKL)

Inhibit PTH

Question 5

What does vitamin D deficiency cause? State some symptoms.

Answer 5

Lack of bone mineralisation
Softening of bone (can lead to bowing of the legs) Bone deformities
Bone pain
Severe proximal myopathy

(Rickets in children, osteomalacia in adults)

Question 6

State some causes of vitamin D deficiency.

Answer 6

Inadequate dietary intake 
Lack of sunlight
Receptor defects (rare - autosomal recessive resistant to vitamin D treatment)
Liver or Renal failure 
Gastrointestinal malabsorptive states

Question 7

What is usually measured to gauge the level of calcitriol? What condition must be fulfilled for this to be a good measure of calcitriol?

Answer 7

25-hydroxycholecalciferol

This is only a good measure in the case of normal renal function

Question 8

Describe how you would diagnose vitamin D deficiency.

Answer 8

Plasma Calcium = LOW
Plasma 25-hydroxycholecalciferol = LOW
Plasma PTH = HIGH (secondary hyperparathyroidism stimulated by the hypocalcaemia)
Plasma Phosphate = LOW

Radiological findings e.g. widened osteoid seams

Question 9

What would you expect the plasma phosphate level to be in someone with renal failure and why?

Answer 9

HIGH – because there is a decrease in plasma excretion via the kidneys

Question 10

What would you expect the plasma calcium level to be in someone with renal failure and why?

Answer 10

LOW – because they are not producing as much calcitriol (due to renalfailure interfering with 1-alpha hydroxylase) so there is less calcium absorption in the small intestines

Question 11

What are the consequences of hypocalcaemia caused by renal failure?

Answer 11

There is a decrease in bone mineralisation and an increase in bone resorption (because of an increase in PTH) leading to osteitis fibrosa cystica The imbalance in calcium and phosphate can also lead to the formation of salts that can be deposited in extra-skeletal tissue causing extra-skeletal calcification

Question 12

What can vitamin D excess lead to?

Answer 12

Hypercalcaemia and hypercalciuria (due to increased intestinal absorption of calcium)

Question 13

What can vitamin D excess result from?

Answer 13

Excessive treatment with active metabolites of vitamin D, as in patients with chronic renal failure Granulomatous disease – granulomatous tissue has 1-hydroxylase so it can be a source of ectopic calcitriol

Question 14

What is the action of PTH?

Answer 14

Increase Ca2+ reabsorption from kidney

Increase Ca2+ reabsorption from bone

Increase Calcitriol formation (Regulate 1alpha hydroxylase)

Question 15

How is PTH regulated?

Answer 15

Ca2+ sensing receptor on parathyroid cells inhibits PTH when bound. (Calcium provides negative feedback)

Question 16

How is phosphate regulated?

Answer 16

PCT cell has Na+/PO4 3- co-transporter (absorbs PO43-) PTH inhibits this - increases excretion

FGF23 - Fibroblast growth factor 23 (from osteocytes) also promotes excretion

Calcitriol inhibited by FGF23 to reduce PO43- absorption from gut

Question 17

What are the (broad) effects of hyper and hypo calcaemia?

Answer 17

Hypercalcaemia (>2.6 mmol/L) blocks Na+ influx - less excitability

Hypocalcaemia (<2.2mmol/L) enhances Na+ influx - More excitability

Question 18

What are some consequences of HYPOcalcaemia

Answer 18

CATs go numb: Convulsions, Arrythmias, Tetany, Parathesia

Chvostek’s sign - tap facial nerve below zygomatic arch, positive response = facial muscle twitching positive response indicates neuromuscular irritability

Trousseau’s sign - elevate BP through cuff - positive sign = carpopedal spasm clawed hand

Question 19

What are some causes of hypercalcaemia?

Answer 19

Vitamin D deficient
Low PTH - Surgical, AI (rare) Mg deficiency
PTH resistance - pseudohypoparathyroidism
Renal failure - 1 alpha hydroxylase impairment

Question 20

What are some consequences of HYPERcalcaemia?

Answer 20

Stones, abdo moans and psychic groans

S
Polyuria and thirst
Nephrocalcinosis, renal colic, Chronic renal failure

AM
Anorexia, nausea, dyspesia, constipation, pancreatitis

PG
Fatigue, depression, impaired concentration, altered mentation
Levels above 3mmol/L can cause coma

Question 21

What are some causes of HYPERcalcaemia?

Answer 21

Parathyroid tumour - hyperparathyroidism
Malignant tumour - Ectopic PTH-like peptide
Conditions causing high bone turnover - Hyperthyroidism, Paget’s
Vitamin D intoxication

Question 22

What are some differential diagnoses of hypercalcaemia?

Answer 22

1’ - High Ca2+, High PTH, Low Phosphate

Malignancy - High Ca2+, Low PTH, Low Phosphate

Question 23

How is vitamin D deficiency treated?

Answer 23

Normal renal function - Give 25(OH)D for patient to convert Either as D2 (Ergocalciferol) or D3 (Cholecalciferol)

Impaired renal function - give Vitamin D preparations as no 1 alpha hydroxylase E.g Alfacalcidol - 1alpha hyrdoxycholecalciferol

Question 24

How does dynamic formation of bone occur?

Answer 24

Osteoblasts - make osteoid
Osteoclasts - resorb bone

Osteblasts express RANKL, binds to precursor osteoclast RANK-R leads to differention into mature osteoclasts..

Question 25

What is the arrangement of healthy bone?

Answer 25

Cortical - hard
Trabecular - spongy
Lamellar arrangement - alternates layers

Question 26

What are the consequences of excess phosphate?

Answer 26

Osteitis fibrosa cystica - bone cysts ‘Brown tumours’
Treatment - low phosphate diet, phosphate binders, Alphacalcidol
Parathyroidectomy in 3’

Vascular calcification - phosphate binds to Ca2+

Question 27

What is Osteoporosis and what can cause it?

Answer 27

Osteoporosis - reduced bony trabeculae, higher risk fractures >2.5 SD below average value for healthy at age (T score) DEXA femoral neck and lumbar spine

Hypogonadism
Endocrine - cushings, hyperthyroid
Iatrogenic - glucocorticoids, heparin
MENOPAUSE

Question 28

What are some Osteoporosis treatments?

Answer 28

HRT - Oestrogen (increases endometrial/breast cancer risk) give progestrogen
Venous thromboembolus risk increases

Bisphosponates - bind to hydroxyapatite, injected by osteoclasts impairs their function decreases prognetor maturation, may kill osteoclasts good for osteoporosis, malignancy, paget’s, severe hypercalcaemia

Cause GI disruption, don’t eat or take drugs around time
OSTEONECROSIS OF THE JAW - risk in cancer patient
May oversupress bone balance - cause atypical
fractures

Denosumab - human monoclonal antibody binds RANKL (once every few month SC)

Teriparatide - recombinant PTH fragment (more effective for formation than resorption)
Daily SC, 3rd line treatment SUPER FUCKING EXPENSIVE

Question 29

What is paget’s disease?

Answer 29

Chaotic bone formation, excessive osteoclast activity, excessive osteoblast compensation

woven bone formed - disorganised and mechanically weaker than lamellar bone

Bone hypertrophy, deformity and weakness
NO ONE KNOWS WHY? Tends to happen over 50

Increased vascularity, deafness, radiculopathy

MOST COMMON PLACES - skull, thoracolumbar spine, pelvis, femur, tibia

Plasma Ca2+ normal, plasma alkaline phosphatase increased [BONE]

lytic lesions, radionuclide bone scan demonstates skeletal extent