Endocrine Bone Disorders

Question 1

What is the most important vitamin D metabolite?

Answer 1

1, 25-dihydroxycholecalciferol (calcitriol)

Question 2

What is the principle effect of calcitriol?

Answer 2

Increase calcium, magnesium and phosphate absorption in the small intestines

Question 3

What are the other effects of calcitriol?

Answer 3

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)

Question 4

What does vitamin D deficiency cause? State some symptoms.

Answer 4

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

Question 5

What are the different names for vitamin D deficiency in children and adults?

Answer 5

Children – Rickets

Adults – Osteomalacia

Question 6

State some causes of vitamin D deficiency.

Answer 6

Inadequate dietary intake  
Lack of sunlight  
Receptor defects  
Renal failure  
Gastrointestinal malabsorptive states

Question 7

Which step, in vitamin D metabolism, required UV light?

Answer 7

The conversion of 7-dehydrocholesterol in the skin to cholecalciferol (vitamin D3) requires UV light

Question 8

Describe the two hydroxylation reactions in vitamin D metabolism.

Answer 8

Cholecalciferol is firstly hydroxylated to form 25-hydroxycholecalciferol in the Liver
It then goes to the kidneys where it undergoes its next hydroxylation (by 1-hydroxylase) to form 1, 25-dihydroxycholecalciferol (calcitriol)

Question 9

What can stimulate 1-hydroxylase in the kidneys?

Answer 9

Parathyroid Hormone (PTH)

Question 10

How can lack of sunlight cause vitamin D deficiency?

Answer 10

It will mean that less 7-dehydrocholesterol is being converted to cholecalciferol

Question 11

How can liver disease cause vitamin D deficiency?

Answer 11

The liver is where the first hydroxylation takes place and where 25-hydroxycholecalciferol is stored so liver disease can interfere with this step in vitamin D metabolism

Question 12

How can renal failure cause vitamin D deficiency?

Answer 12

The second hydroxylation step takes place in the kidneys (via 1-alpha-hydroxylase) so renal failure can interfere with 1-alpha-hydroxylase activity

Question 13

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

Answer 13

25-hydroxycholecalciferol

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

Question 14

Describe how you would diagnose vitamin D deficiency.

Answer 14

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 15

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

Answer 15

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

Question 16

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

Answer 16

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 17

What are the consequences of hypocalcaemia caused by renal failure?

Answer 17

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 18

What can vitamin D excess lead to?

Answer 18

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

Question 19

What can vitamin D excess result from?

Answer 19

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 20

What is Paget’s disease?

Answer 20

Very active (increased), localised but disorganised bone metabolism –usually slowly progressive. 
There is increased bone breakdown and bone formation.

Question 21

What is Paget’s disease characterised by histologically?

Answer 21

Abnormal, large osteoclasts

Question 22

State some symptoms of Paget’s disease.

Answer 22

Increased vascularity (warmth over affected bone)
Increased osteoblast/osteoclast activity
 Initially increased osteoclast activity
 Followed by increased osteoblast activity (leading to thickening of deformed bone)
Most commonly affected bones are: pelvis, femur, tibia, skull, and spine
Increased incidence of fracture
Bone pain

Question 23

Describe how you would diagnose Paget’s disease.

Answer 23

Plasma calcium = NORMAL
Plasma ALP (alkaline phosphatase) = HIGH
Radiological findings:
 Loss of trabecular (spongy) bone
 Increased bone density
 Deformity
Radioisotope (technetium) scanning can be performed to indicate areas of involvement

Question 24

What are the two components of bone in which 95% of the body’s calcium is stored?

Answer 24

Inorganic mineral component –65%
 Stored as calcium hydroxyapatite crystals between the collagen fibrils
Organic (osteoid) component –35%
 Collagen fibres (95%)

Question 25

What is the normal plasma calcium range?

Answer 25

2.2-2.6 mmol/L

Question 26

State 2 hormones that increase plasma calcium concentration.

Answer 26

Calcitriol | PTH

Question 27

State a hormone that decreases plasma calcium concentration.

Answer 27

Calcitonin

Question 28

What are the 2 direct effects of PTH?

Answer 28

Increased mobilisation of calcium in bone | Increased calcium reabsorption in the kidneys and stimulation of 1a-hydroxylase

Question 29

What are the 2 direct effects of calcitriol?

Answer 29

Increased calcium absorption from the small intestine | Increased mobilisation of calcium in bone

Question 30

What can stimulate PTH release?

Answer 30

Hypocalcaemia

Question 31

State 4 signs of hypocalcaemia.

Answer 31

Parasthesia Arrhythmias Convulsions Tetany

Question 32

What effect does hypocalcaemia have on excitable tissues?

Answer 32

It sensitises excitable tissue --> neuromuscular excitability

Question 33

State 2 clinical signs of neuromuscular irritability due to hypocalcaemia.

Answer 33

Chvostek’s Sign  Tap the facial nerve just below the zygomatic arch  Positive = twitching of facial muscles Trousseau’s Sign  Pump the blood pressure cuff for several minutes  Induces carpopedal spasm

Question 34

State 4 causes of hypocalcaemia.

Answer 34

``` Hypoparathyroidism (e.g. due to surgery) Vitamin D deficiency Pseudohypoparathyroidism Renal failure (impaired 1-alpha hydroxylase) ```

Question 35

Describe the effect of hypercalcaemia on neuronal excitability.

Answer 35

It reduces neuronal excitability and you get atonal muscles

Question 36

What are the main signs and symptoms of hypercalcaemia?

Answer 36

Stones, abdominal moans and psychic groans Stones – renal effects  Polyuria + polydipsia  Nephrocalcinosis = deposition of calcium in the kidneys (can cause renal colic) Abdominal moans – GI effects  Anorexia, nausea, constipation, pancreatitis, dyspepsia Psychic groans – CNS effects  Fatigue, depression, impaired concentration, altered mentation, coma

Question 37

What are the 2 main causes of hypercalcaemia?

Answer 37

Primary Hyperparathyroidism (e.g. parathyroid adenoma) Malignancy (e.g. bone tumours/metastases --> increased bone turnover --> increased plasma calcium; tumours can also produce PTH-like peptide)

Question 38

State 2 other causes of hypercalcaemia.

Answer 38

Conditions of increased bone turnover (e.g. hyperthyroidism, Paget’s) Vitamin D excess (rare)

Question 39

Describe how you would differentiate between primary hyperparathyroidism and malignancy causing hypercalcaemia.

Answer 39

In primary hyperparathyroidism there is no negative feedback because the parathyroid adenoma will be producing PTH autonomously  Plasma Calcium = HIGH  PTH = HIGH In malignancy, the negative feedback will be intact as it is due to increased bone turnover due to bony metastases  Plasma Calcium = HIGH  PTH = LOW

Question 40

Describe the treatment of vitamin D deficiency in the case of normal renal function.

Answer 40

Give 25-hydroxy vitamin D This can be in the form of:  Ergocalciferol = 25-hydroxy vitamin D2  Cholecalciferol = 25-hydroxy vitamin D3

Question 41

Describe the treatment of vitamin D deficiency in the case of renal failure.

Answer 41

Alfacalcidol = 1-hydroxycholecalciferol

Question 42

What do osteocytes produce?

Answer 42

Type 1 collagen and other extracellular matrix components

Question 43

What is RANK ligand?

Answer 43

An osteoclast-activating factor – it increases the activation of osteoclasts It stimulates the maturation of osteoclasts from osteoclast precursors If there are more mature osteoclasts, you get more bone resorption

Question 44

Define osteoporosis.

Answer 44

Having a bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average for young healthy adults (usually referred to as a T-score of -2.5 or lower) BMD is measured using Dual Energy X-ray Absorptiometry (DEXA)

Question 45

State some predisposing conditions for osteoporosis.

Answer 45

``` Post-menopausal oestrogen deficiency Age-related deficiency of bone homeostasis Hypogonadism in young men and women Endocrine conditions (e.g. Cushing’s syndrome, hyperthyroidism, primary hyperparathyroidism) Iatrogenic (e.g. prolonged use of glucocorticoids, heparin) ```

Question 46

What are the benefits of oestrogen replacement to prevent osteoporosis in post-menopausal women?

Answer 46

It has an anti-resorptive effect in bone and, hence, prevents bone loss

Question 47

What are some cautions and risks of oestrogen replacement?

Answer 47

In patients with a uterus (i.e. not had a hysterectomy), you must give additional progestogen to prevent endometrial hyperplasia and reduce the risk of endometrial carcinoma Risks:  Breast cancer  Venous thromboembolism

Question 48

Name 2 selective oestrogen receptor modulators and their effects.

Answer 48

Selective oestrogen receptor ANTAGONISTS – Tamoxifen  Antagonises ERs in the breast  Oestrogenic activity in bone  But, oestrogenic activity in uterus, which limits its use in osteoporosis Selective oestrogen receptor AGONIST – Raloxifene  Oestrogenic in bone  Anti-oestrogenic in breast and uterus  But there is a risk of stroke and venous thromboembolism

Question 49

What are the 1st, 2nd and 3rd line treatments for osteoporosis?

Answer 49

Bisphosphonates Denusomab Teriparatide

Question 50

What are bisphonates analogues of?

Answer 50

Pyrophosphate

Question 51

Give 2 examples of bisphosphonates.

Answer 51

Alendronate | Sodium etidronate

Question 52

Describe how bisphosphonates work.

Answer 52

They bind avidly to hydroxyapatite crystals in the bone and are ingested by osteoclasts They impair the ability of osteoclasts to resorb bone It also decreases the maturation of osteoclasts and promotes osteoclast apoptosis

Question 53

State some uses of bisphosphonates.

Answer 53

``` Osteoporosis Malignancy – reduces bony pain Paget’s disease – reduces bony pain Severe hypercalcaemic emergency  I.V. saline to rehydrate  Then bisphosphonates ```

Question 54

Describe the pharmacokinetics of bisphosphonates.

Answer 54

They are orally active but poorly absorbed Must be taken on an empty stomach Accumulates at the site of bone mineralisation and remains a part of the bone until it is resorbed

Question 55

State 4 unwanted actions of bisphosphonates.

Answer 55

Oesophagitis Flu-like symptoms Osteonecrosis of the jaw (greatest risk in cancer patients receiving IV bisphosphonates) Atypical fractures (due to over-suppression of bone remodelling)

Question 56

What is denusomab and how often does it need to be given?

Answer 56

It s a human monoclonal antibody It binds to RANKL and inhibits osteoclast formation and activity It is given subcutaneously every 6-12 months

Question 57

What is teriparatide and how often does it need to be given?

Answer 57

Recombinant fragment of PTH Increases bone resorption and formation – but formation exceeds resorption Daily subcutaneous injections EXPENSIVE

Question 58

What is strontium ranelate?

Answer 58

Not used anymore Stimulates bone formation and reduces bone resorption Increased risk of MI and thromboembolism