Endocrine Bone Disorders Flashcards by Owen Vineall

What is the most important vitamin D metabolite?

1, 25-dihydroxycholecalciferol (calcitriol)

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What is the principle effect of calcitriol?

Increase calcium, magnesium and phosphate absorption in the small intestines

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What does vitamin D deficiency cause? State some symptoms.

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

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State some causes of vitamin D deficiency.

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

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

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

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Describe the two hydroxylation reactions in vitamin D metabolism.

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)

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What can stimulate 1-hydroxylase in the kidneys?

Parathyroid Hormone (PTH)

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How can lack of sunlight cause vitamin D deficiency?

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

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How can liver disease cause vitamin D deficiency?

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

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How can renal failure cause vitamin D deficiency?

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

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

25-hydroxycholecalciferol

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

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Describe how you would diagnose vitamin D deficiency.

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

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

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

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

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

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What are the consequences of hypocalcaemia caused by renal failure?

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

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What can vitamin D excess lead to?

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

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What can vitamin D excess result from?

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

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What is Paget’s disease?

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

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What is Paget’s disease characterised by histologically?

Abnormal, large osteoclasts

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State some symptoms of Paget’s disease.

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

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Describe how you would diagnose Paget’s disease.

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

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State 2 hormones that increase plasma calcium concentration.

Calcitriol

PTH

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State a hormone that decreases plasma calcium concentration.

Calcitonin

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What are the 2 direct effects of PTH?

Increased mobilisation of calcium in bone

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

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What are the 2 direct effects of calcitriol?

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

What can stimulate PTH release?

Hypocalcaemia

State 4 signs of hypocalcaemia.

Parasthesia Arrhythmias Convulsions Tetany

What effect does hypocalcaemia have on excitable tissues?

It sensitises excitable tissue --> neuromuscular excitability

State 2 clinical signs of neuromuscular irritability due to hypocalcaemia.

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

State 4 causes of hypocalcaemia.

``` Hypoparathyroidism Vitamin D deficiency Pseudohypoparathyroidism Renal failure (impaired 1-alpha hydroxylase) ```

Describe the effect of hypercalcaemia on neuronal excitability.

It reduces neuronal excitability and you get atonal muscles

What are the main signs and symptoms of hypercalcaemia?

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

What are the 2 main causes of hypercalcaemia?

``` 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) ```

State 2 other causes of hypercalcaemia.

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

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

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

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

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

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

Alfacalcidol = 1-hydroxycholecalciferol

What do osteocytes produce?

Type 1 collagen and other extracellular matrix components

What is RANK ligand?

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

Define osteoporosis.

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)

State some predisposing conditions for osteoporosis.

``` 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) ```

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

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

What are some cautions and risks of oestrogen replacement?

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

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

Bisphosphonates Denusomab Teriparatide

What are bisphonates analogues of?

Pyrophosphate

Give an example of bisphosphonates.

Alendronate

Describe how bisphosphonates work.

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

State some uses of bisphosphonates.

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

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

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

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

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

Channel for phosphate reabsorption in kidney

FGF23

Calcitriol effects osteoclasts

Activation of their precursors to become osteoclasts

Calcitriol effects on osteoblasts

Stimulate them to make osteoclast activating factors (RANKL)

Calcitriol effects small intestine

Increased calcium and phosphate reabsorption

Other name for vitd2

Ergocalciferol

Treatment of primary hyperparathyroidism

Parathyroidectomy

What bone cells express PTH and calcitriol receptors

Osteoblasts

Formation of bone tissues

Collagen laid down in alternating orientations which is mechanically strong

Secondary bone disease to secondary hyperparathyroidism

Osteitis fibrosis cystica

2 effects of FGF23

Promotes kidney excretion of phosphate and blocks GI absorption of phosphate

Uses of calcium in body

``` Form bone and teeth Muscle contraction Enzyme function Blood clotting Normal heart rythm ```

Reason for changes in sensitisation of muscle when calcium concentration changes

In low ecf Ca there is a greater Na influx and vice versa

Calcitriol effects in kidneys

Increased calcium reabsorption and reduced phosphate by blocking phosphate/sodium channel