Bone Pain - Biochemistry

Question 1

Describe the hydroxylation of vitamin D

Answer 1

1. Supply is from the sun (Pro-vitamin D₃), limited numer of foods (Vitamin D₃) and food supplement (Vitamin D₂) which is known as calciferol
2. Calciferol is hydroxylated in the liver to form calcidion (25 hydroxy vitamin D = 25OHD)
3. Calcidiol is converted into the active hormone, calcitriol [1,25 Di-hyrdoxy vitamin D = 1,25(OH)₂D]

Question 2

Calcium and phosphate are regulated through 4 important organ systems. Descibe the role of each organ.

Answer 2

1. The gut - where calcium and phosphate are absorbed
2. Bone- where calcium and phosphate are mineralised and resorbed
3. Kidneys - where the quantity of calcium of phosphate is regulated, and they are absorbed from pre-urine
4. Thyroid gland - calcitonin (CT), parathyroid hormone (PTH)

Question 3

Describe the function of calcium in plasma and bone

Answer 3

Plasma Ca

• 50% protein bound (Abumin
• 50% ionised

Bone

• Stiffness and structure
• -1kg calcium in average body size
• Stored in hydroxapatite - 99% (combination f calcium, phsophate and hydroxy)
• ‘Resevoir’ for plasma Ca - If too little Ca is coming in from the gut/too much Ca is lost from urine it is replenshed

Question 4

List 5 regulatory functions of calcium

Answer 4

1. Neurotransmission
2. Reproduction
3. Hormone action
4. Cellular growth
5. Enzyme growth

Question 5

What is the normal range of plasma (albumin adjusted) calcium?

Answer 5

Albumin adjusted calcium is between 2.2 and 2.6 mmol/L

Question 6

a) What level of Ca is considered as hypocalcaemia?
b) List the signs and symptoms of hypocalcaemia

Answer 6

a) Albumin adjusted Ca

b)

• Parathesia (numbness, tingling)
• Muscle spasm and tetany (a disorder of increased excitability)
• Chvostek’s sign (twitching of facial msucles in response to tapping over the facial nerve) and Trousseau’s sign (carpopedal spasm induced by pressure applied to the arm by an inflated sphygmomanometer cuff)
• Seizures/fits
• Cardic abnormalities including arrythimias, hypertrophy, hypotension, cardiac failure
• Coma

Question 7

a) What level of Ca is considered as hypercalcaemia?
b) List the signs and symptoms of hypercalcaemia

Answer 7

a) Albumin adjusted Ca > 2.6 mmol/L

b)

• Nausea
• Peptic ulcers
• Renal stones
• Renal failure
• Polyuria
• Soft tissue calcification
• Mental disturbances
• Depression

Question 8

Describe the difference between the main role of parathyroid horomone (PTH) and calcitonin (CT)

Answer 8

Parathyroid hormone acts to increase blood calcium levels, while calcitonin acts to decrease blood calcium levels.

Therefore CT opposed the role of PTH

Question 9

a) What is the main role of parathyroid hormone (PTH)
b) Describe 5 speicifc roles of Parathyroid hormone (PTH)

Answer 9

a) Parathyroid hormone acts to increase blood calcium levels

b)

1. Stimulates bone resorption, particularly when plasma Ca is high, by stimulcating osteoblastic function
2. Stimulates release of calcium into plasma when plasma Ca is low
3. Stimulates absorption of Ca in the kidneys to decrease urinary loss of calcium
4. Increases urinary excretion of phosphates to decrease plasma phosphate
5. Stimulates the production of active hormone vitamin D (1,25 Vit D) which in turn stimulates the absorption of calcium and phosphate from food in the intesine

Question 10

a) What is the main role of calcitonin (CT)
b) Describe the role of Calcitonin (CT)

Answer 10

a) CT acts to decrease blood calcium levels
b) CT increases when Ca plasma increases.It inhbitis the activity of osteoclasts to prevent bone resorption. This prevents Ca and phosphate from being released into the blood. This ensures that Ca that is in bone remains there and urinary calcium excretion is increases

CT opposes the role of parathyroid hromone

Question 11

What is the main and most important role of 1,25 hydroxy vit D [1,25(OH)₂D]

Answer 11

To increase calcium and phosphate absorption from food in the gut

Question 12

Describe the 4 roles of 1,25 hydroxy vit D [1,25(OH)2D] in bone

Answer 12

1. Stimulates bone resorption, particularly when PTH is also high
2. Stimulates calcium incorporation in growth plates and bone
3. Chondrocyte and osteoblast maturation
4. Bone formation and mineralisation

Question 13

Describe the 2 roles of 1,25 hydroxy vitamin D in the parathyroid gland

Answer 13

1. Inhibits Ca and phosphate
2. Indirectly and directly decreases the amount of PTH that is releases from the parathyroid gland

Question 14

Discuss the role of vitamin D [1,25(OH) Vit D] in bone metabolism

Answer 14

1. Main and most important action is to increase calcium and phosphate absorption from the food in the gut
2. Function in bone

• Stimulates resorption, partculary when PTH is also high
• Stimulates calcium incorporation in growth plates and bone
• Chondrocyte and osteoblast maturation
• Bone formation and mineralisation

3. Stimulates (in congestion with PTH) calcium reabsorption (not a strong effect)
4. Inhibits its own production of 25 Vit D (precursor) and stimulates its own breakdown metabolism
5. Parathyroid gland

• Inhibits Ca and phosphate
• Indirectly and directly decreases the amount of PTH that is released from the parathyroid gland

6. Stimulates FGF23

Question 15

Describe the 2 roles of fibroblast growth factor (FGF23)

Answer 15

1. Stimulates the excretion of phosphate in urine
2. Has a major effect on vitamin D metabolism - particulary stimulates catabolism of 1.25 Vit D and 25 Vit D to non-active metabolites

Question 16

Intestinal Ca absoroption varies between 15-50%. List 4 things that percentage Ca absorption depends on

Answer 16

1. Intake
2. Active absorptions
3. Life stage (postmenopausal decreases 0.21%)
4. Physiological state: growth, pregnancy, lactation

Question 17

List 3 sources of calcium

Answer 17

1. Dairy products
2. Cereals and cereal products
3. Green leafy vegetables

Question 18

List 3 sources of Vitamin D

Answer 18

1. Majority: Skin synthesis
2. Diet: oily fish, meat, eggs, fortified spreads
3. Fortified cereals and cereal products

Question 19

List 4 causes of calcium deficiency

Answer 19

1. Low supply - low dietary intake of dairy
2. Low absorption - Vit D deficiency
3. Low absorption - phosphate and phytate binding
4. GI disorders leading to low absorption

Question 20

List 5 causes of vitamin D deficiency

Answer 20

1. Low sunshine exposure
2. Low dietary supply - low consumption of Vit D rich foods, nenonatal anc infancy
3. Low absorption
4. Obesity
5. High loss and/or utilisation

Question 21

What can both calcium and vitamin D deficiency lead to?

Answer 21

2’hyperparathyroidism

Question 22

Describe calcium resorption in kidney

Answer 22

• In a healthy kidney the huge amount of Ca sent there is 97% reabsorbed and that takes place throughout the whole of the kidney
• In distal convulated tube is only where PTH mediated Ca reabsorption takes place. Iplies PTH only has a limited capacity to ensure not much Ca is lost

Question 23

Describe phosphate reabsorption and excretion in kidneys

Answer 23

• In a healthy kidney reabsorption of phosphate % is dependant on dietary intake
• The kidneys plays a key role in excreting phosphates if too much is consumed
• In renal impairment the body has an issue excreting phosphates, causing hyperphosphatemia. This is associated with a strong risk of increase in CVD

Question 24

Describe the function of the endocrine system in vitamin D metabolism

Answer 24

1. Vit D from diet is hydroxylated in the liver
2. This circulates in the liver
3. Then goes to the kidneys where it’s converted to 1,25(OH)₂Vit D
4. This is returned again

Question 25

Describe the relationship between 25OHD and 1,25OHD

Answer 25

* Plasma [250OH Vit D] and [1,25(OH)₂Vit D] are not or only weakly related * Plasma [1,25(OH)₂Vit D] is weakly related to functional or health outcomes and vary tightly regulated

Question 26

Describe the auto/paracrine function in vitamin D metabolism

Answer 26

* A lot of 25OH is not hyrdoxylated in the kidney for endocrine effects and therefore reflected in plasma * However, alot of 25OH is also hyrodxylated in all kinds off tissue e.g., breast tissue, placenta, bone and intestines * A lot of 1,25OH is broken down in these tissues and therefore no reflected in plasma * This is why if you want to know about vitamin D status and its availability to the body you measure 25OHD and not 1,25OHD because it doesn't reflect its function in plasma

Question 27

If you want to know about vitamin D status and its availability to the body, why must you measure 25OHD and not 1,25OHD?

Answer 27

* Alot of 25OHD is also hydroxylated in all kinds of tissue e.g., breast tissue, placenta, bone, and intestines * A lot of 1,25OHD is broken down in these tissues so it is not reflected in plasma * This is why if you want to know about vitamin D status and its availability to the body you measure 25OHD and not 1,25OHD because it doesn’t reflect its function in plasma

Question 28

List the clinical symptoms of vitamin D deficieny in adults and children

Answer 28

* Non-specific * Fatigue * Generalized muscle, joint and bone pain, and hyperalgesia (increased severity to pain) * Muscle weakness, especially of the extremities and pelvic region manifesting in difficulties in rising from a sitting or squatting position or a wadling gait * Fragility fracture, with prolonged bone loss

Question 29

List the clinical symptoms of vitamin D deficiency specifically in children

Answer 29

* Bone deformities * Cardiac problems * Hypocalcaemic fits

Question 30

List the groups of people who are at increases risk of low 250HD (of a general healthy population) and explain why this is the case

Answer 30

* Dark skinned individuals - can produce same amount of Vit D in skin but takes loneger because the pigment in their skin acts as a barrier for UVB * Concealing dress style - little UVB exposure * Little UVB exposure * Obesity - bigger distribution volume * Adolescents - may be due to diet and use of Vit D for growth spurt * Frail eldery - limited exposure to sun + lose a lot of Vit D through kidney * Exclusively breast-fed babies - very little vid D in breast milk (so Vit D needs to be supplemented in from birth onward) * Winter * Specific groups including: renal disease, GI disorders, coeliac, ICU patient, sever liver disease, tuberculosis, HIV

Question 31

Name 2 conditions caused by vitamin D deficiency

Answer 31

1. Rickets 2. Osteomalacia

Question 32

What processes are affected in Rickets?

Answer 32

* Chondrocyte function affected (hypertrophy) and leading to apoptosis of chondrocytes * Lack of calcification of GP cartilage

Question 33

What processes are affected in osteomalacia

Answer 33

* Lack of calcification of osteoid * Osteoblast, osteoclast and osteocyte function affected

Question 34

Describe what is needed to diagnose rickets

Answer 34

* Clinical features - widening of growth plates (most detectable in wrists, knees, and ribs) * Radiology - widening of growth plates, bowing of legs * Medical and diet history * Biochemistry - Blood (25OHD, Ca adjusted for albumin, bone alkaline phosphatase) and urine (Calcium and phosphate)

Question 35

Describe the role of vitamin D supplements in older people

Answer 35

Bone * Prevention/treatment of bone loss and osteoporosis * Prevention/treatment of 2'hyperparathyroidism * Prevention/treatment of osteomalacia * Treatment of bone pain Physcial perfromance and fall risk * Skeletal muscle mass and strength postively related to bone density * Fall prevention and improvement of balance * Treatmentof muscle pain and weakness Important as co-therapy when on osteoporosis treatment