2. BONE & METABOLISM

Question 1

What 5 hormones are involved in the endocrine control of bone remodeling?

Answer 1

• Endocrine control of bone remodeling acts at a distance
  1. PARATHYROID HORMONES
  2. THYROID HORMONES - control the rate of chondrocyte differentiation i the growth plates, in the absence of thyroid hormones, there’s no linear growth
  3. GROWTH HORMONE - regulates osteoblast differentiation
  4. INSULIN-LIKE GROWTH FACTOR
  5. OESTROGEN - low oestrogen leads to increased osteoclast activity

Question 2

What three organs/tissues are involved in Calcium metabolism?

Answer 2

1. GASTROINTESTINAL/GI TRACT - Ca2+ is reabsorbed from the diet
2. KIDNEYS - Ca2+ is reabsorbed from the renal tubules after filtration by teh glomerulus, also excreted
3. BONE - Ca2+ is stored in the bone as calcium hydroxyapatite, bone resorption leads to a release of Ca2+

Question 3

What stimulates PTH release from the parathyroid glands?

Answer 3

• The parathyroid glands are located at the back of the thyroid gland & produce PTH (parathyroid hormone)
• PTH is released in response to low levels of calcium (hypocalcaemia)
• The parathyroid glands detect the drop in calcium

Question 4

What are the four main effects of PTH in response to low Ca2+?

Answer 4

1. BONE RESORPTION - release of Ca2+ from calcium hydroxyapatite store
2. INCREASED REABSORPTION OF CALCIUM from the kidneys
3. DECREASED REABSORPTION OF PHOSPHATE from the kidneys
4. Increased active VITAMIN D3 PRODUCTION by the kidneys

Question 5

How does PTH stimulate bone resorption in response to low calcium?

Answer 5

• PTH leads to bone resorption, which releases calcium
• PTH acts DIRECTLY on osteoblasts to produce RANKL
• PTH acts INDIRECTLY on osteoclasts via RANKL stimulating osteoclast differentiation

Question 6

How does PTH stimulate osteoclast differentiation to cause bone resorption?

Answer 6

1. PTH binds to PTH1 receptors on osteoblasts stimulating osteoblast differentiation
2. Osteoblasts differentiate to produce RANKL
3. RANKL stimulates osteoclast differentiation
4. Osteoclasts break/resorb bone, leading to a release of calcium

Question 7

What’s the effect of intermittent PTH & continuous PTH on bone remodeling?

Answer 7

• INTERMITTENT PTH = ANABOLIC effect due to the initial stimulation of osteoblasts.
• PTH binds to PTH1 receptors on osteoblasts, causing osteoblast differentiation leading to bone formation. The production of RANKL isn’t enough for osteoclast differentiation to overcome the osteoblast differentiation
• CONTINUOUS DELIVERY OF PTH = CATABOLIC EFFECT due to osteoclast differentiation
• The increased production of RANKL stimulates osteoclast differentiation. The osteoclast differentiation overcomes the osteoblast differentiation leading to bone resorption

Question 8

What are the two effects of Active Vitamin D3 produced in response to low Ca2+?

Answer 8

• In response to low calcium , PTH is released. PTH causes increased production of Vitamin D3 by the kidneys
• Vitamin D3 has two main effects:
  1. INCREASED CALCIUM REABSORPTION from the GI or intestines
  2. The high levels of calcium resulting from vitamin D3 mean that vitamin D3 INHIBITS PTH
• Vitamin D3 also increases phosphate reabsorption

Question 9

How is Active Vitamin D3 synthesised?

Answer 9

• Vitamin D3 can be acquired from sunlight or our diet
• Vitamin D3 is converted to 25-hydroxy Vitamin D3 by the liver
• 25-hydroxy Vitamin D3 is converted to 1,25 - dihydroxy Vitamin D3 by the kidneys
  VITAMIN D3 –> 25-HYDROXY VITAMIN D3 –> 1,25 - DIHYDROXY VITAMIN D3

Question 10

What two factors inhibit PTH production?

Answer 10

1. High calcium levels (hypercalcemia)

2. Active Vitamin D3 (negative feedback)

Question 11

What three tissues are involved in phosphate metabolism?

Answer 11

1. GASTROINTESTINAL TRACT/GI - Reabsorption of phosphate via Vitamin D3
2. BONE - Release of phosphate from bone store
3. KIDNEYS - Phosphate reabsorption or excretion

Question 12

What is FGF 23?

Answer 12

• FIBROBLAST GROWTH FACTOR 23 is synthesized in response to high phosphate levels (hyperphosphataemia)
• It acts to decrease phosphate levels & interacts with PTH & & Vitamin D3

Question 13

What is FGF 23 released by?

Answer 13

• Osteocytes detect high levels of phosphate and produce FGF23
• PTH & Vitamin D3 can also act to stimulate FGF 23 release

Question 14

What are the three effects of FGF23?

Answer 14

1. DECREASED PHOSPHATE REABSORBTION/INCRAESED PHOSPHATE EXCRETION
2. DECREASED PTH PRODUCTION - to prevent release of phosphate by bone resorption
3. DECREASED VITAMIN D3 PRODUCTION - to prevent reabsorption of phosphate by the intestines

Question 15

What is a metabolic bone disease?

Answer 15

• A metabolic bone disease refers to a group of bone disorders characterized by reduced bone mass & strength due to deficiencies in minerals, hormones, vitamins

Question 16

What is rickets/ostomalacia?

Answer 16

• RICKETS/OSTEOMALACIA refers to a bone disorder where the osteoid is laid down normally but is unable to be mineralized. There’s DEFECTIVE MINERALISATION of bones meaning that the bones are soft
• In children = Rickets, Adults = osteomalacia
• Can be caused by two types of deficiency

Question 17

What are the two types of deficiency that can cause osteomalacia?

Answer 17

1. DEFICIENCY OF VITAMIN D3 leading to hypocalcemia. Not enough Vitamin D3 means that not enough calcium is reabsorbed. Not enough calcium to be stored in bone
2. DEFICIENCY OF PHSOPHATE. hypophosphatemia, not enough phosphate to be stored in bone
   - Osteomalacia can be caused by hypocalcemia & hypophosphatemia

Question 18

**What is oncogenic osteomalacia & what deficiency is it caused by?

Answer 18

• ONCOGENIC OSTEOMALACIA is caused by a deficiency in phosphate
• Mesenchymal tumours produce excess FGF23 which leads to a loss of phosphate due to increased excretion & decreased reabsorption

Question 19

What are the consequences of osteomalacia?

Answer 19

1. BOWING OF LEGS - Bone is too soft to support body weight with the correct morphology, so it changes shape leading to bowing
2. LOOSER ZONES - Fractures found in adults with osteomalacia in one side of the bone
3. GROWTH PLATES GET WIDER

Question 20

What is hyperparathyroidism?

Answer 20

• HYPERPARATHYROIDIM is caused by excess levels of PTH. It is usually caused by an enlargement of the parathyroid gland leading to overproduction of PTH
• The excess PTH can lead to bone resorption, hypercalcemia, hypophosphatemia

Question 21

What are the consequences of hyperparathyroidism?

Answer 21

1. HYPERCALCEMIA - Excess PTH leads to excess calcium reabsorption. The high Ca2+ no longer inhibits PTH
2. HYPOPHOSPHATEMIA - excess PTH leads to decreased phosphate reabsorption
3. OSTEITIS FIBROSA CYSTICA

Question 22

What is osteitis fibrosis cystica?

Answer 22

• Osteitis fibrosis cystica is a consequence of hyper parathyroidism
• It is a late manifestation of unchecked primary primary hyperparathyroidism
• Osteitis fibrosis cystica is a skeletal disorder characterized by inflammation of the bones due to cysts forming in the bones. It also involves bone being converted to fibrous tissue.

Question 23

What are some primary causes of hyperparathyroidism?

Answer 23

1. PARTHYROID ADENOMA/TUMOUR - leads to excess PTH production
2. CHIEF CELL HYPERPLASIA - chief cells are cells found within the parathyroid gland, hyperplasia of these cells leads to enlargement of the parathyroid gland

Question 24

*What are some secondary causes of hyperparathyroidism?

Answer 24

1. Chronic renal deficiency - interferes with Vitamin D3 production so Vitamin D3 doesn’t inhibit PTH
2. Vitamin D3 deficiency - lack of vitamin D3 means a reduced inhibition of PTH

Question 25

What are the 4 clinical signs for hyperparthyrodism?

Answer 25

1. Stones (kidney stones) 2. Pains (bone from excess bone resorption) 3. Abdominal groans (acute pancreatis) 4. Psychic groans (Psychosis or depression)