LECTURE 19 - parathyroid gland and calcium regulation

Question 1

What are the general functions of the skeleton?

Answer 1

Mechanical - support and muscle attachments
Protective - for vital organs and marrow
Metabolic - ion homeostasis (calcium and phosphate especially)

Question 2

What is soluble calcium needed for?

Answer 2

• excitable tissue
• muscle/nerves
• cell adhesion

Question 3

Why does calcium homeostasis occur?

Answer 3

• to keep serum calcium levels at 2.1-2.6mM

Question 4

How is calcium homeostasis maintained?

Answer 4

• calcium can be obtained from GI tract (from diet)
• kidney can help redistribute calcium
• as a last resort there is calcium available from the skeleton

Question 5

What are the parathyroid glands?

Answer 5

• there are 4 glands near the thyroid
• they regulate calcium homeostasis and phosphate levels
• secrete parathyroid hormone (PTH) in response to low calcium or high phosphate

Question 6

What does parathyroid hormone (PTH) do?

Answer 6

• increases calcium reabsorption in renal distal tubule
• increases intensity calcium absorption (via activation of vitamin D)
• increases calcium release from bone (stimulates osteoclast activity
• decreases phosphate reabsorption

Question 7

What happens when calcium levels are too low?

Answer 7

• calcium sensing receptors detect low calcium levels
• increase PTH secretion
• first act on kidney to recover calcium from urine, decreased urinary calcium, increased urinary phosphate
• increased 1,25D3 production (active form of vitamin D), tried to increase calcium and phosphate from intestine
• last resort is to promote release of calcium from bone into bloodstream

Question 8

What is parathyroid hormone?

Answer 8

• 84 amino acid peptide but biological activity in first 34 amino acids (PTH 1-34), half-life = 8 mins
• cleaved to smaller peptides
• assayed by two site assay (to avoid detecting fragments)
• normal adult reference range = 1.6 - 6.9 pmol/L
• binds to G protein coupled receptors mainly in kidney and osteoblasts

Question 9

How does negative feedback affect PTH?

Answer 9

• PTH transcription (mRNA production) is inhibited by 1,25D3

- PTH translation (mRNA to protein synthesis) is inhibited by increased serum calcium

Question 10

What is Vitamin D?

Answer 10

• precursor form (inactive) = 25-hydroxyvitamin D
• Vitamin D2 = found in plants
• Vitamin D3 = found in animals
• active form = 1,25-dihydroxyvitamin D (hormone that binds to VDR receptor)

Question 11

What is calcitonin?

Answer 11

• produced by thyroid c-cells (parafollicular)
• released in hypercalcaemia, inhibits bone resorption
• not essential to life
• two calcitonin genes product from a single gene and primary RNA transcript

Question 12

How does calcitonin work?

Answer 12

• hypercalcaemia causes calcitonin production
• shut downs calcium release from bone
• PTH levels also drop (thus active Vitamin D also drops)

Question 13

What is Fibroblast Growth Factor 23 (FGF23)?

Answer 13

• produced by bone cells
  (osteocytes and maybe osteoblasts)
• released in response to high serum PO4 (phosphate)
• increases renal excretion of PO4 and suppress renal synthesis of activate vitamin D
• main inducer of FGF23 appears to be 1,25D3

Question 14

What is the basic structure of bones?

Answer 14

• 2 epiphysis (growth plates) at each end separated by diaphysis (made of cortical bone)
• growth plates are the bits that grow, made of cancellous (trabecular) bone (aka spongy bone)

Question 15

What is bone made of?

Answer 15

• specialised connective tissue
• extracellular matrix which us able to calcify
• collagen fibres with preferential orientation (approx 90% of protein content)
• non-collagenous proteins essential to bone function e.g. osteocalcin, osteonectin, osteopontin, used as markers for bone turnover
• calcification occurs with formation of hydroxyapatite crystals - mixture of calcium and phosphate
• contains several types of cells

Question 16

What are osteocytes?

Answer 16

• embedded in calcified bone matrix

- have long processes which contact other osteocytes and osteoblasts

Question 17

What are osteoblasts?

Answer 17

• bone forming cells which produce matrix constituents and aid calcification
• originate from mesenchymal stem cells (bone marrow stem cells or connective tissue mesenchymal cells)
• classical marker - alkaline phosphate, osteocalcin

Question 18

What are osteoclasts?

Answer 18

• bone resorbing cells usually found in contact with calcified bone surface - in lacunae
• multinucleated = originate from bone marrow lineage
• produce acid (to resorb mineral) and enzymes (to resorb matrix)
• attachment to bone very important - integrins
• classical markers = carbonic anhydrase, tartrate-resistant acid phosphate (TRAP), RANK, calcitonin receptor

Question 19

What is primary hyperparathyroidism?

Answer 19

• parathyroid tumour (usually benign adenoma)
• causes hypercalcaemia and low serum phosphate
• loss of -ve feedback from hypercalcaemia
• treated with surgery

Question 20

What are the clinical features of HPT?

Answer 20

• Neuro: lethargy/ confusion
• GI: constipation/ pancreatitis
• Neuropsychiatric: depression
• Renal: thirst/ polyuria/ renal stones
• Rheumatic: joint pain/ fracture
• Cardiac: hypertension

Question 21

What is secondary HPT?

Answer 21

Renal disease (kidney disease)

• increased phosphate, decreased activation of vitamin D
• treated with phosphate binders or vitamin D analogues

Question 22

What is renal osteodystrophy - chronic kidney disease- mineral and bone disorder (CKD-MBD)?

Answer 22

• losing urinary calcium
• retaining high levels of phosphate (FDF23 levels increase)
• can cause hypocalcaemia
• elevated PTH and FDF23

Question 23

What is rickets/ osteomalacia?

Answer 23

• vitamin D deficient
• called rickets when affecting growing skeletons (children)
• lack of mineralisation of collagen component of bone (osteoid)
• failure to absorb sufficient calcium from GI tract
• dietary/ lack of sunlight, rarely inherited
• rickets occurs at osteoid as growth plate is weak (bow legs) and growth plate expands to compensate (swollen joints)
• osteomalacia - bone pain, pseudofractures
  treated with vitamin D replacement

Question 24

What is osteoporosis?

Answer 24

• loss of bone mass/ density = both mineral and osteoid decreased (leads to increased fracture risk)
• male and females show gradual decline in bone density from early adult peak
• postmenopausal osteoporosis = rapid decline in female bone density following decline in oestrogen at menopause
• oestrogen deficiency increases bone remodelling rate and degree of bone resorption
  TREATMENT: hormone replacement (oestrogen), bisphopshates (osteoclast poisons), Denosumab (RANK ligand antibody), PTH (intermittently)