Calcium homeostasis and the parathyroid gland

Give an overview of the skeleton’s functions

Mechanical: support and muscle attachments

Protective: for vital organs and marrow

Metabolic: ion homeostasis, especially calcium and phosphate

Epiphysis

The ends of a bone, the round parts

Metaphysis

The middle bit between the epiphysis and the diaphysis (shaft)

What is cancellous bone

Trabecular bone

Includes the epiphysis and metaphysis 

Lateral loading, strength under pressure. honeycomb like. 

large surface area- much easier to access calcium and phosphate than cortical bone

individually weak, collectively strong

diaphysis

the length of the bone (shaft) before the round bits (in between the epiphysises)

made up of cortical bone (compact or lamellar)

strong under compression, basic protection

what is bone made of?

specialised connective tissues

extracellular matrix which can calcify

collagen fibres with a preferential orientation (follow specific orientation structure)

some non-collagenous proteins essential to bone function (regulators)

calcification occurs with the formation of hydroxyapatite crystals- calcium phosphate crystals incorporate into bone to give it its structure 

how does bone remodelling work

in trabecular bone- cycles of remodelling

constantly eating away and replacing- catabolic clearance, anabolic laying down of new bone

osteoclasts

responsible for bone resorption (munch through the bone, bone clearing)

found in contact with calcified bone surface in lacunae

multinucleated

produce acids to resorb mineral and enzymes to resorb matrix (markers)

attach to bone with integrins

osteoblasts

Bone formation, lay down collagen (aid calcification + produce matrix constituents)

created when collagen structure calcifies over time and some of the osteoblasts left behind become osteoblasts

bone lining cells

initiate bone remodelling 

osteocytes

mechanosensing, orchestrates microfracture repair (sense damage)

created when the collagen calcifies and some of the osteoblasts left behind become them

communicate with osteoblasts to fix damage

significance of calcium

essential for:

• nerve innervation of muscle + muscle contraction

• bone mineral deposition

• blood clotting

• nerve impulse transmission

hypocalcemia symptoms

• muscle spasms

• cramps

• seizures

• paresthesia (pins and needles/tingling/numbness)

Outline the calcium cycle

1. about a gram a day is taken in, about 0.8 grams are lost

2. 0.2 grams go to serum

3. within the serum, can turn into bone ( ½  a gram liberated from bone a day, ½ a gram taken up- homeostasis)

4. lose 1 gram/day in urine, then 0.8 grams reabsorbed from kidneys 

what do the parathyroid glands do? (generally)

regulate calcium and phosphate levels

secrete PTH (parathyroid hormone) in response to low calcium and high phosphate

have g-protein coupled receptors

what does PTH do?

• increases calcium reabsorption in renal distal tubule

• increases intestinal calcium absorption via action of vitamin D

• increases calcium release from bone (stimulates osteoclast activity, enhancing bone resorption)

• decrease phosphate reabsorption

outline the structure of PTH

84 amino acids but biological activity in the first 34 amino acids

• gets cleaved into smaller peptides

has an n-terminal and a c-terminal

assayed (measured) by two site assay 

PTH receptor expressed primarily in bone, kidney, cartilage 

outline PTH function in the kidney

• stimulates production of the active form of vitamin D- 125D3

• increases distal tubular reabsorption of calcium + inhibits PO4 reabsorption

outline the negative feedback mechanisms involved in PTH

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

• PTH translation (mRNA —> protein synthesis) inhibited by increased serum calcium 

once calcium released, should feedback to parathyroid to stop production of PTH

How does PTH work to rectify hypocalcaemia?

1. parathyroid glands increase PTH secretion

2. increased bone resorption

3. increase in urinary phosphate, decrease in urinary calcium, increase in 1,25D3 production

4. increase in calcium absorption in intestine, increase in phosphate absorption

5. serum calcium raises, feeds back to parathyroid glands to stop production of PTH

how does PTH work to rectify hyperphosphataemia?

same as hypocalcaemia, but pay attention to the kidneys- increase in urinary phosphate, decrease in urinary calcium, increase in 1,25D3 production 

calcium supersedes this system 

functions of vitamin D

• increases calcium and phosphate absorption in intestines

• important in osteoblast differentiation/osteoclastogenesis to increase bone remodeling

• deficiency in vitamin D or calcium —> osteomalacia (low mineral content)

• technically a steroid hormone

how do we get vitamin D3?

UV radiation and diet (eggs, fish)

UV radiation converts 7-dehydrocholesterol in skin —> vitamin D3

outline the process through which vitamin D turns into 1,25D3

vitamin D3 from light + diet go to blood, then liver

liver converts to 25-hydroxyvitamin D3 (inactive)

in the kidneys, D3 + PTH = 1,25D3

outline calcitonin

• produced by thyroid c-cells (parafollicular)

• released in hypercalcaemia, inhibits bone resorption by acting on osteoclasts (osteoclasts have calcitonin receptor, calcitonin turns them off)

• not essential to life

• ‘i’m going to protect bone’ hormone

outline the production of calcitonin

• example of alternative splicing (look at you knowing what that means :)

• two calcitonin gene products from a single gene and primary RNA transcript- calcitonin and calcitonin gene-related peptide

outline how the parathyroid rectifies serum hypercalcaemia 

1. reduction in PTH secretion as instructed by parathyroid glands

2. calcitonin acts on bone to reduce bone resorption

3. reduction in urinary phosphate and 1,25D3 production, increase in urinary calcium 

4. reduction in calcium and phosphate absorption in the intestines

list the metabolic bone diseases (that you need to know)

1. hyperparathyroidism

2. rickets/osteomalacia

3. renal osteodystrophy

4. osteoporosis 

what is primary hyperparathyroidism?

• making parathyroid hormone regardless of feedback = raised serum PTH

• caused by a parathyroid tumor (usually benign adenoma)

• cause hypercalcaemia and low serum phosphate, loss of negative feedback from hypercalcaemia

• treatment = surgery

clinical features of hyperparathyroidism

Symptoms caused by electrolyte imbalance

Neuro: lethargy and confusion

Renal: thirst/polyuria, renal stones (caused by lots of calcium going through kidneys)

GI: constipation, pancreatitis

Rheumatic: joint pain, fracture

Neuropsychiatric: depression

Cardiac: hypertension

outline secondary hyperparathyroidism

caused by renal disease

increased phosphate, decreased activation of vitamin D- kidneys can’t absorb Ca2+ or produce VD

absorbing less calcium in digestive tract, parathyroid gland compensates by producting more PTH

loss in bone content as calcium lost in urine + not absorbed in diet

treatment with phosphate binders or vitamin D analogues

outline tertiary hyperparathyroidism

long-standing secondary HPT —> irreversible parathyroid hyperplasia 

usually seen when renal disease corrected 

elevated PTH over extended period —> enlarged parathyroid 

use of endocrine glands heavily over time = build up, disuse of endocrine glands over time = atrophy

outline vitamin D/calcium deficiency

—> osteomalacia (low mineral content) due to lack of mineralisation of osteoid

intestinal calcium absorption capacity decreases with age + vitamin D levels are low in the elderly

softer bone, more likely to break or pseudofracture

low vitamin D —> low intestinal calcium absorption

outline osteomalacia

Rickets when affects growing skeleton- osteomalacia when affects adult skeleton

bones unduly soft, loss of calcium from bones

rickets: osteoid at growth plate is weak —> bow legs, growth plate expands to compensate (swollen koints)

• as it grows longer, without calcification, compression from body weight = bendy bones

osteomalacia —> bone pain and pseudofractures

causes of rickets and osteomalacia

• dietary/lack of sunlight

• inherited (rarely)

calcium + vitamin D supplementation highly effective in reducing fractures, their actions reduce PTH levels and prevent osteoclast mediated bone resorption

outline renal osteodystrophy

reduced renal mass- ‘knackered kidney’

• reduction in urinary phosphate, increase in urinary calcium, reduction in 1,25D3 production (unable to secrete more phosphate, therefore higher serum levels)

• leads to hyperphosphataemia, hypocalcaemia and decreased active 1,25D3

outline osteoporosis

• low bone mass, micro-architectural deterioration of bone tissue

• increase in bone fragility + susceptibility to fracture

• less resistant to compressive force, decrease in bone porosity

osteoporosis 

• loss of bone mass/density = both mineral and osteoid decreased. normal bone but less of it, increased fracture risk 

• osteoporosis of aging- males + females have gradual decline in bone density from early adult peak

• postmenopausal osteoporosis = rapid decline in female bone density following decline in estrogen at menopause

• estrogen deficiency increases bone remodelling rate + degree of bone resorption

• treatment = hormone replacement, biphosphonates 

draw a bone + its components