Bone + Metabolism Flashcards
Inorganic Bone
> 65%
Storehouse for 99% of Calcium in the body
Calcium hydroxyapatite
85% of the phosphorus, 65% sodium, magnesium
Organic Bone
> 35%
> bone cells and protein mix
Endocrine regulation of bone - hormones
Parathyroid hormone -
Thyroid hormone - necessary during brain development- controls rate at which sites differentiate in the growth plates + its absence
Growth hormone - regulates osteoclasts differentiation
Insulin like growth factor - involved in site differentiation and linear growth, also has roles in osteoclasts and osteoblast differentiation
Oestrogen - inhibits bone remodelling by inhibiting osteoblast differentiation and activity + direct effects on other bone types
What is it necessary to maintain calcium levels?
Necessary to maintain our calcium in our extra cellular fluids, blood etc., within a narrow homeostatic range. This is explaining a tiny fraction of the body’s total fraction of calcium.
What areas are included during calcium metabolism?
GI Tract (calcium intake ~1g/day), Kidney (calcium excretion in urine, moderated by reabsorption), Bone (reservoir to maintain homeostasis)
What is PCH (Parathyroid Hormone)?
A hormone produced by parathyroid glands, which acts to increase circulating calcium levels.
Low Calcium detected
Ca2+ levels fall below homeostatic range (low circulating/low serum calcium)
Detected in parathyroid glands = stimulating the release of PTH
PTH increases bone reabsorption (bone cells) , breaking down some of our bone and releasing the Ca2+ and phosphate stored within that bone into the circulatory system.
High serum calcium
Closes the feedback loop, as high serum calcium inhibits it’s production in the parathyroid, as does high levels of circulating active vitamin D.
How do bones cells help with reabsorption and then release of calcium and phosphate?
PTH has a direct effect on osteoblasts and indirect effects on osteoclasts via the H1 receptor found on osteoblasts. Stimulates osteoblasts to produce RANKL and inhibits their production of OPG. = increase the paracrine ration of RANKL available = increase osteoblast activity, osteoblast differentiation == increases bone reabsorption and break down hydroxyapatite crystals, releasing calcium and phosphate from the reabsorbed bone into circulation.
What are PTH’s roles, in regard to calcium homeostasis?
General effect: BONE TURNOVER
- Reabsorption from bone to release calcium and phosphate
- Also stimulates osteoblast differentiation: intermittent PTH is anabolic (treating patients and then letting patients recover), Continuous PTH is catabolic (continually treating it, results in loss in bone mass)
- acts on the kidneys to reduce the excretion of calcium from the kidneys by increasing calcium reabsorption.
What is bone turnover?
The general effect of PTH. It’s the frequency with which the bone remodelling cycle occurs.
Synthetic PTH
Has been produced and used as a drug treatment for various bone disorders, normally called PTH1 - 34. It consists of the first 34 A.A of PTH.
PTH reabsorption Summary
PTH acts to release calcium from the bone by indirectly stimulating osteoclasts through increasing RANKL production in the osteoblasts and inhibiting OPG production.
PTH effect on Kidneys
- Acts to reduce the excretion of calcium from the kidneys, by increasing calcium reabsorption. The amount of calcium in the bloodstream is increased by preventing excretion of calcium.
- Also increases the amount of phosphate excreted by the kidneys, by decreasing the reabsorption of phosphate. More phosphate is filtered out to the kidneys and excreted.
- Increases the production of Active Vit. D3., hormone produced by the kidneys.
Active Vitamin D3 Production
Most pro hormone form for Vitamin D3 in our skin, when it is exposed to UV Radiation from the sunlight.
This is then converted to 25-hydroxy vitamin D in the liver
Then in the kidneys, it can be converted to 1,25 dihydroxy vitamin D3 or Active vitamin D3
Active Vitamin D3 effects
- Acts in the GI Tract to increase calcium absorption from our diets (in the absence, very little calcium can be absorbed)
- Goes to the parathyroid and acts there to inhibit the release of PTH
What 3 areas are vital in maintaining phosphate levels?
- GI tract, where phosphate is reabsorbed from the diet
- Kidney, where it is excreted in the urine
- Bone, where it’s stored
Bone mineral density (BMD)
The amount of mineral in bone tissue. Can be measured in a scanning process called dual-energy X-ray absorptiometry (DXA or DEXA). Low BMD indicates increased fracture risk.
Osteoporosis
Severe loss of BMD leading to thinner, weaker bone and increased fracture risk.
Osteomalacia
A pathological condition where new bone cannot be mineralized.
Parathyroid gland
Four small glands located on the back of the thyroid. Secrete parathyroid hormone in response to decreases in plasma calcium.
Parathyroid hormone (PTH)
Maintains plasma calcium within physiological limits. Decreases in plasma [Ca] increase PTH secretion. Has complex action on bone, increasing bone turnover via actions in osteoblasts. Intermittent treatment with synthetic PTH has an anabolic effect, continuous treatment is catabolic resulting in loss of BMD.
Vitamin D
Strictly speaking, a hormone not a vitamin. Synthesised in skin in presence of sunlight but can also be obtained in the diet. Dietary or skin-synthesized vitamin D is biologically inert. It is converted into a prohormone (25(OH) vitamin D3) by the liver, which, in turn, is converted into the active form (1,25(OH)2 vitamin D3, or calcitriol) by a hydroxylase enzyme in the kidney.
FGF23
Fibroblast growth factor 23. A hormone produced by the osteocytes in response to high plasma [PO4] acts in the kidney to decrease phosphate reabsorption and the parathyroid to inhibit PTH release.
calcium metabolism
diagram • Gastrointestinal tract – Calcium intake ~1g/day • Kidney – Calcium excretion in urine – Moderated by reabsorbtion • Bone – Reservoir to maintain homeostasis
phosphate metabolism
diagram
Osteocytes are endocrine cells
• Embedded in lacunae in mature bone • Connected via processes through canalicular channels • Form a mechanosensory network throughout bone • Osteocytes communicate with systemic circulation as well as bone cells • High serum phosphate stimulates FGF23 synthesis in osteocytes
FGF23
• Fibroblast Growth Factor-23
• In 2000, activating mutations in FGF23 were identified in
patients with autosomal dominant hypophosphatemic
rickets
• Acts to increase phosphate excretion in the kidney.
FGF23 actions to reduce serum phosphate
diagram
What is a metabolic bone disease?
• A group of diseases that cause reduced bone mass and reduced
bone strength
• Due to imbalance of various chemicals in the body (vitamins,
hormones, minerals, etc)
• Cause altered bone cell activity, rate of mineralisation, or
changes in bone structure
• Osteoporosis is a metabolic bone disease
Rickets / Osteomalacia
• Defective mineralisation of normally synthesized bone matrix
• Rickets in children
• Effectively two types
– Deficiency of vitamin D3 (causing hypocalcemia)
– Deficiency of Phosphate
• Oncogenic Osteomalacia
– mesenchymal tumours producing excess FGF23
Bone in Osteomalacia
Normal bone:
Green – mature mineralised bone - most
Orange – unmineralised osteoid - little
Osteomalacia:
Green – mature mineralised bone – very little
Orange – unmineralised osteoid - most
diagrams
Osteomalacia - outcomes
• bone pain/tenderness • fracture • proximal weakness • bone deformity
Bowing of long bones
Widening of growth plates
LoosersZones
diagrams
Hyperparathyroidism
• Excess PTH – Hypercalcemia – Hypophosphatemia • Primary – parathyroid adenoma (85-90%) – chief cell hyperplasia • Secondary – chronic renal deficiency – vit D deficiency • Osteitis fibrosa cystica
mnemoic
• Stones (Kidney stones)
• Bones (Pain from osteitis fibrosa cystica
and excess bone resorption)
• Abdominal Moans (acute pancreatitis)
• Psychic Groans (psychosis & depression)
