Bone Metabolism Flashcards
How is bone mass normally maintained?
What regulates this?
Balance between activity of:
• Osteoblasts which produce matrix and bone mineralization
• Osteoclasts which break it down (degrade the matrix and cause resorption)
Process is tightly regulated by local endocrine factors • Hormones • Vitamins • Stress • Inflammation • Growth factors • cytokines
What factors affect formation and resorption by osteoblasts/clasts?
• Glucocorticoids o Inhibits osteoblasts • Estrogen o Inhibits osteoclasts and stimulates osteoblasts • Thyroid hormones o Stimulates osteoclasts • Growth hormone nd IGF1 o Stimulates osteoblasts • Calcitonin o Inhibits osteoclasts
What things can shift bone turnover to favour resorption?
- Decrease in sex hormones
- Drugs- glucocorticoids
- Hyperparathyroidism
- Cushings Syndrome
- Kidney disease
- GIT absorptive issues
- Genetic causes- affect enzymes that regulate bone metabolism
What is the leading cause of osteoporosis?
Who is it most common in?
- It is the most common bone disease
- Leading cause is a drop in oestrogen in women and testosterone in men
- Most common in post-menopausal Caucasian women
What is Osteoporosis?
- Systemic condition characterized by low bone mass and deterioration in bone microarchitecture
- Leads to increased bone fragility and increased fracture risk
Where is the bodies calcium usually stored?
Why is this clinically important?
- 99% is stored in the bone as ca hydroxyapatite
- 1% is dissolved in blood and ECF
- Bound to plasma proteins, small organic molecules (Phosphate) and free ions
- This means that If the body needs calcium, it needs to come from this store
Why is calcium homeostasis important?
- It is essential for key cellular processes
- Heart and muscle contraction
- Nerve conduction
- Exocytosis
- Activity of enzymes
- There is a tight control of extra and intracellular calcium levels via transporters, pumps and binding proteins
- If there is a dietary deficit in calcium it will be resorbed from the bone
What are the clinical consequences of high or low blood calcium?
- Hypercalcaemia
- Fractures due to excessive resorption of bones making them prone to break after minor trauma
- Formation of renal stones
- Proximal myopathy
- Pancreatitis
- Mental changes
- Usually due to primary hyperparathyroidism
- Hypocalcaemia
- Paraesthesia
- Cramps
- Tetany
- Agitation
- Seizures
What are the key players in calcium homeostasis, and how do they interact?
Parathyroid hormone
• Fast acting
• Responsible for the minute to minute control of serum calcium concentration
• Calcitriol
• Slow acting and maintains day to day control of serum calcium concentration
What are the main target organs in calcium homeostasis?
- Intestine
- Kidney
- Bone
Parathyroid hormone: What is its role? Where is it produced/Secreted? What regulates this ? What does it target and what are the effects?
Role:
• The most important regulator of blood calcium and phosphate
• Primary hormone regulating bone metabolism/remodelling
Produced and secreted:
• Parathyroid gland
• Synthesized as a preprohormone
Regulation:
• Secretion is dependent on serum calcium
• Calcium binds to a Calcium sensing receptor (CaR)
• This is a GPCR expressed on many cells
• Signalling cascade leads to SUPPRESSION of PTH secretion and cell proliferation
• Inhibited by - high plasma Ca
• Stimulated by- low plasma ca
Targets:
• Bone
• Causes resorption via increased osteoclast activity
• Increased calcium mobilisation
• Kidney
• Increased calcium reabsorption
• Decreased calcium excretion in urine
• Increased production of active vitamin D
o This acts on the small intestine to increase calcium absorption from the diet
Effect:
• Increased blood calcium
What is the Ca/PTH axis feedback loop?
What is the clinical significance of this?
- PTH is the principal modulator of plasma ca levels
- ECF Ca levels are the primary determinant of PTH secretion
- Comparing calcium and PTH levels can show where there is a problem in the axis
- Examples
- Low calcium with low PTH = PTH not responding ? Hypoparathyroidism
- High Calcium with High PTH = Gland producing too much PTH ? Hyperparathyroidism
- Low calcium with high PTH = response is correct- need to evaluate for non parathyroid problem
Calcitonin
Where is it produced/Secreted?
What regulates this ?
What does it target and what are the effects?
Produced:
• Thyroid C cells (main source)
• Also in other tissues (lung, intestine and mammary gland)
Targets: • Kidney • Increases excretion of calcium • Bone • Increases deposition in bone by inhibiting osteoclasts • Prevents resorption • Intestine • Decreases uptake
Aim:
• Decrease blood calcium levels
Vitamin D2/D3
What are the different forms?
Where is it produced?
Solubility/trasnport?
Vitamin D2 = ergocalcigerol
• Sourced from plan and yeast
Vitamin D3 = Cholecalciferol
• Most is produced by the skin in photochemical synthesis
• Exposure of the precursor to UV radiation
• Some is ingested in small amounts in fish
Activity:
• In the D2 or D3 form it is a pro-hormone with little significant biological activity
• Needs to be metabolised to an active form
- Lipid soluble steroid hormone
- Transported in the blood by transcalciferin
- Vitamin D binding protein
- Long half life - 5-12 hours
Calcitriol:
How is it synthesized?
What are its actions?
Solubility/binding?
- Vitamin D3 must be metabolised within the body to become the active form - calcitriol
- Liver forms the intermediate form - Calcidiol
- Kidney transforms this into the active form calcitriol under the stimulation of PTH
- The lipid soluble hormone Binds to intracellular Vitamin D receptors
- Effects gene expression to cause protein synthesis
Acts on • Bone: • Regulates bone remodeling • Gut • Inreases calcium and phosphate absorption • Muscle • Increases growth , strength and contraction • Increases immune function • Decreases inflammation • Epithelial cells • Increases differentiation • Decreases proliferation • Causes apoptosis
What happens to calcium absorption when there is a vitamin D deficiency?
- It is not efficiently absorbed
* Calcitriol controls synthesis of genes and increases expression of proteins that promote transcellular transport of ca
What happens when blood Calcium levels fall?
PTH
• Low calcium causes stimulation of PTH secretion
• PTH acts directly on bone to induce osteoclastic resorption from bone
• PTH increases synthesis of Calcitriol by the kidney
• PTH increases reabsorption of calcium from the glomerular filtrate preventing loss in the urine
Calcitriol
• Calcitriol increases intestinal absorption of calcium
• Calcitriol can stimulate osteoclasts indirectly by stimulating osteoblasts to release factors that stimulate differentiation
• Not as potent as PTH
• Slow acting
• Role in normal bone remodeling
What do PTH , calcitriol and calcitonin do In the case of normal calcium levels?
PTH
• Inhibition of PTH synthesis
• Decrease in PTH levels
• Less mobilization of calcium from the bones
Calcitriol
• Enhances absorption of Ca and phosphorus from the small intestine
• This helps to maintain a proper balance that assists Calcitonin to mineralize the bone matrix
Calcitonin
• Reduces osteoclastic bone resorption and allows excess calcium to deposit in bones
• Decreases PTH synthesis
How common is Vitamin D deficiency?
What are the effects of a mild/Moderate deficiency?
What are the effects of a severe deficiency?
- More than 40% of the world is vitamin D deficient
- 1 in 5 children
- Can be due to :
- Reduced intake
- Age related factors
- Decreased sun exposure
- Sunscreen use
- Decline in renal function
- Mild to moderate deficiency
- Decreased calcium absorption resulting in decreased serum calcium
- Increased PTH causing increased tubular resorption of calcium and bone resorption
- Decreased bone density
- High bone turnover
- Increased fracture risk in older people
• Severe Vitamin D deficiency
• <15 nM
• Blood calcium below normal
• Can cause secondary hyperparathyroidism
o PTH also causes phosphorus loss via the urine leading to a decreased serum phosphate
o This imbalance causes a defect in bone mineralization
• Children get rickets
• Adults get Osteomalacia
Phosphorus- How abundant is it? Where is it stored? What do cells use it for? Dietary sources?
- It is the most abundant mineral after calcium
- The bulk is stored in bone (85%) as mineralized hydroxyapatite ECM giving the bone strength
- Every cell contains phosphate anions
- Complexed to proteins or lipids
- Nucleic acids in DNA and RNA
- Needed for energy production
- Used as a chemical buffer in serum and urine
- Most unprocessed food has it
How is phosphate balance maintained- ie ?
Renal cotransporter:
• There are sodium- phosphate co transporters in the proximal renal tubular cells
• If there is low dietary phosphate intake there is an increase in expression of transporters leading to increased renal phosphate absorption
• In excess intake the opposite occurs and there is less transporters expression and more phosphate is excreted in urine
FGF-23
• FGF 23 = 23 fibroblast growth factor (phosphaturic hormone)
• Secreted from bone
• Works on the kidney
• Secreted in response to HIGH dietary intake or serum phosphate levels
• It works on the Sodium phosphate cotransporter to decrease expression of transporters
• Causes:
• Inhibition of phosphate reabsorption (Similar to PTH)
• Increased excretion of phosphate (Similar to PTH)
• Decreases calcitriol synthesis resulting in decreased gut phosphate absorption (Opposite to PTH)
• Aim:
• To decrease serum phosphate level
What happens if the FGF-23 is excessively elevated?
What causes it?
- Phosphate levels will become too decreased
- Linked to rare forms of hereditary hypophosphataemic rickets and osteomalacia
- Most often found in chronic kidney disease
- Decreased glomerular filtration
- Decreased kidney phosphate excretion
- Increased FGF 23 secretion from bone
- Decreased calcitriol through inhibition of hydroxylase in the kidney
- Low blood calcium
- Secondary hyperparathyroidism
Very broadly what are the effects of the following on ca and phosphate levels?
PTH
Calcitriol
PTH :
• Increases Calcium
• Decreases Phosphate
Calcitriol
• Increases Calcium
• Increases Phosphate
What are some causes of hypercalcaemia?
What is the reference range?
> 2.6 • Hyperparathyroidism • Primary, secondary, tertiary • Increased absorption of calcium • Malignancy • Vitamin D intoxication • Thiazide diuretics • Renal insufficiency • Thyrotoxicosis • Familial hypocalciuric hypercalcaemia • Sarcoidosis
