Bone homeostasis Flashcards
What is bone turnover influenced by?
Calcium, phosphate, magnesium metabolism
PTH and 1,25 (OH)2 D
Also other hormones such as TSH, cortisol, oestrogen and androgens
What is a key endocrinological axis invovled?
calcium-PTH axis
By what and how is calcium regulated
Via two hormones; PTH and 1,25 (OH)2 D (calcitrol)
Vitamin D - acts on kidney to reduce Ca excretion and the small intestine to increase absorption of calcium.
PTH senses serum calcium and can initate increased calcium similar to vit D or via calcium storages (bone) minerilisation
- PTH also acts to release phophate
What is the activation process of vitamin D?
Cholesterol in the skin becomes vitamin D3 upon light exposure. Vitamin D is firstly hydroxylated in the liver to 25 (OH) vit D. Then hydroxylated again in the kidney to produce active form - 1,25 (OH)2 D
How does PTH act on kidneys?
Induces 25-OH vit D-1-alpha hydroxylase to increase the activation of vit D
- increases calcium reabsorption in the distal convoluted tubule
- Decrease phosphate uptake in proximal tubule
- Inhibits Na+H+ antitransporter activity which favors a mild hyperchloremic metabolic acidosis in hyperparathyroidism
PTH on the bone?
PTH stimulate bone resorption or bone formation depending on PTH conc and duration
- chronic exposure leads to increased bone reabsorption.
- PTH alters activity of osteoblasts and indirectly on osteoclasts
- Occurs via the binding of PTH to receptor to generate cAMP second messenger for intracellular messaging
How is calcium homeostasis affected in renal failure?
- Fall in Ca due to not enough activation of vit D
- increase in phosphate, because kidneys dont excrete excess
- increase in PTH - stimualted by low Ca. If continual then can cause secondary hyperparathyroidism
- Renal failure leads to hypercalcaemiac due to hyperparathyroidism
True or false: Calcium is the only affector to PTH secretion.
False.
Changes in phosphate can indirectly affect PTH secretion.
Hypomagnasaemia has been shown to reduce PTH secretion as the process is Mg dependent.
- Not seen in mild hypomagnasaemia
Function of osteoblast
- produce matrix which mineralises to form osteoid - coordinate minerlisation of bone
- become quiescent and flatten to becom lining cells
- respond to hormonal control to activate osteoclast
- regulate osteoclast maturation by soluble factors and cognate interaction, resulting in bone resorption - also express the necessary RANKL
- the osteoblast function requires high amounts of ATP
Function of osteocytes
- cells inisde the bone which sense mechanical stres to initate remodelling
- transport mineral into and out the bone
Function of osteoclasts
- dissovle bone by solubiling mineral - resorption
- effects change in bone structure
Explain bone remodelling.
Osteoblasts produce RANKL which activates RANK on osteoclast precursors
- stimulates cell to differentiate in mature osteoclast
- activated RANK induces expression of c-Fos which binds to DNA and activates genes required for osteoclast function
Disorders of the bone?
Osteomalacia - inadequate minerilisation of bone
osteoporosis - reduced bone mineral density
Pagets disease - excessive reabsorption and formation leading to weak and misshapen bones
Renal osteodystrophy - kidneys fail to maintain Ca and PO4
Rheumatoid osteoarthritis - systemic inflammatory disease
Forms of calcium measurement.
Serum calcium and ionised calcium
- ionised is hard to measure, but can be done using a ABG machine
Adj Ca account for changes in albumin
- albumin may mask hypercalcaemia
- interpret with caution in extremes of pH
Forms of calcium measurement.
Serum calcium and ionised calcium
- ionised is hard to measure, but can be done using a ABG machine
Adj Ca account for changes in albumin
- albumin may mask hypercalcaemia
- interpret with caution in extremes of pH
- guesstimate
Hypercalcaemia causes.
Increased Gi absorption - elevated Vit D or PTH
Increased bone resorption - increased bone turnover
Decreased bone minerilisation - elevated PTH
Decreased urinary excretion - elevated PTH and Vit D
Common causes:
primary hyperparathyroidism
Malignant disease
Causes of hyperphosphataemia.
Pseudohyperphosphataemia - haemolysed specimen, myeloma, delayed seperation
Increased phosphate input - IV PO4, Rectal PO4, Cell death
Reduced phosphate excretion
- Reduced eGFR due to acute or chronic renal failure
- Increased renal tubule reabsorption can be physiological or pathological
Causes of hypophosphataemia
Inadequate absorption
Abnormal urinary phosphate loss
- primary or secondary hyperthyroidism
- osmotic diuresis
- Diuretic
Shifts of phopshate from ECF to cells
- <1% in extracellular space
- Recovery from DKA
- Refeeding syndrome
- Respiratory alkalosis
Describe the two types of bone tissue.
Compact
- Forms outer shell of bones consisting of very hard bones arranged in concentric layers
- Account for 80% of bone mass
Cancellous
- Located beneath the compact bone
- Consist of a meshwork of bony trabeculae with many interconnecting spaces containing bone marrow
- Accounts for remaining 20% of total bone mass but nearly 10x surface area of compact bone
How is the differentiation/activation of osteoclasts regulated?
- The activaiton of c-FOS activates IFN-beta which prevents further osteoclast activation
- Furthermore, osteoprotegerin is soluble protein released from osteoblasts that bind to RANKL preventing RANK activation - competitive inhibition
Match the following disorders
A. Osteomalacia B. Rheumatoid osteoarthritis C. Osteoporosis D. Renal osteodystrophy E. Pagets disease
- Systemic inflammatory disease
- Kidneys fail to maintain Ca and PO4
- Inadequate minerilisation of bone
- Excessive resorption and formation leading to weak and misshapen bones
- Reduced bone mineral density
A3 B1 C5 D2 E4
What occurs in calcium homeostasis during hypercalcaemia?
- Increased Gi absorption
- Increased bone resorption
- Decrease bone mineralisation
- Decreased urinary excretion
What occurs in calcium homeostasis during hypocalcaemia?
- Decrease GI absorption
- Decreased bone resorption
- Increase bone mineralisation
- Increased urinary excretion
Causes of hypocalcaemia?
Most common
- Acute or chronic RF
- Hypoparathyroidism
- Hypomagnesaemia
- Vit D deficiency
Parathyroid
- agenesis
- destruction
Non-thyroid
- vit D deficiency or resistance
- Altered Vit D metabolims
- Acute pancreatitis
- Acute rhabdomyolysis
What are some technical errors that may cause low calcium readings?
EDTA contamination
Multiple transfusions with citrated blood products
Hyperphosphatemia effect
- Increase GI absorption
- Increased bone resorption
- Decrease bone mineralisation
- Decrease urinary excretion
What are some characteristics of hypophosphataemia
- Decrease GI absorption
- Decreased bone resorption
- Increase bone mineralisation
- Increased urinary excretion
Causes of hyperphosphataemia
Pseudohyperphsophataemia occurs in haemolysed specimens
Reduced PO4 excretion
- Reduced eGFR due to renal failure
- Increased renal tubule reabsorption due to recovery from vit D deficiency or reduced PTH
Causes of hypomagnesaemia
Decreased intake Loss from body Renal - Alcoholism - Diuresis - Drugs - Hypercalcaemia
Causes of hypermagnesaemia
- Impaired renal function
- Large Mg load; IV contamination, post cardiac surgery
Rarely:
- Excessive tissue breakdown
- Lithium treatment
- Addisons
