Metabolic Bone Disease - Biochemistry Flashcards
What makes the bone strong
Mass
Material properties (mineral and matrix)
Microarchitecture
Macro-architecture
Describe the age related changes in bone mass
Peak bone mass reached during mid 20s
Stable around the 40s where consolidation occurs
Declines at around after 40
Men have a slower loss than women, who lose fast in early menopause
What are biochemical investigations in bone disease
Bone profile (calcium, corrected calcium/albumin, phosphate, alkaline phosphatase)
Renal function (PTH, 25-hydroxy vit D)
Urine (calcium/phosphate, NTX)
Summarise the bone remodelling cycle
A microcrack crosses the canaliculi and severs the osteocyte processes, inducing osteocyte apoptosis
This signals to the surface lining cells, which release factors to recruit cells from the blood and marrow to the remodelling compartment
Osteoclasts are generated locally and resorb the matrix and the mitrocrack
Then osteoblasts deposit new lamellar bone
Osteoblasts that become trapped in the matrix become osteocytes
What is the ‘corrected’ calcium level?
This compensates for changes in protein level (if proteins are high, it compensates down)
How is corrected calcium calculated
corrected calcium = calcium + 0.02(45-albumin)
What is the normal range for serum calcium concentration and describe the distribution of calcium.
2.15-2.56 mmol/L
46% plasma protein bound (albumin)
47% free calcium
7% complexes (with phosphate or citrate)
Describe the effects of PTH in:
a. Bone
b. Kidneys
Bone
Acute release of available calcium
Stimulation of osteoclasts and inhibition of osteoblasts
Increased bone resorption (decreased bone mass) through the RANK system
Kidneys
Increased calcium reabsorption in the distal tubule
Increased phosphate excretion
Increased stimulation of 1-alpha hydroxylase (increasing calcitriol production)
Where does the PTH-mediated increase in calcium reabsorption take place in the nephron?
Distal convoluted tubule
Where does the PTH-mediated increase in phosphate excretion take place in the nephron?
Proximal convoluted tubule
What electrolyte is PTH dependent on
Magnesium
Hypomg leads to low PTH and hypocalcaemia (important for alcoholics)
What is the half life of PTH
8 minutes
Short half-life ; allows intraoperative sampling
What can PTH receptor be activated by
PTHrP and PTH
PTHrp cis produced by some tuours, and so hypercalcaemia may be first presenting feature ie small cell ca lung
How does the parathyroid gland monitors serum Ca
Calcium-sensing receptor
What is the relationship between PTH levels and Ca2+ levels in vivo and describe the minimum and set point
Steep inverse sigmoidal curve
MINIMUM: even at high calcium levels there is base-line PTH secretion
SET-POINT: point of half maximal suppression of PTH; steep part of slope;
Small perturbation causes large change PTH
What are the causes of primary hyperparathyroidism
Parathyroid adenoma
Parathyroid hyperplasia
parathyroid CA
Familial syndromes (MEN1, MEN 2A, HPT-JT)
Which age group (+ gender ratio) does primary hyperparathyroidism affect
50s
3:1 female to male
2% of post-menopausal develop
How is primary hyperparathyroidism diagnosed
Elevated total/ionised calcium with PTH levels elevated (or in upper half of normal range)
Corrected calcium > 2.6mmol/l
What are the clinical features of primary hyperparathyroidism
Thirst polyuria Tiredness, fatigue, muscle weakness Stones Abdominal moans Psychic groans
What is the danger of high serum calcium
Can cause diuresis
May become a medical emergency
What are the risks of a chronically elevated PTH
Increase stone risk
Increases cortical bone resorption
Increased fracture risk
What are the biochemical findings in primary hyperthyroidism
Increased calcium
Decreased phosphate
Elevated PTH (or in upper range)
Increased urine calcium excretion
What is the half life of vit D binding proteins
3 days
Then filtered by kidney
Describe the effects of calcitriol on kidneys and small intestine
Kidneys
Increased Ca2+ and phosphate reabsorption (Stimulated by increased phosphate absorption from small intestine) in the DISTAL tubule
Small intestine
Increase Ca2+ and phosphate absorption in the duodenum
Explain how vitamin D is synthesised
- 7-dehydrocholesterol is converted to cholecalciferol by UV light (or cholecalciferol acquired from diet)
- Converted to 25-cholecalciferol in the liver
- Conversion to Calcitriol in the kidney by 1-alpha-hydroxylase
- Calcitriol acts on small intestine, bone and kidney
What are the effects of vitamin D on the bone and kidney
Bone - Acts on osteoblasts to increase formation of osteoclasts through RANKL
Increases osteoblast differentiation and bone formation
Kidney - facilitates PTH action increase Ca reabsorption in distal tubule
What are the signs and symptoms of rickets
Symptoms
Bone pain and tenderness (axial)
Muscle weakness (proximal)
Lack of play
Signs Age dependent deformity Myopathy Hypotonia Short stature Tenderness on percussion
What are the vitamin D related causes of rickets/osteomalacia
Dietary
GI - small bowel malabsorption, pancreatic insufficiency, liver/biliary disturbance
Chronic renal failure
Rare hereditary
type 1 - 1a-hydroxylase
type 2 - defective VDR for calcitriol
For each of the following state whether it would be high, low ornormal in the serum of a Rickets patient:
a. Calcium
b. Phosphate
c. Alkaline Phosphatase
d. 25-OH cholecalciferol
e. PTH
f. URINE phosphate
a. Calcium - low/normal
b. Phosphate - low/normal
c. Alkaline Phosphatase - high
d. 25-OH cholecalciferol - low
e. PTH - high
f. URINE phosphate - high
High urine phosphate
Glycosuria, aminoaciduria, high pH, proteinuria
What can cause PCT phosphate loss
FGF-23
PTH
Where is FGF-23 produced and what effect does it have that is the same and unlike PTH
osteoblast lineage cells, long bones
Like PTH - causes Phosphate loss
Unlike PTH - inhibits activation of Vit D by 1 alpha-hydroxylate
What does the damaging of the kidney proximal tubule cause
Phosphaturia
Stops 1-alpha-hydroxylation of vitamin D
What are the causes of Fanconi’s syndrome
Multiple myeloma
Heavy metal poisoning: lead, mercury
Drugs: tenofovir, gentamycin
Congenital disease: Wilsons, glycogen storage diseases
How does oestrogen deficiency lead to a decrease in bone mineral density
Increases the number of remodelling units
Causes remodelling imbalance with increased bone resorption (90%) compared to formation (45%) due to enhanced osteoclast survival and activity
Deeper and more resorption pits
Decreased osteocyte sensing
What do deep resorption pits in bone lead to
Trabecular perforation and cortical excess excavation
How is osteoporosis diagnosed
Serum biochem should be normal if primary. Exclude all other causes.
- Check for vit D deficiency
- Check for secondary endocrine causes
- Exclude multiple myeloma
- May have high urine calcium
What can be used biochemically to assess the activity of bone
Markers of none formation and resorption which are dynamic
What is the best predictor of fracture risk and what is used to measure it
Bone density (BMD) represents 70% of total risk
DEXA
What makes up collagen type 1 and what cell is it produced by
2 alpha-1, 1 alpha-2
Osteoblast
What can be used as a marker of bone formation that is linked to collagen production?
P1NP = Procollagen type 1 N-terminal Propeptide
Extension peptides that are cut off during collagen synthesis
What can be used as a measure of bone resorption that is linked to collagen production?
Pyridinium ring linkage
These can be used to measure bone resorption; serum CTX, urine NTX
3 hydroxylysine molecules on adjacent tropocollagen fibrils condense
to form a PYRIDINIUM ring linkage
Why is a corrected calcium used
Hyperventilating → alkalosis which causes more Ca to bind to protein so that free levels drop
Venous stasis may falsely elevate LEVELS
What happens if rickets/vit D deficiency is left untreated
Leads to hypocalcaemia
Leads to neuromuscular irritability and seizures
Leads to bradycardia which may lead to arrhythmias and heart failure
What are the issues with using bone markers is diagnosis
Reproducibility: CV 20%
Positive association with age
Need to correct for Cr
Diurnal variation in urine markers (peak 4-8am)
What are the uses of bone markers
Common use is alkaline phosphatase
Paget’s
Osteomalacia
Boney metastases (prostate with PSA)
What is BSPA and what disorders may cause an increase in it
Bone-specific alkaline phosphatase
Increased in → Paget’s disease → Osteomalacia → Bone metastases → Hyperparathyroidism →Hyperthyroidism
How does renal osteodystrophy cause hypercalcaemia
- GFR drops
- Increased serum phosphate
- Reduction in 1,25 Vit D/ calcitriol
- Secondary hyperparathyroidism develops to compensate
- Hypocalcaemia develops
- Parathyroid become autonomous and causes hypercalameia
