Musculoskeletal 2 - MBD Biochemistry Flashcards
What makes bone strong?
- Mass
- Material properties (collagen, woven vs lamellar, mineralisation, microcracks)
- Microarchitecture (trabecular thickness, connectivity, and cortical porosity)
- Macroarchitecture (hip axis length, diameter)
List the biochemical investigations in bone disease
Serum:
- Bone profile (calcium, corrected calcium, phosphate, alkaline phosphatase, creatinine)
- Renal function (PTH, 25-hydroxy vitamin D)
Urine
- Calcium/phosphate
- NTX (N Telopeptide of Collagen)
List the biochemical changes in osteoporosis
- No change in chalcium, phosphate, or alkaline phosphatase
- Increase or no change in bone formation
- Increase in bone resorption
List the biochemical changes in osteomalactia
- Calcium may be the same or decreased
- Low phosphate
- High alkaline phosphatase
- Low vitamin D
- High PTH
- High urine phosphate
List the biochemical changes in pagets
- Calcium the same or increased
- Phosphate the same
- Alkaline phosphatase increased
- Hone formation increased
List the biochemical changes in primary hyperparathyroidism
- High calcium
- Low or normal phosphate
- Low or normal alkaline phosphatase
- Increased bone resorption
List the biochemical changes in renal osteodystrophy
- Decreased or normal calcium
- Increased phosphate
- Increased alkaline phosphatase
List the biochemical changes in metastases
- Increased calcium
- Increased phosphate
- Increased alkaline phosphatase
- Increased bone resorption
How are serum calcium measurements corrected?
- Conc calcium + 0.02(45 - conc albumin)
- High albumin will result in lower true (free) calcium
- 47% free ionised
Describe parathyroid gland production of PTH
- Inverse sigmoidal function between PTH and calcium levels
- Even at high calcium levels there is a base-line PTH secretion (MINIMUM)
- The set point is the point if half maximal suppression of PTH (steep part of slope). A small alteration causes large change in PTH
Describe calcium reabsorption and resorption caused by PTH
- Active calcium absorption in the distal tubule of kidney
- Sodium calcium exchanger and calcium ATPase
- Reabsorption via calbindin
- Bone resorption through the RANK system (increases RANK-L which causes activation of osteoclasts)
List the stats relating to primary HPT and its causes
- 50s female 3:1 male (2% post menopausal develop)
Causes
- Parathyroid adenoma (80%)
- Parathyroid hyperplasia (20%)
- Parathyroid CA (<1%)
- Familial syndromes (MEN1, MEN2A, HPT-JT)
How is primary HPT diagnosed?
- Elevated total/ionised calcium with PTH levels frankly elevated (or high normal)
- Decreased serum phosphate
- Hypercalcaemia and high PTH subjects in the normal range are not normal physiologically due to lack of inhibition
Why do patients with primary hyperparathyroidism get polydipsia and polyurea?
- High serum calcium causes diuresis
- Calcium is absorbed passively transceulluarly
- Increased water enters collecting duct (calcium of 3 is the same as taking frusemide)
How does activated vitamin D affect gut calcium absorption?
- Increases
- Passive paracellular linear
- Active in the duodenum
List the classical vitamin D actions
- Reabsorption of calcium and phosphate in the duodenum (MAIN)
- Increases osteoblast formation and synergises with PTH
- Facilitates PTH in the kidney to increase calcium reabsorption
- Reduces PTH secretion and increases FGF-23 production from bone
What is the definition of vitamin D deficiency?
- 75nmol/L as muscle function is better at those levels.
- PTH levels rise below this.
List the symptoms and signs 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
List the vitamin D related causes of rickets/osteomalacia
- Dietary
- GI - malabsorption, pancreatic insufficiency, liver/biliary disturbance, drugs (phenytoin/phenobarbitone)
- Renal (chronic renal failure)
- Rare hereditary (vitamin D dependent rickerts type 1 deficiency of 1 a hydroxylase or type 2 defective VDR for calcitriol)
How does FGF-23 act?
- Produced by osteoblast lineage cells when high phosphate is detected at the bone (following absorption in the gut)
- Causes phosphate loss
- Inhibits activation of vitamin D by 1 alpha hydroxylase
What does FGF-23 excess cause?
Rickets/osteomalacia
List the genetic and acquired causes of osteomalacia due to hypophosphataemia?
- Kidney looses phosphate
- Hypophasphataemia can be isolated - eg. X-linked hypophosphataemic rickets (FGF-23 levels permanently high) or autosomal dominant hypophosphataemic rickets
- Oncogenic osteomalacia (mesenchymal tumour produces FGF-23)
- Fanconi syndrome
What is fanconi syndrome?
Damage of the kidney proximal tumour causes phosphaturia and stops 1a hydroxylation of vitamin D
List causes of osteoporosis
High turnover (increased resporption greater than increased formation)
- Oestrogen deficiency
- Hyperparathyroidism
- Hyperthyroidism
- Hypogonadism
- Heparin
- Cyclosporine
Low turnover (decreased formation more pronounced than decreased resorption)
- Liver disease
- Heparin
- Age over 50
Increased resorption and decreased formation
- Glucocorticoids
How does oestrogen deficiency cause menopausal bone loss?
- Oestrogen inhibits PTH release
- Increased number of remodelling units
- Remodelling imbalance with increased bone resorption (90%) compared to bone formation (45%)
- Remodelling errors - deeper and more resorption pits(trabecular perforation and cortical excess excavation)
- Decreased osteocyte sensing
How is osteoporosis diagnosed?
- Biochemistry is used to exclude other causes
- Biochemistry will be normal if primary
- Check for vitamin D deficiency, hyperparathyroidism, hyperthyroidism and hypogonadism
- Exclude multiple myeloma
- High urine calcium
- DEXA scans (single best predictor of fracture risk)
How do DEXA scans work?
- Measure transmission through the body of X rays of two different photon energies
- Dual energy X ray absorptiometry
- T-score is compared to a 25 year old bone density
- Measure at vertebral and hips (commonest types of fracture, vertebral responds quickly to treatment)
List the markers of bone formation?
- Alpha 1 and Alpha 2 chains of type 1 collagen produced by osteoblast form extension peptides
- Extension peptides can be measured in the blood (eg. P1NP formed from procollagen)
List the markers of bone resorption?
- Serum CTX (carboxy-terminal collagen crosslinks)
- Urine NTX (N-telopeptide of collagen - stable product of bone resorption)
- Used in monitoring the response to treatment
- From collagen breakdown
List the problems with urinary collagen cross links
- Reproducibility
- Positive association with age
- Need to correct for creatinine
- Diurnal variation in urine markers (higher in the morning, as bone grows most at night)
What is alkaline phosphatase used to diagnose and monitor?
- Pagets
- Osteomalacia
- Boney metastases
What is BSAP?
- Bone specific alkaline phosphatase
- Tissue specific form (liver vs bone) so can be used to see if it is from bone or the liver
- Essential for mineralisation, regulating concentration of phosphocompounds
- Increased in pagets, osteomalacia and bone metastases
List the possible pathways of metabolic bone disease
- Increasing bone resorption
- Decreasing bone formation
- Altering bone structure
How active is cancellous bone?
- Remodelling 5% anytime
- Total skeleton remodells over 7 years
- Continuous exchange of ECF with bone fluid reserve
How is peak bone mass affected by exercise?
- Increases bone dimensions and changes bone shape
- Changes trabecular volumetric BMD
- Bone modelling by bone growth in the periosteum and resorption of endosteum to push the bone outwards (happens in males more, females grow less and have more endosteum)
Describe the bone remodelling process
- Crack is formed, and setected by the osteocytes.
- Osteocytes apoptose to release RANKL. They signal for haematopoietic cells to enter the bone, differentiate to the osteoclasts and perform resorption of bone
- Osteoblasts then reverse this by remanufacturing and laying down new bone, which is then mineralised.
- Osteoblasts form new lining cells or new osteocytes
- Osteoclasts last a few weeks, and osteoblasts months
List the effects of PTH
- Increase bone resorption to releae calcium and phosphate
- Increase phosphate excretion
- Increase calcium reabsorption
- Increase calcitriol formation
- Increase CaHPO4 absorption
List the clinically relevant points relating to PTH
- Mg dependent
- Half life 8 minutes
- The receptor is also activated by PTHrP (tumours)
What percentage of patients with elevated PTH get kidney stones?
20%
When is operation performed in primary HPT?
- Calcium 0.25mmol/l
- > 10mmol 24 hour urine calcium or stones
- Reduced Creatinine clearance (<60)
List the consequences of hypocalcaemia
- Neuromuscular irritability (parasthaesias, muscle twitching, seizures, bronchospasm)
- Cardiac signs (hypotension, heart failure, arrythymia, prolonged QT interval)
- Trousseaus sign and chvosteks sign
List the causes of fanconi syndrome
- Multiple myeloma
- Heavy metal poisoning (lead/mercury)
- Tenofovir or gentamycin
- Congenital disease (wilsons, glycogen storage diseases)
MOST COMMON CAUSE of hypophosphaemia
What is used to measure response to anabolic treatments?
P1NP (procollagen type 1 N propeptide) rises to peak in 3 months and predicts response
What is renal osteodystrophy?
- Increasing serum phosphate
- Reduction in 1,25 vitamin D
- Secondary hyperparathyroidism develops (GFR under 60)
- Unsuccessful and hypocalcaemia develops
- Later the parathyroids become autonomous causing hypercalcaemia
