Metabolic bone disease: biochemistry Flashcards
what is metabolic bone disease?
A group of diseases that cause a change in bone density bone strength by 1. INCREASING bone resorption 2. DECREASING bone formation 3. Altering bone structure
And may be associated with disturbances in mineral metabolism
What are the 5 common metabolic bone disorders?
Primary hyperparathyroidism
Rickets/ Osteomalacia
Osteoporosis
Paget’s Disease
Renal osteodystrophy
symptoms in these disease:
- metabolic
- specific to bone
Metabolic
- Hypocalacaemia
- Hypercalcaemia
- Hypo/Hyperphosphataemia
Specific to bone
- Bone Pain
- Deformity
- Fractures
what does the bone calcium do?
-hydroxyapatite
-cancellous bone metabolically active
remodelling
continuous exchange of ECF with bone fluid reserve
What makes a bone strong?
-the 4 Ms
Mass
Material properties (matrix and mineral)
- collagen
- woven versus lamellar
- mineralisation
- microcracks
microarchitecture
- trabecular thickness
- trabecular connectivity
- cortical porosity
microarchitecture
- hip axis length
- diameter
what might be used to assess bone structure and function?
Bone histology
Biochemical tests
Bone mineral densitometry, e.g. osteoporosis
Radiology
what is the age related changes in bone mass like?
Men have greater bone mass than women
bone mass increases, no increase from 27 to 42 (called consolidation), then decreases. For women there is a sharp drop in bone mass during menopause
how can growth and exercise change peak bone mass?
change in bone dimensions
change in bone shape
change in trabecular volumetric BMD
what is bone remodelling
bone has a structure designed to absorb energy
irreversible PLASTIC deformation does occur resulting in microfractures, which dissipate the excess energy, generally limited to the interstitial bone between osteons . If these accumulate bone strength will be compromised.
Bone remodeling is the process by which these areas are repaired, each osteon essentially represents a previous remodelling event.
describe the bone remodelling cycle
Bone remodelling occurs in the basic multicellular unit, seen here.
Activation occurs
A microcrack crosses canaliculi, so severing osteocyte processes causing osteocytic apoptosis. This is thought to act as a signal to the connected surface lining cells (which are osteoblast lineage), which along with the osteocytes release local factors that attract cells from blood and marrow into the remodeling compartment. For the resorption phase to start osteoclasts are generated locally and resorb matrix and the offending microcrack, then successive teams of osteoblasts deposit new lamellar bone. Osteoblasts that are trapped in the matrix become osteocytes; others die or form new, flattened osteoblast lining cells.
what are the biochemical investigations that can be used in bone disease?
Serum Bone profile -calcium - corrected calcium (albumin -phosphate -alkaline phosphatase
Renal function
- creatinine
- parathyroid hormone
- 25-hydroxy vitamin D
Urine
- Calcium/ Phosphate
- NTX
biochemical changes table
see ppt
calcium balance systems
Calcium is most abundant mineral in body; 1kg
Mainly in BONE
Huge fluxws in /out of bone; it is not a metabolicaaly inert tissue
Cancellous bone has a huge blood supply; respiratory physiologists tell you the alveolar surface area for gas exchange is TENNIS court; bone is many times greater.
Thinking about calcium is easy
GUT whats comig in; 1g day recommended intake
Kidney whats going out
BONE flux; your compensatory mechanism
how do serum calcium measurements need correction?
We measure in serum is a TOTAL calcium
free; the active form
complexed; to P and citraate
protein-bound to ALBUMIN
So the corrected calcium a lab gives you compensates for the protein level; if protein levels are HIGH they compensate down; o.o2 for each g/l of albumin PROBLEMS occur in acid-base disturbance
If HYPERVENTILATE; get alkalosis which causes more ca to bind to prtotein so that free levels drop; all experienced this;tingling
venous stasis may falsely elevate LEVELS
How does PTH regulate serum calcium levels?
If plasma calcium drops within seconds have secretion of PTH from pre-formed stores
Acts on 2 systems
1.Bone acute release of available calcium; not in hydroxyapatite crystals
more chronically INCREASED osteoclast activiyty to re-absorb bone
- Kidney Increased ca re-absorption in the distal conv tubule; the only site where ca re-absorption is under active hormonal controlStimulation of 1alpha Ohase activity , so increasing actiavated vit D production, which leads to increased gut re-abs of ca;
Decreases 24 oh ase activityIncreases p excretion by inhibiting the NAP cotransporter in the proximal tubule
clinically relevant points about PTH
- 84 amino acid peptide
but N1-34 active - Mg dependent
- T 1/2 8 min
- PTH receptor is activated
also by PTHrP
how does the parathyroid gland monitor serum Ca through the calcium-sensing receptor?
A steep inverse sigmoidal function
relates PTH levels and Cao2+ in vivo.
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
**MINIMUM This is important in diagnosis.
Even in Hyperacalcaemia of malig PTH will be detectable; lower half normal rangs
PTH drives active calcium absorption in
the distal tubule of the kidney
how does PTH cause bone resorption?
RANK system
how is primary HPT diagnosed?
Primary hyperparathyroidism is diagnosed by
‘an elevated total/ionised calcium with PTH levels frankly elevated
or in the upper half of the normal range’
(ie. Corrected Calcium > 2.60 mmol/l with PTH > 3.9 pmol/l (nr 1.0 - 6.8))
Subjects with hypercalcaemia and a PTH in the upper half of the normal range are physiologically not normal
It is important to note that such ‘non-suppressed’ concentrations are entirely compatible with the diagnosis of Primary HPT
clinical features of primary HPT
Thirst, polyuria
Tiredness, fatigue, muscle weakness
“Stones, abdominal moans and psychic groans”
Renal colic, nephrocalcinosis, CRF Dyspepsia, pancreatitis Constipation, nausea, anorexia Depression, impaired concentration Drowsy, coma
Patients may also suffer fractures secondary to bone resorption
high serum calcium causes a diuresis
frusemide
diuresis results in hypercalciuruia
Chronically elevated PTH causes:
Chronically elevated PTH causes increased cortical bone resorption
Increased bone turnover
Acute/ pulsed PTH : anabolic
Chronic: catabolic
Cortical > cancellous
biochemical findings in primary HPT
- Increased serum calcium by absorption from bone/gut
- Decreased serum phosphate renal excretion in proximal tubule
- PTH in the upper half of the normal range or elevated
- Increased urine calcium excretion
- Cr may be elevated
how is VIT D metabolised?
Discuss metabolism
Action
INTESTINE 1,25(OH)2Vitamin D activates Ca and P absorption;
Bone synergises with PTH to increase osteoclastic osteolysis
differentiation agent for osteoclast precursors
Kidney facilitates PTH action in distal t. to increase Ca reabsorption
Excess 1oh ase occurs in granulomatoud disesae ie sarcoid, TB
Vit D binding protein half life
Vit D binding protein (DBP): t 1/2 3 days, filtered by kidney
activated Vitamin D increases ?
activated Vitamin D increases gut calcium absorption
VIT D actions on:
- intestine
- bone
- kidney
- feedback
INTESTINE 1,25(OH)2Vitamin D activates Ca and P absorption
duodenum (TRPV6, calbindin)
Vit D increases active calcium transport in gut
Bone Synergises with PTH, acting on osteoblasts to increase
formation of osteoclasts through RANKL
Increases osteoblast differentiation and bone formation
Kidney facilitates PTH action to increase Ca reabsorption
in distal tubule (inducing TRPV5, calbindin)
Feedback: parathyroid directly to reduce PTH secretion
bone to increase FGF-23 production
Rickets:
- define
- symptoms
- signs
“inadequate Vitamin D activity leads to defective mineralisation
of the cartilagenous growth plate (before a low calcium)”
Symptoms
Bone pain and tenderness (axial)
Muscle weakness (proximal)
Lack of play
Signs Age dependent deformity Myopathy Hypotonia Short stature Tenderness on percussion
causes of rickets/osteomalacia:
Vitamin D related Dietary Gastrointestinal Small bowel malabsorption/ bypass Pancreatic insufficiency Liver/biliary disturbance Drugs- phenytoin, phenobarbitone
Renal Chronic renal failure
Rare hereditary Vitamin D dependent rickets:
type I deficiency of 1 α hydroxylase
type II defective VDR for calcitriol
Dietary
Factors lack of sunlight
decreased production with age
not added to foods xcept USA
GI v common in gastrectomies
now coeliac ,
DRUGS increase p450 cytochrome activity that inactivates vitD
FGF-23 cause what?
FGF-23 cause PCT phosphate loss, aswell as PTH
FGF-23
32KD protein
Produced by osteoblast
lineage cells, long bones
LIKE PTH causes P loss
UNLIKE PTH inhibits
activation of Vit D by
1 α OH ase
PTH action on phosphate generated in Ca resorption is?
PTH action on phosphate generated in Ca resorption is backed up by FGF-23
even when calcium and vit D levels are normal, osteomalacia and phosphate can also get:
can also get with renal phosphate loss, when calcium and
Vitamin D levels are usually normal’
Kidney forced to lose phosphate
‘isolated’ hypophosphataemia X-linked hypophosphataemic Rickets 1;20,000 mutations in PHEX; high levels of FGF-23 toddlers with leg deformity, enthesopathy, dentin anomalies Autosomal dominant hypophosphataemic rickets (ADRR) variable age of onset; may improve cleavage site for FGF-23 mutated, so high FGF-2 oncogenic osteomalacia mesenchymal tumours produce FGF-23, causes phosphaturia and stops 1α OHase
FGF-23 excess can cause
FGF-23 excess can cause rickets/osteomalacia
Kidney proximal tubule damaged causes
Kidney proximal tubule damaged
causes phosphaturia and stops 1α hydroxylation of Vit D
Fanconi Syndrome
leads to
Fanconi Syndrome multiple myeloma heavy metal poisoning: lead, mercury drugs: tenofovir, gentamycin congenital disease: Wilsons, glycogen storage diseases
osteoporosis is due to:
low bone density
osteoporosis causes
high turnover- increased bone resorption greater than bone formation
low turnover- decreased bone formation more pronounced than decreased bone resorption
increased bone resorption and decreased bone formation
what does estrogen deficiency do to bone?
Increases the number of remodelling units
Causes remodelling imbalance with increased bone resorption (90%) compared to bone formation (45%) Enhanced osteoclast survival and activity
Remodelling errors. Deeper and more resorption pits
lead to Trabecular perforation
Cortical excess excavation
Decreased osteocyte sensing
biochemistry in osteoporosis is used to exclude other causes
Serum biochemistry should all be normal if primary
Check for Vit D deficiency
Check for secondary endocrine causes
Primary hyperparathyroidism PTH high Primary hyperthyroidism free T3 high TSH suppressed Hypogonadism Testosterone low
- Exclude multiple myeloma
- May have high urine calcium
what is the main tool to assess osteoporosis
Bone Density (BMD) is the main tool to assess for osteoporosis
Dual energy X-ray absorptiometry- current method
Measures transmission through the body of X-rays of two different photon energies
Enables densities of two different tissues to be inferred, i.e. bone mineral, soft tissue
define osteoporosis based on BMD:
T-score = (measured BMD – young adult mean BMD) / young adult standard deviation
T-score = -2.5 OSTEOPOROSIS
-1 to -2.5 OSTEOPAENIA
> -1 NORMAL
why central measurements?
Vertebral Commonest fracture Increasing incidence after aged 60 Measure of cancellous bone Metabolic bone; quickest response to treatment
Hip
2nd commonest #, > 70, costs and mortality
Fracture Risk Assessment Tool (FRAX) uses hip BMD
why are bone markers useful
Markers of bone formation and resorption give us
insight into activity
Unlike BMD they are DYNAMIC
Divided into markers of FORMATION
RESORPTION
describe collagen synthesis 1
2 ‘Alpha 1’ and 1 ‘Alpha 2’ chain of type I collagen
produced by the osteoblast join
Extension peptides cut off
these propeptides can be measured in blood
P1NP = Procollagen type 1 N-terminal Propeptide
describe collagen synthesis 2
3 hydroxylysine molecules on adjacent tropocollagen fibrils condense
to form a PYRIDINIUM ring linkage
These can be used to measure bone resorption; serum CTX, urine NTX
Bone resorption markers are used in monitoring osteoporosis treatment- HOW
Monitoring of response to treatment with anti- resorptive drugs (BMD change 18mnths)
bone resorption markers fall in 4-6 weeks expect a 50% drop of urine NTx by 3 months
what are the problems with cross links?
- Reproducibility: CV 20%
- Positive association with age
- Need to correct for Cr
- Diurnal variation in urine markers
what is the clinical use of bone formation markers
Only one in common usage is ALKALINE PHOSPHATASE
Use in diagnosis and monitoring of
Pagets
Osteomalacia
Boney metastases (prostate with PSA)
NOW P1NP is being use as a predictor of response to ANABOLIC
treatments
PTH treatment rises to peak in 3 months;
predicts response
BSAP
- types
- role
- uses
Types tissue-specific form; liver vs bone intestine, germ cell, placental forms Role essential for mineralisation regulates concentrations of phosphocompounds Uses Consistent within an individual; t ½ 40 hours
Increased in Paget’s disease Osteomalacia Bone metastases Hyperparathyroidism Hyperthyroidism
what is Chronic Kidney Disease Mineral Bone Disorder
Skeletal remodeling disorders caused by CKD contribute
directly to to heterotopic calcification , especially vascular
The disorders in mineral metabolism that accompany CKD
are key factors in the excess mortality caused by CKD
CKD impairs skeletal anabolism, decreasing osteoblast
function and bone formation rates
renal osteodystrophy:
- biochemistry
- so what occurs?
Biochemistry
Increasing serum phosphate
Reduction in 1,25 Vit D (calcitriol)
SO
Secondary Hyperparathyroidism develops to compensate
BUT
unsuccessful and HYPOCALCAEMIA develops
LATER
Parathyroids AUTONOMOUS (tertiary)
causing HYPERCALCAEMIA
progression of secondary HPT
Parathyroid hyperplasia develops in tandem with the progressive decline in renal function.
The constantly increasing functional demand on parathyroid glands (mainly as a result of hypocalcaemia) drives cell proliferation.
Initially, the parathyroid glands respond by increasing the proportion of secretory (chief) cells within the gland and then by increasing the total number of cells, resulting in diffuse hyperplasia of the gland.1
In diffuse hyperplasia, cell growth is polyclonal, but is accompanied by down-regulation of the CaR and VDR.1
As CKD progresses to stage 5 (end-stage renal disease [ESRD]), parathyroid hyperplasia evolves even further; monoclonal abnormalities lead to nodular hyperplasia of the glands.2,3 These grossly enlarged parathyroid glands are associated with significantly reduced expression of CaRs and VDRs.4,5
Parathyroid glands with nodular hyperplasia therefore become less responsive to serum calcium levels6,7 and resistant to the medical treatment of SHPT.6,8
