Biochemistry of metabolic bone disease Flashcards
Define metabolic bone disease
A group of diseases that cause a change in
- bone density
- bone strength
by
- INCREASING bone resorption
- DECREASING bone formation
- Altering bone structure
(may be associated with disturbances in mineral metabolism)
Outline the metabolic and bone specific symptoms in metabolic bone disease
METABOLIC
Hypocalacaemia
Hypercalcaemia
Hypo/Hyperphosphataemia
BONE-SPECIFIC
Bone pain
Deformity
Fracture
How many calcium and phosphates in hydroxyapatite
10 Ca2+
6 PO43-
What percentage of bone is remodelling at a time
5%
How often is the entire skeleton replaced
7 years
What makes a bone strong
and outline each part
Mass
Material properties
Microarchitecture
Macroarchitecture
Outline material properties as a factor of bone strength
Collagen cross linking? (like CXH)
mineralisation,
woven/lamellar (disorganised, where lamellae not organised along stress lines i.e acute healing or pagets_,
microcracks (stress in mortar lines during exercise)
Outline microarchitecture properties as a factor of bone strength
Trabecular thickness, trabecular connectivity and cortical porosity
i.e. in spine post menopause lose thickness and connection in trabecular bone, which cannot be reformed
Outline macroarchitecture properties as a factor of bone strength
Genetic but can be improved by sport.
Hip axis length and diameter
How can bone structure and function be assessed
Bone histology
Biochemical tests
Bone mineral densitometry, e.g. osteoporosis
Radiology
Outline age related changes in bone mass
Peak bone mass in mid 20s
Stable until around 40
Men slow loss
Women fast loss in early menopause
How does growth and exercise change peal bone mass
Increases:
Change in bone dimesion and shape
and
Change in trabecular volumetric bone mineral density
How can bone modelling be optimised during growth
In tibia, more bone placed anteriorly and posteriorly… optimise deposition so as not to waste mass
Increase in the bending strength ratio, which is the ration of the anteroposterior length: mediolateral
greater periosteal apposition?
Differentiate bone modelling and bone remodelling
During bone modeling (construction), bone
is deposited without prior resorption on the periosteal
surface, increasing its external diameter as occurs in
growth.(6,7) During bone remodeling (reconstruction), osteoclasts resorb a small volume of bone which is replaced by osteoblasts
What determines the external dimension and shape of bone and what determines the size of the medullary cavity
External dimension: deposition of
bone tissue on the periosteum
Medullar cavity size:endocortical resorption
Why is bone thicker during growth
periosteal apposition exceeds endocortical resorption so that the cortex thickens
What occurs during usual ageing
and then during post-menopause period
Normal ageing: adter ephiphysial closure, advancing
age is associated with a slowing of periosteal apposition and
endocortical resorption
during post menopause:
The periosteal bone formation is not that much impaired, but the endocortical bone resorption increases (because oestrogen causes osteoclast apoptosis but this reduces in menopause so resoprtion increases, an dis not compensated for by an increase in formation)
What does each osteon represent
A previous remodelling event
The accumulation of what could cause compromised bone strength
In every dya life, microfractures will occur between osteons, and these need to be repaired. This is essentially the remodelling process. Osteoclasts come in and remove the damaged bone and stimulate osteblasts to come in and lay down new bone
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.
Outline how osteoclasts receive signal in bone remodelling
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 along with the osteocytes release local factors that attract cells from blood and marrow into the remodeling compartment
Lining cells are of what lineage
Osteoblast
What must occur in order for resorption to take place
Osteoclasts must be generated, which occurs due to local factors
Outline the reversal and then formation stage of bone remodelling
Following osteoclastic resorption of 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.
Outline the stages of the bone remodelling cycle
Activation, resorption, reversal, formation
Which biochemical investigations can be poerofrmed in bone disease
Bone profile:
calcium,corrected calcium (albumin), phosphate, alkaline phosphatase
Renal function:
creatinine
PTH
25-hydroxy vitamin D
Urine:
Calcium/ Phosphate
NTX ( biochemical marker of bone metabolism and the most sensitive and specific indicator of bone resorption)
State the biochemical changes in osteoporosis
Ca2+, phosphate, Alk P, bone formation and resorptin
Normal Ca2+ Normal phosphate Normal Alk P Increased/normal bone formation Increased bone resorption
State the biochemical changes in osteomalacia … calcium phosphate and alk P
Ca2+ low (or normal if corrected by increased PTH)
P low (increased excretion due to PTH)
Alk P increased a bit
State the biochemical changes in pagets
Ca, P, Alk P, Bone formation/resorption
Ca2+ normal (maybe slightly increased), P normal, Alk P increased a lot! Bone formation increased a lot
State the biochemical changes in primary HPT
Ca, P, Alk P, Bone formation/resorption
Ca2+ high, P normal/low, Alk P high or normal, bone resorption greatly increased
Outline biochemical changes in renal osteodystrophy
Ca2+, P and Alk P
Ca2+= low or normal
P= increased
Alk P= high
Outline biochemical changes in metastases
Ca2+ high, P high, Alk P high and bone resorption high
Mass of calcium in the body
1kg
How much calcium usually ingested and excreted a day
1gm in, 850mg out (through GI), 150mg out (through urine)…
look at diagram slide 19
bone is compensatory mechanism
What does total calcium comprise
Protein bound (46%), free/ionised (47%)and complexed (7%)
What can calcium be complexed to
Phosphate and citrate
You can remember this as when phosphate increases is renal osteodystrophy, calcium binds to it, reducing free Ca2+ (but it’s the fact that the kidney cannot hang on to Ca2+ that actually causes the biochemical change)
What does corrected calcium mean
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
What occurs in alkalosis and to what consequence
Free/ionised –> protein bound…. free levels drop and tingling results
What could falsely elevate calcium levels
Venous stasis
How does PTH regulate Ca+2
PTH increases Ca2+ reabsorption from the kidney, and increases phosphate excretion
PTH increases bone resoprtion, liberating Ca2+ and phosphate
PTH increases the activity of 1a-hydroxylase which converts 25 cholecalfiverol to 1,25 cholecalciferol (calcitriol, active vit D)
NOTICE, not the gut
T/F… PTH secretion occurs within seconds of reduced plasma calcium
T, due to preformed stores
T/F PTH can release Ca2+ from the hydorxyapatite crystals of bone in an acute process
F Bone acute release of available calcium; not in hydroxyapatite crystals more chronically INCREASED osteoclast activiyty to re-absorb bone
Where within the kidney will PTH increases Ca2+ reabsorption
the distal conv tubule; the only site where ca re-absorption is under active hormonal control
How does PTH increase gut absorption of Ca2+
NOT DIRECTLY…. by increased Vit D
How does PTH increase phosphate excretion
by inhibiting the NAP cotransporter in the proximal tubule
What type of hormone is PTH
PEPTIDE:
84 AA but only N1-34 active
PTH is dependent on what. When could this be a problem
Mg
Alcoholics may have hypomagnaesia
Half life of PTH and the clinical relavance
t1/2= 8 mins….
allows intraoperative sampling
T/F PTH receptors on the cell membrane is linked to cAMP, and is activated exclusively by PTH
TRUE- it is cAMP linked
BUT
Can also be activated by PTH related peptide (PTHrp cis produced by some tuours, and so hypercalcaemia may be first presenting feature ie small cell ca lung)
How does PTH correspond to Ca2+ levels in the blood
Steep inverse sigmoidal function
relates PTH levels and Cao2+ in vivo.
Calcium sensing receptor on the PTH glands
Low Ca2+= high PTH
High Ca2+=low PTH
BUT STILL BASELINE PTH secretion even if Ca2+ is really high (e.g. in hypercalcaemia of malignancy, PTH detectable, in lower half of normal range )
What would PTH be like in primary HPT
Does not have to be high, could just be upper half of normal…. with raised Ca2+, PTH should be at baseline, so even upper half of normal, is abnormal in this situation
What is the set point of PTH secretion?
point of half maximal
suppression of PTH
Small perturbation causes large change PTH
usually around 0.9mM
How does PTH work on the kidney
PTH drives active calcium absorption in the distal tubule of the kidney
???
How does PTH/Vitamin D3 work on bone
What is OPG
They act on osteoblasts to increase expression of RANKL. Also increases M-CSF
this activates osteoclast progenitors which causes then to proliferate and differentiate into pre-fusion osteoclasts
pre-fusion osteoclasts fuse to form activated osteoclasts
OPG (Osteoprotegerin) is the body’s inhibitor of the RANKL to prevent osteoclast differentiation and proliferation
Typical age of primary HPT and sex ration
50s, female 3:1 male
2% post menopausal develop
Causes of primary HPT
Parathyroid adenoma (80%)
Parathyroid hyperplasia (20%)
Paraythroid CA (<1%)
Familial syndromes MEN 1 (2%), MEN 2A, HPT-JT
How is primary HPT diagnosed
High Ca2+ with PTH frankly elevated or in the upper half of normal range IMPORTANT TO REMEMBER UPPER HALF
Corrected Calcium > 2.60 mmol/l with PTH > 3.9 pmol/l (nr 1.0 - 6.8)
What are the clinical features of primary HPT
Mainly due to HYPERCALCAEMIA
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
FRACTURES SECONDARY TO BONE RESORPTION
Why does high calcium cause a diuresis
It basically shuts down the triple transporter and the channel which allows K+ to go from the ascending limb cell to the urine…… more solute in the filtrate causes diuresis
hypercalciuruia …. leading to increased stone risk
Hypercalcaemia can be likened to which drug
Loop diuretic e.g. frusemide
Short term eevated PTH increases stone risk
F: chronically elevated
Elevated PTH causes increased bone reoption of which type of bone
Cortical>cancellous
Metabolic effect of acutely raised PTH and chronically raised PTH
Acute/ pulsed PTH : anabolic
Chronic: catabolic
T/f Chronically elevated PTH increases fracture risk
T
Biochemical findings in primary HPT
- Raised serum Ca2+
- Upper half of normal/frnakly elevated PTH
- Low serum phosphate (renal excretion in the PCT)
- High calcium in the urine
- Cr may be elevated
Action of vitamin D
- Intestine- 1,25(OH)2Vitamin D activates Ca and P absorption
- Bone- synergises with PTH to increase osteoclastic osteolysis….. differentiation agent for osteoclast precursors.
also Increases osteoblast differentiation and bone formation
- Kidney-facilitates PTH action in distal t. to increase Ca reabsorption (TRPV 5 , calbindin)
In what case might you get high levels of vitamin D
Toxicosis (too many supplements rare)
Granulomatous disease e.g. sarcoid/TB leads to excess 1OH hydroxylase
How is vit D absorbed in the gut
Passive: paracellular linear
Active: up to 40%….. saturable, in the duodenum. Stimulated by 1,25 vitD (TRPV6, calbindin)
What percentage of Ca+2 is absorbed in each part of gut
Panopto?
20 – 60% load
Duodenum/jejenum
Also colon
On which channels does vitamin D act and where
On TRPV channels, TRPV5 in kidney and TRPV6 in gut
How does vitamin d feedback
parathyroid directly to reduce PTH secretion
bone to increase FGF-23 production
How does vit D change calcium absorption in the gut
Increases ACTIVE calcium transport
When would PTH rise
When 25 OH D less than 30ng/ml…
gut Ca absorption can increase up to 80nmol/l
Define rickets
inadequate Vitamin D activity leads to defective mineralisation
of the cartilagenous growth plate (before a low calcium)
Symptoms of rickets
Bone pain and tenderness (axial)
Muscle weakness (proximal)
Lack of play
Signs of rickets
Age dependent deformity Myopathy Hypotonia Short stature Tenderness on percussion
Causes of rickets/osteomalacia
VIT. D related:
Dietary
GI: Small bowel malabsorption/ bypass, Pancreatic insufficiency (remember ADEK are fat soluble so need bile to be absorbed), Liver/biliary disturbance drugs/coeliac/gastrectomy
Renal: chronic renal failure
Rare hereditary: vit. D dependent rickets
Which drugs could cause vit. D defic. and why
phenytoin, phenobarbitone
INCREASE P450 cyctochrome activty which nactites vt D
Outline types of hereditary vit D
type I deficiency of 1 α hydroxylase
type II defective VDR for calcitriol
T.F production of vit D decreases w age
T
Outline the biochemistry in rickets
Ca- N/low Phosphate- N/low Alk P-high 25(OH)vit D- low PTH- high (secondary HPT in compensation)
Urine- high phosphate,
glycosuria, aminiaciduria, high pH, proteinuria
Which molecules act to reduce reabsoprtion of phosphate in the PCT
PTH (inhibits NaP cotransporter)
FGF-23 also does this
How is FGF-23 similar to and different from PTH
LIKE PTH causes P loss
UNLIKE PTH inhibits
activation of Vit D by
1 α OH ase
Where is FGF-23 produced
Produced by osteoblast
lineage cells, long bones
When is FGF-23 helpful
When bone is being resorbed…. increase in phosphate release and calcium release….
this phosphate is excreted by PTH, and this actionis backed up by FGF-23
Outline the biochemistry of renal osteodystrophyn
Due to problem with kidney:
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 HPT)
causing HYPERCALCAEMIA
