clinical and biochemical features of metabolic bone disease

Question 1

what is a metabolic bone disease

Answer 1

a group of diseases that causes a change in bone density and bone strength

by indreaing resorption or decreasing bone formation or altering bone structure

it may be associated with disturbances in mineral mechanism

Question 2

what are the 5 common metabolic bone disorders *

Answer 2

primary hyperthyroidism

rickets/osteomalacia

osteoporosis

pagets disease

renal osteodystrophy

Question 3

what are metabolic symptoms of bone diseases

Answer 3

hyper/ocalcaemia

hyper/ophosphtaemia

Question 4

what are the bone symptoms of metabolic bone disorders

Answer 4

deformity

fracture

Question 5

what is hydroxyapatite made of

Answer 5

calcium and phosphorus

Question 6

how is cancellous bone metabolically active

Answer 6

remodelling - 5% body is remodelling at any time

whole skeleton remodels over 7years

acts as a ca reserve - there is a balance with blood and bone

Question 7

what makes a bone strong

Answer 7

mass - genetic

material properties - collagen cross-linking, woven/lamella, mineralisation (young bone less mineralised so ductile, older is more brittle), microcracks

microarchitecture - trabecular thickness, trabecular connectivity, cortical porosity (holes in corticies - when teenager, grow fast and fracture)

macroarchitecture - hip axis length and diameter

Question 8

summarise the age related changes in bone mass *

Answer 8

build bone up until 20s,

stable until 40

lose

accelaratd loss in women in menopause - lose 30% of bone mass

both men and women have a slow phase

Question 9

how can exercise change bone mass

Answer 9

change in dimention - add perisoteum

change in shape - lay down bone specific to force

Question 10

describe bone remodelling during the growth of the tibea

Answer 10

lay bone down in anterior and posterior compartments - specific to minimise the mass of bone that is layed down

therefore there is increased bending strength anterio-posteriorly, than medio-laterally

bone is layed down in the periosteum region and resorbed from the endosteum

Question 11

descrieb teh sexual dismorphism in bone growth

Answer 11

men develop bigger bones with a bigger cavity

women’s bones have thicker endosteum so are stronger, as they get older - endocortical bone resorption and periosteal bone formation occurs - never matches mens

Question 12

descrieb cortical bone microfractures *

Answer 12

the bone has a structure to absorb energy - cortex has osteons and alternating density of lamellae

irreversible plastic deformation does occur - causing microfractures that dissipate the energy - they crack the matrix - usually limited to the interstitial bone between osteons - if they accumulate the bone strength will be comprimised

this is detected so has to be repaired

they are repaired through bone remodelling

each oseton represents a previous remodelling event

Question 13

describe the bone remodelling cycle *

Answer 13

activation phase - osteocytes detect a microcrack - the crack crosses canaliculi so severing the osteocyte’s dendritic processes

this causes osteocytic apoptosis

this acts as a signal to the connected surface lining cells which are of osteoblast lineage

the lining cells and osteoblasts release factors that attract cells from the blood and marrow into the remodelling compartment, these cells are monocytes and

resorption phase - osteoclasts are generated locally from the recruited cells - they resorb the matrix and the offending microcrack

reversal phase - switch from resorption to formation, osteoclasts are apoptosed

formation - then osteoblasts deposit new lamellae bone

the osteoblasts that are trapped in the matrix become osteocytes, others die or form new osteoblast lining

osteoblasts last months, clasts last weeks so have to keep recruiting clasts

this is happening all over the skeleton

Question 14

what are the biochemical investigations in bine disease *

Answer 14

serum

• bone profile - ca, corrected ca, phosphate, alkaline phosphate, mg

renal func

• creatinine
• PTH
• 25-hydroxy vut D

urine

• ca/phos
• NTX (bone resorptoion marker)

Question 15

summarise Ca balance

Answer 15

some absorption from GIT but not very efficient

reabsorb some from kidney - but excrete some, this cannot be helped

there is a big influx in and out of bone - cancellous bone has a huge supply

Question 16

how do you correct serum ca measurements

Answer 16

total ca is 2.15-2.56mmol/L

46% of this is protein bound

47% is fress ionised

7% is complexed

measure ionised in casualty

acid base balance affects ca - in alkalosis ca bind to protein = ca drop = tinglking feeling

venous stasis might falsely elevate levels

corrected ca = [ca] +0.02(45-[albumin])

if albumin is high, true ca is low - corrected ca compensates for the protein level

Question 17

explain how PTH regulates ca levels *

Answer 17

has the predominant role in min by min ca reg

if ca drops PTH increases in minutes

immediately causes bone resorption by stimulating osteoclasts - releases ca and phos

acts on kidney - increase ca resorption in DCT, increase phos excretion by inhibiting NAP co-transporter in PCT (phosphaturic hormone), increases 1a hydroxylation so increases vit D activation = increase in intestinal ca and phos absorption

Question 18

clinical relevance of PTH response system

Answer 18

84aa peptide but N1-34 is active - this is used clinically

mg dependant - alcoholics have low mg = low ca

PTH half life - 8mins - so can be measured intraoperatively

PTH receptor activated by PTHrP during breast feeding - releases ca from bone, PTHrP also produced by tumours so hypocalcaemia might be a presenting feature of a tumour

Question 19

describe the relationship between PTH and ca *

Answer 19

a steep inverse sigmoidal function relates PTH and Ca

minimum - even at high levels there is always some PTH production

set-point - point of half max suppression of PTH, steep part of slope, small perturbation causes large change in PTH

Question 20

describe the mechanism by which PTH drives ca reabsorption *

Answer 20

PTH increases the number and activity of TRPV5/6 (ca channels)on the lumen - increase ca reabsroption

also increases the active transport of ca into the blood out of the cells

Question 21

describe how PTH causes bone resorption through the RANK system *

Answer 21

increases RANKL production = increase in osteoclast differentaition

Question 22

how common is primary hyperparathyroidism *

Answer 22

occurs in 50s

female:male 3:1

2% people develop it post-menopausally

Question 23

what are the causes of primary hyperparathyroidism *

Answer 23

mainly parathyroid adenoma - benign

parathyroid hyperplasia - genetic condition when under 40

parathyroid carcinoma <1%

rare familial syndromes - MEN1, MEN2a HPT-JT

Question 24

how do you diagnose primary hyperparathyroidism *

Answer 24

an elevated total/ionised ca with PTH levels frankly elevated or in the upper half of normal range (this is inappropriately high)

corrected ca >2.6mmol/l with PTH>3.9pmol/l (normal range 1-6.8)

Question 25

clinical features of primary hyperparathyroidism \*

Answer 25

thirst polyuria tiredness/fatigue muscle weakness fractures due to secondary bone resorption 'stones, abdominal moans, psychic groans' * renal colic, nephrocalcinosis, chronic renal failure * dyspepsia (excess acid production), pancreatitis, constipation, nausea, anorexia * impaired concentration, drowsy, coma

Question 26

describe how high serum ca can cause diuresis \*

Answer 26

high Ca is sensed on teh basolateral membrane, this inhibits the Na Cl K transporter ion the apical membrane - stop resorption of these = loss of water this can become med emergancy if Ca \>3mmol/L - act like a loop diuretic

Question 27

effect of PTH on renal stone risk \*

Answer 27

elevated PTH causes an increased renal stone risk caused before diagnosis after surgery, incidince of stones goes almost back to normal

Question 28

effect of high PTH on bone resorption \*

Answer 28

increases cortical boen turnover acute/pulsed PTH is anabolic - downregulates sclerostin in osteocytes chronic increase = catabolic occurs more in cortical bone than cancellous

Question 29

effect of chronically elevated PTH on fracture risk \*

Answer 29

increases - 3x higher

Question 30

what are the biochemical findings in primary hyperparathyroidism&

Answer 30

increased serum ca - by absorption from bone and gut decreased serum phos - renal excretion in PCT PTH in upper half of normal, or elevated increase urine ca - huge filtered load mean surpass max renal resorption creatine might be elevated - renal damage

Question 31

describe production of vut D \*

Answer 31

7-dehydrocholesterol from skin turned to cholecalciferol by UV - difficult in UK oily fish give you cholecalciferol in liver cholecalciferol is converted to 25-cholecalciferol in kidney converted to calcitriol under PTH and 1a hydroxylase in kidney 25-cholecalciferol is also converted to 24,25 D, an inactive metabolite vitamin D binding protein has a half life of 3 days and is filtered by the kidney

Question 32

actions of vit D \*

Answer 32

vit d acts on intracellular receptors to alter the rate of transcriptionof certain genes in the GIT - increase ca transport proteins called calbindin-D proteins = increased uptake of ca ca and phos absorption in SI ca and phos release from bone, differentiation agent for osteoclast precursers ca resorption and phos excretion from kidney

Question 33

how does vit d increase gut ca absorption\*

Answer 33

it activates TRPV6 and calbindin in duodenum passive - paracellular transport we need AT to get enough ca to account for the 200mg/d obligatory losses - this active transport is vit d dependant

Question 34

effect of vit d on bone \*

Answer 34

synerges with PTH acting on osteoblasts to increase formation of osteoclasts through RANKL increase osteoblast differentiation and bone formation - by increasing Ca levels it keeps PTH levels low therefore protects bone structure - this is a secondary action

Question 35

effect of vit D in kidney \*

Answer 35

fascilitates PTH action to increase ca resorption in distal tubule - including TRPV5 and calbindin

Question 36

what is the definition of vit d def

Answer 36

vit d deficiency is 25 OH D \<50nmol/l vit d insufficiency is 40-72.5nmol/l this is because this is the level that PTH production plateus, ie less than this and the PTH production is increased to compensate

Question 37

what is rickets \*

Answer 37

inadequate vit d activity leads to defective mineralisation of the cartilaginous growth plate - before a low ca

Question 38

symptoms of rickets \*

Answer 38

lack of play because of prox myopathy and axial bone pain and tenderness

Question 39

signs of rickets \*

Answer 39

age dependant derformity myopathy hypotonia short stature tenderness on percussion

Question 40

causes of rickets \*

Answer 40

dietry lack sunlight GI - small bowel malabsorption/bypass, panc insufficiency (alcoholism), liver/bilary disturbance, drugs - phenytoin, phenobarbitone (increase p450 cytochrome activity that increases vit d) renal - chronic renal failure rare hereditory - type 1 is deficiency of 1a hydroxylase, type 2 is defective VDR for calcitriol

Question 41

biochemistry for rickets \*

Answer 41

ca - normal or low phos normal or low (normal if PTH risen to compensate) alk phos - high 25 oh vit d - low urine: phos - high, glycosuria, aminoaciduria, high pH, proteinuria - urine readings are rare

Question 42

descrieb the action of FGF-23 \*

Answer 42

it is made by osteoblasts in the long bone when they sense phosphorus NPT2a and NPT2c receptors reabsorb phos - if stimulated by FGF-23 or PTH these receptors are internalised = waste phosphate FGF-23 also inhibuts activation of vitd by 1a hydroxylase acts as a back up to PTH - have to get rid of ca phos otherwise it goes into tissues

Question 43

describe osteomalacia and phosphate \*

Answer 43

can also get renal phos loss when ca and vut d levels are usually normal _kidney forced to lose phosphate_ isolated hypophosphtaemia - X linked hypophosphtaemic rickets - mutations in PHEX = high levels of FGF-23 = toddlers with leg deformity, enthesopathy, dentin anomolies autosomal dom hypophosphtaemic rickets (ADRR) - variable age of onset, may improve, cleavage site for FGF-23 mutated so high FGF-2 osteogenic osteomalacia - in mesenchymal tumours, produce FGF-23 - causes phosphaturia and inhibit 1a hydroxylase _kidney proximal tubule damaged_ waste glucose, aa and protein and lose phos causes phosphaturia and stops 1ahydroxylation of vit D faconi syndrome is most common - multiple myeloma, heavy metal poisening (lead/mercury), drugs - tenofovir, gentamycin, congenital disease (wilson's, glycogen storage disease)`

Question 44

what is seen in the bone in osteoporosis \*

Answer 44

weak laterally loss of trabeculae lost connectivity cannot reform the connections

Question 45

causes of high turnover osteoporosis \*

Answer 45

oestrogen def - primarily in post-menopausal women hyperparathyroidism hyperthyroidism hypogonadism - premature ovarian insufficiency cyclosporine heparin

Question 46

causes of low turnover osteoporosis \*

Answer 46

liver disease - primary bilary cirrhosis heparin age \>50 chronic kidney disease

Question 47

cause of osteoporosis with increased resorption and decreased formation \*

Answer 47

glucocorticoids

Question 48

how does oestrogen deficiency cause menopausal bone loss \*

Answer 48

increases the number of remodelling units causes increased bone resorption compared to formation - enhanced osteoclast survival and activity remodelling errors - deeper and more resorption pits = trabecular perforation and cortical excess excavation decreased osteocyte sensing - when young bone senses when exercise - osteocytes die in menopause - cant tell that you are exercising - cant keep bone density up there is a disproportionate loss of cancellous bone in women

Question 49

biochemistry in osteoporosis \*

Answer 49

is used to exclude other casues serum biochem should be normal if primary check for vit d def check for secondary endocrine causes * primary hyperparathyroidism - PTH high * primary hyperthyroidism - free t3 high, TSH suppressed * hypogonadism - testosterone low exlude multiple myeloma by electrophoresis may have high urine ca

Question 50

what is the best predictor of fracture risk \*

Answer 50

BMD - represents 70% of fracture risk

Question 51

explain DEXA \*

Answer 51

measures transmission through the body of x-rays of 2 different proton energies enables densities of bone mineral and soft tissue to be inferred

Question 52

how do you calculate a T score \*

Answer 52

measured BMD - young adult mean BMD divide by young adult SD

Question 53

how does fracture risk change with BMD \*

Answer 53

1 SD reduction = 2.5 increase in risk of fracture

Question 54

why do you ise central measurements for osteoporosis DEXA \*

Answer 54

vertebral * commonest fracture * increasing incidence after age 60 * measure of cancellous bone * metabolic bone - quickest response to treatment hip * 2nd commonest site * increase incidence after age 70 * has costs and mortality fracture risk assessment tool FRAX uses hip BMD

Question 55

summarise bone markers as use for diagnosis \*

Answer 55

in most bone diseases teh bone cycle is disrupted markers indicate boen activity they re dynamic markers of formation and resorption

Question 56

markers of bone formation \*

Answer 56

2 a1 and 1 a2 chain of type 1 collagen are produced by osteoblasts extension peptides are cut off - these can be measured in blood P1NP (procollagen type 1 N-terminal propeptide) - this is a procollagen molecule that is released from the N terminal when type 1 collagen is layed down -- 3 hydroxylysine molecules on adjacent tropocollagen fibrils condense to form pyridinium ring linkage - cross link C and N terminal can measure this in urine - indicator of bone resorption

Question 57

markers of bone resorption \*

Answer 57

tehy are used to monitor treatment to anti-resorbitive drugs - BMD change 18months markers fall in 4-6weeks expect a 50% drop of urine NTx by 3months do it because the drugs are unreliable and poorly absorbed

Question 58

what is the problem with cross links \*

Answer 58

we grow during night and remodel so have to measure them in the afternoon reproducibility - CV 20% positive association with age need to correct for Cr diurnal variation in urine markers

Question 59

what is the clinical use of bone formation markers \*

Answer 59

only one in common use is alkaline phosphtase used in diagnosis and monitoring of pagets, osteomalacia, boney metastases (prostate monitoring of PSA) now P1NP is being used as a predictor of response to anabolic treatments - it is a procollagen fragment released from the N terminal when collagen is layed down - PTH treatment rises to peak in 3 months - predicts response

Question 60

describe BSAP \*

Answer 60

role - essential for mineralisation, regulates concentrations of phosphocompounds uses - consistent within individual, half life is 40hours increased in pagets, osteomalacia, bone met, hyperparathyroidism, hyperthyroidism - anything causing increased turnover - bone compensates by increasing mineralisation

Question 61

change in alkaline phosphtase with age \*

Answer 61

higher when growing- need to use age specific range increases \>50yrs especially in post-menopausal women - not used as a marker in osteoporosis

Question 62

describe chronic kidney disease bone mineral disorder

Answer 62

systemic disease skeletal remodelling caused by CKD leads to heterotopic calcification, especially vascular CKD impairs skeletal anabolism, decrease osteoblast function and bone formation rates

Question 63

describe renal osteodystrophy \*

Answer 63

it is a bone disease that results from poor mineralisation due to chronic renal failure increase serum phosphate, reduction in calcitriol if GFR\<60 get secondary hyperparathyroidism in attempt to actiavte vit D this is unsuccessful so hypocalcaemia develops later parathyroids are autonomous causing hypercalcaemia

Question 64

describe the glandular progression of secondary hyperparathyroidism \*

Answer 64

parathyroid hyperplasia develops alongside renal failure the increasing demand on parathyroid glands drives cell proliferation initially the glands respond by increasing proprtion of secretatory chief cells within the gland an dthen increasing the total number of cells = hyperplasia in diffuse hyperplasia, cell growth is polyclonal but is accompanied by down regulation of CaR and VDR as CKD progresses to stage 5 hyperplasia increases and monoclonal abnormalities lead to nodular hyperoplasia of the glands with less CaR and VDRs - they're less responsive to serum ca levels

Question 65

summarise the pathophysiology of CKD-MB

Answer 65

the hyperphosphtaemia binds to ca in circ = metastatic calcification = die of MI or stroke

Question 66

pathology of paget's \*

Answer 66

accelarated rates of bone turnover, abnormoal bone architecture that may lead to deformity may be because of a virus, genetic associations have been identified excessive cellularity and vascularity huge and highly nucleated osteoclasts resultant bone is woven 3 phases 1. osteolytic phase - huge increase in osteolytic activity 2. osteoclast/osteoblast phase - disordered activity as blasts try to fill erosions = woven bone 3. osterosclerotic phase - new sclerotic bone is produced

Question 67

clinical features of paget's \*

Answer 67

may be asymptomatic or cause pain enlargement of the effected bones pathological fractures deafness from nerve compression of bone overgrowth in the skull

Question 68

investigations for paget's \*

Answer 68

serum ca and phos is normal alkaline phosphtase and serum ca are high hydroxyproline present in the urine

Question 69

complication of paget's

Answer 69

secondary osteoarthritis high oputput HF because new vessels form shunts bone sarcoma can occur

Question 70

pathology of renal osteodystrophy \*

Answer 70

caused by: * inadequate renal tissue for making vit D = osteomalacia * high serum phos (in CRF) = hypocalcaemia, precipitates hyperparathyroidism with subsequent bone resorption to release ca stores * haemodialysis - inhibition of calcification of bone matrix = osteomalacia * steroid treatments = osteoporosis/avascular necrosis

Question 71

clinical features of renal osteodystrophy \*

Answer 71

low PTH = low bone turnover in severe CRF - body cant compensate by getting rid of phos = increased phos levels = decreased ca levels = increase in PTH = increased bone resorption high PTH causes fibrosis of the bone marrow - this is osteitis fibrosis cystica failing kidneys cannot activate vit d - ca cannot be resorbed from the GI tract - worsening hypocalc osteosclerosis occurs and chronically there are metastatic calcifications in the skin, eyes, joints and arterial walls parathyroid glands become autonomous

Question 72

pathology of osteomalacia \*

Answer 72

failure of bone mineralisation = softer and wider channels of matrix unmineralisation and underdeveloped epiphyseal cartilage calcification lead to endochondrial bone that is deranged and overgrown presents with muscle and bone pain, looser zones, prox myopathy = waddling rickets = bowing of legs bone biopsy is definitive