week 1 - bone and the skeleton Flashcards
describe osteoblasts
involved in bone formation
remain as resting osteocytes at the end of the bone remodelling cycle
describe osteocytes
dormant
sensitive to stimuli and communicate to osteoblasts
describe osteoclasts
involved in bone resorption
derived from monocyte precursors in marrow
what is bone remodelling
coordinated osteoclastic resorption and osteoblastic proliferation
six steps of bone remodelling
activation resorption osteoblast recruitment osteoid formation mineralization quiescence
two types of bone growth
endochondral ossification - longitudinal
subperiosteal apposition - width
rate of bone remodelling depends on…
growth
hormones and growth / biochemical factors
mechanical stress
RANKL/RANK/OPG pathway
osteoblasts produce RANKL which binds to RANK on osteoclasts and activates them
OPG inhibits RANKL
absence of OPG causes long bone fragility fractures
composition of bone
inorganic - calcium hydroxyapatite
organic - type 1 collagen, proteoglycans, osteocalcin, cytokines/IL
result of loss of mineralization
osteomalacia / rickets
result of low bone mass
osteoporosis, osteogenesis imperfecta
disease resulting from high bone mass
osteopetrosis
disease resulting from high bone turnover
pagets, hyperparathyroidism, thyrotoxicosis
disease resulting from low bone turnover
adynamic disease, hypophosphatasia
describe osteoporosis
reduced total bone mass
adequate mineralisation of present osteoid
relatively increased bone resorption
menopausal osteoporosis
reduced bone mineral mass
estrogen deficiency
corticosteroid induced osteoporosis
steroids increase osteoclastic activity, decrease osteoblastic activity, impair collagen formation and cause increased bone turnover and poor bone formation and healing
corticosteroids increase bone resorption rate and depth and can block osteoblast action
relationship between PTH and ionised Ca
increases while the other decreases
causes of low Ca and high PTH
secondary hyperparathyroidism causes:
renal impairment
vitamin D deficiency
causes of low Ca and low PTH (hypoparathyroidism)
destruction of parathyroid glands idiopathic/autoimmune surgical removal radiotherapy severe magnesium deficiency
causes of high Ca and high PTH
adenoma - in parathyroid glands - uncontrolled PTH causes increased calcium
hyperplasia also causes
causes of high Ca and low PTH
malignancy excess intake granulomatous disorders sarcoid medications
primary hyperparathyroidism
unregulated PTH secretion
hypercalcaemia
markedly increased bone turnover
may retain bone mass
clinical features
boney cavities
kidney stones
abdominal pain, vomiting
depression
signs of hyperparathyroidism on an x-ray
subperiosteal bone resorption
generalized decrease in bone density
brown tumour
chondrocalcinosis - knee, wrist and shoulder
describe pagets disease
rapid bone turnover
bone resorption and formation are increased
disorganised structure
reduced bone strength
risk of fracture
linked to osteosarcoma tumour suppressor gene
describe osteopetrosis
failure of osteoclastic and chondroclastic resorption
failure of remodelling
genetic disorder
describe fluorosis
abnormal matrix mineralization
fluoride replaces calcium in the matrix
describe osteogenesis imperfecta
genetic
collagen one deficiency
low muscle tone
space age bone disease
reduced numbers of osteoblasts
minimal mechanical stress on bone
normal osteoclast numbers
types of calcium in serum
free (unbound) - 47%
bound to albumin - 47%
complexed - 6%
organs involved in calcium homeostasis
kidney, gut, bone, parathyroid glands
describe calcium homeostasis
absorbed mainly in duodenum and jejunum - Ca goes into blood
reabsorbed in kidney
resorption in bone
role of PTH in calcium homeostasis
stimulates renal tubular calcium reabsorption
promotes bone resorption
stimulates formation of calcitriol in kidney which enhances calcium absorption fom gut
calcitriol role in calcium homeostasis
role in promoting calcium and phosphate absorption from gut
increase bone resorption = calcium released
two pathways of calcium absorption
a cell mediated active transport pathway - controlled b calcitriol
passive diffusion - depends on luminal Ca concentration and is unaffected by calcitriol
where in the kidney is calcium reabsorbed
65% in proximal tubule
20% in thick ascending loop of henle
15% in distal convoluted tubule
last two are increased by effects of PTH
where is PTH produced
parathyroid glands
describe the secretion of PTH
regulated by free calcium and is sensed by calcium sensing receptors
as calcium levels fall, PTH rises
what are calcium sensing receptors
g-coupled receptors on parathyroid cells and renal tubules
major role of vitamin D
maintaining serum calcium within normal limits
what does calcitriol do when dietary calcium is inadequate
calcitriol will increase bone resorption via vitamin D receptors on osteoblasts
relationship between PTH and calcitriol
calcium sensing receptor detects fall in ionised calcium
this increases PTH production which is a major stimulus for calcitriol production
PTH production is suppressed directly and indirectly by increasing iCa
hypocalcaemia causes
not enough PTH which could be due to:
neck surgery, autoimmune destruction of parathyroid glands or magnesium deficiency
could be due to a lack of vitamin D - malabsorption, little exposure to sunlight or renal disease (kidneys fail to make active form)
hypercalcaemia causes
inappropriate production of too much PTH due to adenoma of parathyroid gland
inappropriate dosage of vitamin D
malignancy - lung cancer, breast cancer, multiple myeloma
role of phosphate in the body
critical in skeletal development, bone mineralisation
where is phosphate found
85% is in the mineralised matrix of bone
rest is mostly intracellular and bound to lipids and proteins - cell membranes, nucleic acids, enzyme cofactors, glycolytic intermediates and ATP
1% in extracellular fluids
main hormones in phosphate homeostasis
PTH
fibroblast growth factor 23 (FGF 23)
calcitriol
role of PTH and FGF23 in phosphate homeostasis
they inhibit the reabsorption of phosphate by acting on the renal tubule
response to an increase in serum phosphate
PTH and FGF23 production increases - they then act on renal tubule to increase secretion of phosphate by reducing its reabsorption
two types of bone
cortical bone and trabecular bone
functions of osteoblasts
deposition of collagen and noncollagenous proteins
transport of mineral salts
secretes: cytokines/growth factors, enzymes and proteins
some of the factors that stimulate osteoblast expression of RANK ligand
PTH, vitamin D, glucocorticoids, interleukins, TNF-alpha
OPG function
it is a decoy receptor that prevents RANKL binding to RANK
inhibits osteoclast formation, function and survival
what is sclerostin
a protein secreted by osteocytes
it inhibits Wnt signalling in cells
fracture healing process
osteocytes near crack undergo apoptosis
lining cells pull away from bone matrix and form a canopy which merges with the blood vessels
stromal cells are released from sclerostin inhibition and/or exposed to other factors eg. IL-1 and they generate pre-osteoblasts - SCs also secrete M-CSF to help generate pre-osteoclasts
pre-osteoblasts proliferate and secrete other factors - also start to express RANKL
pre-osteoclasts to mature osteoclasts
osteoclasts bind to bone matrix with integrins and secrete acid and cathepsin K to resorb bone
bone-derived GFs IGF and TGF-beta are released
osteoclast undergos apoptosis - regulated by estrogen
pre-osteoblasts mature and secrete OPG instead of RANKL - OBs also secrete osteoid and mineralise it to fill the cavity
some OBs turn into osteocytes, some into lining cells and the rest undergo apoptosis
meanwhile osteoclasts have been re-establishing a network with each other and the lining cells
new matrix will accumulate mineral and increase in density for about 3 years
how do long bones change as we age to an adult
increased length and diameter
how does the spine change as we age to an adult
increased size and trabecular thickness
factors affecting peak bone mass
gender calcium intake growth hormone IGF axis steroid metabolism alcohol gonadal status physical activity smoking
effects of estrogen on bone acquisition
little effect on proliferating chondrocytes
major effect on terminally differentiating chondrocytes and mineralising bone
function of estrogen on bone remodelling
decreased estrogen leads to increased RANKL
risk factors for osteoporotic fractures
age >65 vertebral compression fracture malabsorption syndrome primary hyperparathyroidism hypogonadism early menopause rheumatoid arthritis smoker low dietary calcium intake
determinants of fracture risk
bone strength
extraskeletal conditions - propensity to fall and fall conditions
lifestyle changes for prevention of osteoporosis and fractures
adequate intake of dietary calcium regular muscle strengthening exercise stop smoking drink alcohol at safe levels minimise risk of falls wear a hip protector
treatment of calcium and vitamin d reduces risk of what type of fracture
non vertebral fracture
effects of hormone replacement treatment
prevents bone mineral density decreasing as much with age
effective on vertebral and non-vertebral fractures
effects of selective estrogen receptor moderator
act on estrogen receptors
effective for vertebral fractures
effect of bisphosphonates
increases bone mineral density
reduces fracture risk
effective on vertebral fractures and most biophosphonates are effective on non-vertebral fractures
effects of teriparatide
stimulates bone formation
effective on vertebral and non-vertebral fractures
effects of denosumab
binds to RANKL and inhibits osteoclast formation, function and survival
effective on all fractures
effects of romosozumab
monoclonal antibody that binds and inhibits sclerostin
increases formation, decreases resorption
formation of vitamin d
formed from 7 dehydrocholesterol - converted by a photolysis reaction and then isomerisation to cholecalciferol in the skin
transported to liver
active form of vitamin d
calcitriol
1.25-dihydroxycholecalciferol
principle actions of vit d
binds to vit d receptor becoming a transcription factor that modulates gene expression of transport proteins which are involved in calcium absorption in the intestine
maintains skeletal calcium balance by promoting intestinal calcium absorption, increases osteoclast numbers causing bone resorption, maintains calcium homeostasis via PTH for bone formation
disease from vit d deficiency
rickets/osteomalacia
osteomalacia
characterised by impaired mineralisation of bone leading to an accumulation of unmineralised bone matrix (osteoid)
rickets
newly formed bone of the growth plate does not mineralise causing growth plate to become thick, wide and irregular
clinical features of osteomalacia
initially asymptomatic
bone pain and tenderness
proximal muscle weakness without atrophy
causes of vitamin d deficiency
lack of sunlight bizarre diets partial gastrectomy small bowel malabsorption pancreatic disease chronic renal failure anticonvulsants
diagnosing osteomalacia
imaging
isotope bone scan
serum biochemistry
bone biopsy
vitamin d can be used to treat..
osteomalacia and vitamin d deficiency
causes of rickets
vitamin d dependent rickets hypophosphataemia disorders fanconi syndrome renal tubulopathies hypophosphatasia fat malabsorption
types of vitamin d dependent rickets
1A - vitamin d hydroxylation-deficient rickets
1B - vitamin d hydroxylation-deficient rickets
2A - vitamin d-dependent rickets
2B - vitamin d-dependent rickets with normal vitamin d receptor
describe type 1A and 2A vitamin d dependent rickets
1A - mutation in the CYP27B1 gene - hydroxylation at alpha 1
2A - with/without alopecia - caused by a defect in the vitamin d receptor gene
most common types of vit d dependent rickets
how does FGF23 regulate phosphate homeostasis
blocks phosphate reabsorption and causes excess phosphate loss
FGF23 production
formed in osteocytes
under control of locally bone derived factors that are important for bone mineralisation
describe tumoral calcinosis
defective FGF23 or GALNT3 (enzyme required for normal o-glycosylation of FGF23)
increased calcitriol and phosphate
ectopic calcification to remove excess phosphate
AD hypophosphatemic rickets
FGF23 resistance to proteolysis
low calcitriol levels
x-linked hypophosphataemic rickets
manifesting during late infancy at onset of walking
bowing long bones, widening metaphyses and rachitic rosary - short stature
low phosphate and low calcitriol and increase in FGF23
mutation in PHEX protein
AR hypophosphataemic rickets
affects dentin matrix protein 1 (DMP 1)
involved in osteoblast maturation
exported to extracellular matrix regulating hydroxyapatite
DMP1 inhibits FGF23 expression
leads to bone, cartilage and dentin defects - severe hypophosphataemia and secondary unregulated FGF23
hereditary hypophosphataemic rickets with hypercalcuria
defect of NPT2 phosphate transporter in proximal tubule
hypophosphataemia secondary to defects in proximal tubular phosphate transporter
rickets and short stature
rickets treatments
additional phosphate
adequate 1.25 diOH vitamin d
avoid calciuria and elevated PTH
