endocrine and metabolic bone disorders Flashcards
how much Ca does bone store *
>95% body’s Ca
what are the 2 components of bone
organic components (osteoid - unmineralised bone - 35% bone mass) 95% is made of Type 1 collagen fibres
inorganic mineral component - 65% bone mass - calcium hydroxyapatite crystals fill the space between the collagen fibrils
describe the dynamic remodelling process of bone *
osteoblasts synthesise osteoid and participate in mineralisation/calcification of osteoid (bone formation)
osteoclasts release lysosomal enzymes - break down bone (bone resorption) - they are multinucleated cells with ruffelled membranes
describe osteoclast differentiation
RANKL is expressed on the osteoblast surface (L stands for ligand)
RANKL binds to RANK-R (R=receptor) on osteoclast precurser to stimulate osteoclast formation and activity
how do osteoblasts control bone formation and resorption balance *
tehy ave receptors for pth and active vit d
what are the structures of bone
cortical bone (hard) and trabecular bone (spongy)
both formed in lamellaar pattern = ccollagen fibrils laid down in alternating orientations - mechanically strong
woven bone is dysfuctional bone - has disorganised collagen fibrils so is weaker
what are the effects of vit D deficiency on bone *
= inadequate mineralisation of newly fomred bone matrixx (osteoid) - vit d is needed for this
in children this causes rickets - affects the cartilage of the epiphysial growth plates and bone = skeletal abnormalities and pain, grpwth retardation (short stature) and increased fracture risk
in adults - osteomalacia - this is after epiphysial closure so dont get bowing of legs seen in rickets - just affects bone = skeletal pain, increased fracture risk and proximal myopathy.
normal stresses and weight on abnormal bone cause insufficiency fractures = looser zones (fracture to unmineralised bone). - these are stress fractures
why does vit d deficiency cause waddling gate
from the skeletal pain and proximal myopathy
describe primary hyperparathyroidism
caused by adenoma in the parathyroid gland
cause increased pth production = high ca because increased reabsorption in bone and kidney and pth activates vit d
autonomous production of pth so no -ve feedback
both pth and ca are igh
describe ssecondary hyperparathyroidism
caused by renal failure or vit d deficiency
low or normal ca because need vit d to reabsorb ca from gut (renal failure = cant activate vit d - no 1a hydroxylase)
by -ve feedback this causes a high pth - tis si a physiological response
ca can be normal if pth is raised enough to increase ca reabsorption from bone and kidney
describe tertiary hyperparathyroidism
eg from chronic kidney disease
cant make ccalcitriol (avtive vit d) = ca fall - pth increase = secondary hyperparathyroidism
then all parathyroid glands make more pth to try to increase ca - become autonomous so dont swich off
so have high pth and high ca
how is primary different to secondary hyperparathyroidism
dont have CKD in primary
describe how renal failure relates to bone disease
low renal func = cant 1a hydroxylase vit d = low active vut d = low ca absorption from the gut = hypocalcaemia
also cant excrete phosphate - binds to ca = serum ca decrease = hypocalcaemia
hypocalcaemia = increase in PTH = increased bone resorption = cysts in bone
hypocalcaemia also causes low bone mineralisation (also because low vit D)
increased bone resorption and low bone mineralisation = osteitis fibrosa cystica
high plasma phosphate = vascular calcification of blood vessels
what is osteitis fibrosa cystica
hyperparathyroid bone disease - rare
because of excess bone reabsorption because of high pTH
causes ‘brown tumours’ - not tumours - they are cysts (radiolucent bone lesions)
how do you treat osteitis fibrosa cystica
treat the causes:
- hyperphosphtaemia: low phosphate diet, pospate binders - reduce GI phosphate absorption
give alphacalcidol ie calcitriol analogues - tis is active vut d
paratyroidectomy in tertiary hyperparathyroidism - if have hypercalcaemia and/or hyperparatyroid bone disease
what is osteoporosis *
there is a loss of the bony traberculae = reduced bone mass = weaker bone = predisposed to fracture after minimal trauma
as age get reduction of bone mass - accelarated post menopause
have bome mineral density (BMD) >/=2.5 standard deviations below average value for young healthy adults - referred to as a t score of -2.5 or lower
BMD predicts fracture risk
osteopenia is when you have a BMD on way to osteroporosis
how do you measure BMD
using a DEXA scan - dual energy x-ray absorptiometry of femoral neck lumbar and spine
it involves radiation
mineral (Ca) content of teh bone is measured, te more mineral = te greater the bmd ie bone mass = strength
what is the difference between osteoporosis and osteomalacia
they both predispose to fracture
malacia - due to vit d def = unmineralised bone - serum biochem abnormal: low active vit d, low or low normal ca, high pth - secondary hyperparathyroidism (diagnose on blood test) have painful proximal myopathy
osteoporosis - boen resorption exceeds formation, decreased bone masss, biochem fine, diagnosis with DEXA scan
what are the predisposing factors for osteoporosis
postmenopausal oestrogen deficiency = loss of matrix = increased risk of fracture
age related deficiency in bone homeostasis - men and women - osteoblast senescense
hypogonadism in young women and men - deficient in testosterone or oestrogen
cusings, hyperthyroidism, primary hyperparatyroidism
prologued use of glucocorticoids = reduced bmd
heparin
what are the consequences of a hip fracture
death
permanent disability
not being able to walk
impairment in daily life
what is the treatment for osteoporosis
oeestrogen/selective oestrogen receptor modulators
bisphosphonates
denosumab
teriparatide
how does oestrogen work to treat osteoporosis
it is hormone replacement therapy
it as anti-resorbitive effects on the skeleton adn prevents bone loss
cant give long term - increased risk of breast cancer and venous tromboembolism
if have intact uterus have to have progesterone to prevent endometrial hyperplasia and cancer
what is the mechanism of bisposphonates for osteoporosis
they promote osteoclast apoptosis
they bind to hydroxyapatite which normally mineralises bone
osteoclasts ingest the bispospate bound hydroxyapetite and die - reduced ability to reabsorb bone
= reduced bone turnover
what do you use bisphosphonates for
first line treatment for osteoporosis
hypercalcaemia of malignancy eg zoledronate - reduce bone turnover = reduce bone pain from metastasis and ca release - might improve survival in breast cancer because suppress bone turnover so less likely for micrometastises to become real metastises
pagents disease - to reduce bony pain
if severe hypercalcaemia emergancy - iv fluid initially than bisphosphates
what are the pharmacokinetics of bisphosphonates
orally active but poorly absorbed
take on an empty stomach - food, especially milk reduces drug absorption - can cause dyspepsia = bad compliance
accumulates at te site of bone mineralisation and is part of the bone until it iss resorbed - can be years therefore concerned about use in younger patients
what are the unwanted effects of bisphosponates
oesophagitis - irritate the oesophagus - may require switc to iv
osteonecrosis of the jaw - greatest risk in cancer pts taking iv bisphosponates - made bone adynamic - if having dental surgery ave to have it before you start on this
atypical fractures - oversuppression of bone remodelling
how does denosumab treat osteoporosis
it is a human monoclonal ab
binds to RANKL - inibit osteoclast formation and activity - inibit resorption
it is taken as a subcutaneous injection every 6months
2nd line to biphosphates
ow is teriparatide used to treat osteoporosis
it is a recombinant pth fragment, amino-terminal 34 aa of native pth
inccreases bone formation adn resorption but formation dominates because of the dose you give
3rd line treatment
daily sc injection
expensive
what is pagents disease of bone
when there is accelarated, localised but disorganised bone remodelling
excessive bone resorption - overactive osteoclasts, followed by overactive increase in osteoblast activity
therefore woven bone is formed - this is disorganised and weak so cant withhold stress = vulnerable to fracture
cause bone frailty and hypertrophy and deformity
describe the epidemiology of pagent’s disease
often positive fh - suggesting genetic cause
evidence for viral origin
high prevalence in te uk, n america, australia, scandinavia
men and women affected equally
not usually apparent in people <50 - disease of aging
most asymptomatic until get bone deformity
characterised by abnormal large osteoclasts - excessive in number
what are te clinical features of pagents disease of bone
skull, toracolumbar spine, pelvis, femer and tibia most commonly affected
skull gets frontal bossing
arthritis
fracture - bone not mecanically strong
pain
bone deformity
bowed legs - bone remodelling is all over the place - bot in a structured way
increased vascularity - warmth over affected area because of underlying activity
deafness because of coclear impairment - bone conducntion doesnt work
radiculopathy due to nerve compression - nerve root pain
how do you diagnose pagents disease of bone
normal plasma ca
hig plasma alkaline phosptase - produced by bone, hig because of bone remodelling
plain x rays - lytic lesions (early), thickened, enlarged deformed bones (later)
radionucleotide none scan demonstrate extent of skeletal involvement - it goes to the busy parts of the bone
tibia common place for bone abnormality
what are the treatment options for pagents disease
bisphosphates - elpful to reduce bony pain and disease activity
simple analgesia
what is the outcome you are looking for with statins *
40% reduction in non HDL cholesterol by 3 months
what are SE of statins *
muscle aches and rabdomyolesis (breakdown of muscle) = creatine kinase increase
