endocrine and metabolic bone disorders Flashcards
what is the composition of bone?
- 65%: inorganic minerals (Ca hydroxyapatite)
- 35%: organic components (type 1 collagen)
what do osteoblasts do?
- build up bone (synthesise, mineralise and calcify osteoid)
- express receptors for PTH and calcitrol
what do osteoclasts do?
break down/resorb bone
lysosomal enzymes
What do osteocytes do?
make type 1 collagen and other EC matrix components
describe osteoclast differentiation
- RANKL expressed on osteoblast membrane
- RANK-R binds RANKL
- this stimulates osteoclast formation and activity
what is osteoprotegerin?
- acts as a competitive inhibitor for RANKL
- inhibits
describe the first and second hydroxylation steps
- calcidiol is made in liver (1st)
- calcitriol is made in kidneys (2nd)
what does PTH/calcitrol cause?
- causes bone to release Ca and phosphates
what does PTH do?
causes kidneys to inc. calcitrol synthesis and dec. excretion of Ca
what does calcitriol do?
inc absorption of dietary Ca
what does high EC calcium/ low EC calcium cause?
High EC Ca - Ca blocks Na influx so LESS membrane excitability
Low EC Ca - enables greater influx of Na so more membrane excitability
what are the symptoms of hypocalcaemia?
too much excitability (PCAT):
- parathesia
- convulsions
- arrhythmias
- tetany
signs: Chovstek’s sign, Trousseau’s sign
what is Chovstek’s sign?
tap facial nerve below zymgomatic arch, face twitch
what is Trousseau’s sign?
- inflate BP cuff for minutes
- induces carpopedal spasm
what are the causes of hypocalcaemia?
- Vit D def (low calcitriol)
- renal failure (impaired 1 alpha-hydroxylase activity so low calcitriol)
- low PTH levels
- PTH resistance (pseudohypoparathyroisism)
what are the symptoms of hypercalcaemia?
stones, abdo maons and psychic groans (slows down)
Stones: renal stones
Abdo moans: GI effects
Psychic groans: CNS effects
what are the causes of hypercalcaemia?
- primary hyperparathyroidism (benign adenoma of parathyroid, PTH high, Ca high)
- malignancy (tumours ofen secrete PTH-RP, PTH low, PTH-RP high, Ca high)
- Paget’s disease (condition w/ high bone turn over)
- Vit D toxicosis
what is the active form of Vit D?
calcitriol
what are the effects of calcitriol?
- intestinal absorption of Ca, Mg, PO4
- regulates osteoblast differentiation
- renal effects (inc. Ca reabsorption, dec. PO4 reabsorption)
what happens when there is a Vit D def?
- softening of bone
- bone deformities
- bone pain
- severe proximal myopathy
what is Vit D def called in children and adults?
children - rickets
adults - osteomalacia
what s Vit D3 and Vit D2 called?
Vit D3 - cholecalciferol
Vit D2 - ergocalciferol
what are the causes of Vit D def?
- block in UVB light catalysation
- malsabsorption or bad diet
- liver disease (no 1st hydroxylation)
- renal disease (no 2nd hydroxylation)
- receptor defects
what is primary hyperparathyroidism?
autonomous PTH production due to adenoma
produces a hypercalcaemia
what is secondary hyperparathyroidism?
no calcitriol so lower Ca so more PTH production to try and normalise serum Ca
not hypercalcaemia
what is needed in a diagnosis of Vit D def?
Low - calctriol, Ca, PO4
High - PTH
Radiological findings: widened osteoid seams (bone lesions showing excessive osetoclastic bone resorption)
what is the treatment of Vit D def?
- normal renal function: give synthetic Vit D (kidney hydroxylates futehr)
- impaired renal function (give ready hydroxylated Vit D)
how does low renal function lead to extra-skeletal deposition?
- low renal function can lead to dec. calcitriol and PO4 excretion
- leads to higher serum phosphate that binds Ca in blood
- leads to extra-skeletal deposition
what can Vit D toxicosis lead to?
- hypercalcaemia and hypercalciuria due to inc, intestinal absorption of Ca
what can Vit D toxicosis occur because of?
- excessive treatment of Vit D def
- granulomatous disease (macrophaes in granuloma produce 1 alpha-hydroxylase which overproduces Vit D)
what is osteoporosis?
- condition of reduced bone mass and a distortion of bone microarchitecture which predisposes to fracture after minimal trauma
what is the definition of osteoporosis?
BMD < 2.5 SDs or more
what is BMD measured by?
DEXA
what are the risk factors for osteoporosis?
- post-menopausal oestrogen def
- age related def in bone homeostasis
- hypogonadism in young people
- endocrine conditions (Cushing’s, hyperthyroisism, primary hyperparathyroidism)
- iatrogenic
what are the different drug classes for the treatment of osteoporosis?
- oestrogen receptor modulators (oestrogen HRT, SERMS)
- bisphosphonates
- denosumab
- teriparatide
what is the effect of oestrogen HRT?
- oestrogen has anti-absorptive effects on skeleton
- women with intact uterus need progestogens to prevent endometrial hyperplasia
- used limited, concerns with breast cancer
what are SERMs?
selective oestrogen receptor modulators
- tissue selective ER antagonists e.g. Tamoxifen
- tissue selective ER agonists e.g. Raloxifene
how does Tamoxifen work?
antagonises ERs in breast but has oestrogenic activity in bone
how does Raloxifene work?
oestrogenic activity in bone and anti-oestrogenic activity on breast and uterus
what is the MoA of bisphosphonates?
- bind to hydroxyapatite crystals and are absorbed by osteoclasts (impair ability to resorb bone)
- dec. osteoclast development/ recruitment and promotes osteoclast apoptosis
what are the uses of bisphosphonates?
- first line for osteoporosis
- also used for malignancy, Paget’s and severe hypercalcaemic emergencies
what are the pharmacokinetics of bisphosphonates?
- orally active, porrly absorbed (eat on empty stomach)
- remains at site of action for YEARS so mainly used in elderly
what are the side effects of bisphosphonates?
- oesophagitis
- flu like symptoms
- osteonecrosis of jaw
- atypical fractures
what is denosumab and what does it do?
- human monocloncal antibody
- binds to RANKL and so inhibits osetoclast activation and bone resorption
- taken bi-yearly
- 2nd line drug for osteoporosis
what is teriparatide?
- recombinant PTH fragments
- inc. bone formation and bone resorption
- formation outweighs resoprtion
- 3rd line treatment
- expensive
what happens in Paget’s disease?
- accelerated, localised and disorganised bone remodellung
- excessive bone resorption followed by compensatory inc in bone formation
- leads to formation of woven bone
- bone fragility
- bone hypertrophy and deformity
what are the features of Paget’s disease of bone?
- genetic
- possible viral origin
- affects men and women equally
- disease not apparent under 50yo
- most pt asymptomatic
what is Paget’s characterised by?
- abnormal, large and numerous osteoclasts
which bones are most commonly affected in Paget’s?
- skull
- thoracolumbar spine
- pelvis
- femur
- tibia
what are the clinical features of Paget’s?
- arthritis
- fractures
- pain
- bone deformity
- inc. vascularity (warm to touch)
- deafness
- radiculopathy (due to nerve compression)
what could be used to diagnose Paget’s?
- Ca normal
- ALP inc (due to over activity of bones secreting ALP)
- plain X-rays show lytic lesions (early), thickened, enlarged and deformed bones (later)
how do you treat Paget’s?
- bisphosphonates
- analgesia
