Endo 13: Endocrine + Metabolic Bone disorders Flashcards
What is the function of osteoclasts?
- they release lysosomal enzymes –> which breaks down bone
What is the function of osteoblasts?
- they synthesise osteoid
- -> and allow mineralization/calcification of osteoid
how does osteoclast differentiation occur?
- RANKL = expressed on osteoblast surface
- RANKL binds to RANK-R
- -> to stimulate osteoclast formation + activity
What are the 2 main types of bone?
- cortical bone - hard
- trabecular bone - spongy / trabecular
note: both formed in a LAMELLAR pattern.
What is meant by a lamellar pattern?
- collagen fibrils = laid in alternating orientations
What is the effect of Vit D deficiency on bone?
- normal stress on abnormal bone –> causes insufficiency fractures (looser zones)
- causes waddling gait
Children: Rickets
Adults: Osteomalacia
How does renal failure cause bone disease
- decrease in renal function
- leads to DECREASE in production of calcitriol
- -> results in decrease in phosphate excretion
- -> SO plasma phosphate level INCREASES
- decrease in calcitriol production –> causes decrease in Ca2+ absorption in intestines
- -> leads to hypocalcemia
- -> which leads to PTH release
- PTH breaks down bone matrix to try and restore blood Ca2+ level
- -> leads to osteoporosis
- hypocalcemia –> leads to decrease in bone mineralization
a combination of increased bone resorption + decreased bone mineralization leads to :
a combination of increased bone resorption + decreased bone mineralization leads to :
osteitis fibrosa cystica
how do you get extra skeletal calcification?
if you have imbalance between Ca2+ and phosphate
- some of it form the main salts
- -> which is deposited in the extra skeletal tissue
- -> causing extra skeletal calcification
How do you treat osteitis fibrosa cystica
- hyperphosphatemia
- -> low phosphate diet
- -> phosphate binders
- alphacalcidol (active form of Vit D)
- parathyroidectomy in tertiary hyperparathyroidism.
Define osteoporosis
loss of bony trabecular, reduced bone mass, weaker bone predisposed to fracture after minimal trauma
bone density more than 2.5 S.d below average value for healthy adults
how do you measure BMD?
- dual energy x ray absorptiometry (DEXA)
- mineral Ca2+ content of bone measured:
- -> more mineral = greater bone density
What is the difference between osteoporosis + osteomalacia?
OSTEOMALACIA:
- VIT D deficiency causing inadequately mineralized bone
- abnormal serum biochemistry
OSTEOPOROSIS:
- bone resorption exceeds formation
- decreased bone mass
- normal serum biochemistry
- diagnosis: via DEXA scan
Why is postmenopausal estrogen deficiency a pre disposing condition for osteoporosis?
- oestrogen deficiency –> causes loss of bone matrix
- -> which increases risk of fracture
What are other pre-disposing conditions for osteoporosis?
- postmenopausal oestrogen deficiency
- age related deficiency in bone homeostasis e.g osteoblast senescence
- hyogonadism in young women/men
- endocrine conditions
e. g cushing’s, hyperthyroidism, primary hyperparathyroidism - iatrogenic
e. g prolonged used of glucocorticoids, heparin
What are some treatment methods for osteoporosis?
- bisphosphonates
- denosumab
- teriparatide
How does Oestrogen HRT help with osteoporosis?
- oestrogen has anti-resorptive effects on skeleton
- which prevents bone loss
But prolonged use –> increases risk of breast cancer + venous thromboembolism
How do bisphophonates help with osteoporosis?
bisphophonates = analogues of pyrophosphate
- they bind to hydroxyapatite
- and are ingested by osteoclast
- -> which then impairs the ability of osteoclasts to resorb bone
- it also decreases maturation of osteoclasts from their precursors
- and promotes osteoclast apoptosis
NET RESULT = reduced bone turnover
What are other uses of bisphosphonates?
treatment for:
- osteoporosis
- malignancy
- paget’s disease (reduces bony pain)
- severe hypercalcaemic emergency (IV)
describe pharmacokinetics of bisphophonates.
- orally active but poorly absorbed
- -> so take on empty stomach
- accumulates at site of bone mineralization
- -> and remains part of bone until it is resorbed
What are some unwanted actions of bisphosphonates?
- esophagitis
(need to switch from oral to IV administration) - osteonecrosis of the jaw
(esp in cancer patients) - atypical fractures
(over suppression of bone remodeling in prolonged bisphosphoate use –> rest bisphosphonate use after 5 years)
How do Denosumab work?
- Denosumab = human monoclonal antibody
- it binds to RANKL –> inhibits osteoclast formation + activity
- hence inhibits bone resorption
note: given subcutaneously every 6months/ 12 months
How do Teriparatide work?
- they are recombinant fragments of PTH
- consisting of 34 a.acids
- it increases bone formation + bone resorption
- but formation outweighs resorption
note: daily subcutaneous injection - expensive
What is the 1st/2nd/3rd line of treatment for osteoporosis?
1st: Bisphosphonates
2nd: Denosumab
3rd: Teriparatide
