Pathophysiology of Osteoporosis Flashcards
What are the determinants of bone strength?
Geometry + BMD
What regulates calcium?
Parathyroid hormone (PTH)
Calcitonin
How does PTH regulate calcium?
Increases calcium by stimulating osteoclasts, increasing intestinal absorption + decreases calcium excretion by kidneys
How does Calcitonin regulate calcium?
Decreases calcium by inhibiting osteoclast activity + increasing calcium excretion via kidneys
How does calcium regulation work overall?
Homeostasis remained by PTH + calcitonin
Rise in blood Ca = thyroid release calcitonin = stimulates Ca salt deposit in bone
Falling blood Ca = parathyroid gland release PTH = signals osteoclasts to degrade bone + release Ca into blood
What is osteoporosis?
Skeletal disorder where bone strength is compromised with an increased risk of fracture
What is osteomalacia + rickets?
Abnormal bone formation due to inadequate mineralisation
What are the causes of osteomalacia?
Severe, prolong VitD deficiency
Long term anticonvulsant therapy (eg. phenobarbital)
What is the pathophysiology of osteomalacia?
Normal bone resorption + formation
But body unable to fully mineralise newly formed osteoid tissue = decreased bone strength
What is the treatment of osteomalacia?
High dose of VitD
How does osteoporosis develop?
Osteoclast recruitment increased
Osteoblast-osteoclast coupling interrupted
= factors don’t adequately recruit osteoblasts
Lack of oestrogen = less bone stimulation + deposition = reduced later osteoblast recruitment
What does hormone dysregulation do to osteoporosis?
Accelerate it
= oestrogens + androgens help maintain bone mass
What happens in postmenopausal osteoporosis?
Increases proliferation + activation of osteoclasts
Prolongs survival of osteoclasts
What is type I osteoporosis?
Postmenopausal osteoporosis
= oestrogen deficiency
What is type II osteoporosis?
Senile osteoporosis
= bone loss due to increased bone turnover
How does long-term glucocorticoids cause osteoporosis?
Alteration in Ca absorption = secondary hyperparathyroidism
Inhibitory effect of sex hormone production
Inhibition of osteoblast function
How do anticoagulants (heparin) cause reversible osteoporosis?
Increased osteoclast activity
Decreased osteoblast activity
Antagonist effect on VitK
What other drugs may cause osteoporosis?
GnRH
Antiepileptics (eg. Phenytoin)
Loop diuretics (eg. Furosemide)
How is osteoporosis diagnosed?
BMD
What is the non-pharmacological treatment of osteoporosis?
Stop alcohol + smoking
Increase calcium in diet
Regular exercise
Avoid drugs that induce it
What are the pharmacological therapies for osteoporosis?
Bisphosphonates
Ca
VitD
Oestrogen
Oestrogen receptor modulators (SERM)
How much calcium should the average healthy adult receive?
1000mg
How much calcium should someone over 65/osteoporosis/post-menopausal need?
1500mg
How is total daily Ca achieved?
Diet + diet supplements
What are the drug interactions for calcium?
Fe therapy impairs absorption
Tetracyclines 2hrs apart = avoid intestinal chelation
What are the adverse effects of calcium?
Nausea
Constipation
Abdominal distension
Excess Ca = kidney stones
What is given fir VitD?
Cholecalciferol
How does Cholecalciferol work?
Improves Ca absorption in GI tract
What are the adverse effects of Cholecalciferol?
Hypercalcemia (symptoms: anorexia, nausea + weakness)
What are the drug interactions of Cholecalciferol?
Thiazide diuretics = increase risk of hypercalcemia
What is the mechanism of action of Calcitonin?
Inhibits bone resorption by inhibiting osteoclast activity
How is Calcitonin administrated?
Given by injection (SC/IM)
What must patients do during the treatment of Calcitonin?
Ingest adequate Ca + VitD
What are the adverse effects of Calcitonin?
Nausea + GI discomfort
Initial face flushing + dermatitis
Pruritis at site of injection
What is the adverse effect of nasal Calcitonin?
Rhinitis
What is the indication of Calcitonin?
2nd line treatment for osteoporotic patients who cannot tolerate other antiosteoporotic agents
What is the indication of bisphosphonates?
1st line treatment for prevention of osteoporotic fractures
How do bisphosphonates work?
Reduce bone absorption by inhibiting osteoclasts
By binding to hydroxyapatite on bone mineral surface
Taken up by osteoclast + modify activity
Induce apoptosis
Where are bisphosphonates excreted from?
Kidneys
= not recommended for patients with impaired renal function
What are the adverse effects of bisphosphonates?
Oesophagitis, gastritis + peptic ulcer
Mild fever
Aches following parentals
What is the mechanism of action of oestrogen?
Supress bone resorption
What are the adverse effects of oestrogen?
Increase incidence of breast + endometrial cancers
Increase risk of DVT + gall bladder disease
What are the indications of SERMs?
Postmenopausal women at risk for osteoporosis who cannot take bisphosphonates
Post menopausal women at increased risk for breast cancer
What is the indication of Teriparatide (recombinant PTH)?
Severe osteoporosis in men + postmenopausal women
What is the mechanism of action of Teriparatide (recombinant PTH)?
Supplements production of parathyroid hormone
Regulates calcium-phosphate balance + stimulates new bone growth
What is the administration of Teriparatide (recombinant PTH)?
Injected daily S/C
Use limited to 2-year duration
What are the adverse effects of Teriparatide (recombinant PTH)?
Postural hypertension
Hypercalcemia
Associated with osteosarcoma
What are the contraindications of Teriparatide (recombinant PTH)?
Untreated hyperthyroidism
Recurrent urolithiasis
What is RANKL?
Mediator of osteoclast differentiation, activation + survival = primary mediator of bone resorption
What is osteoprotegerin?
Alternative binding site for RANKL (decoy receptor), which cannot activate cellular signalling
What is Denosumab?
Monoclonal Ab to RANKL
What does Denosumab do?
Reduces osteoclast development = increases BMD
= reduces risk of fractures
What is the mechanism of action of Denosumab?
RANKL to surface of pre-osteoclast
Activation of RANK by RANKL = maturation of osteoclast
Denosumab inhibits maturation by inhibiting RANKL
NO osteoclast = no bone resorption
