96 - Drugs Affecting Bone Flashcards
Proportions of trabecular and cortical bone
Bones are 20% trabecular, 80% cortical
Effect of tetracycline on teeth
When consumed during tooth development, binds to calcium ions. Leads to yellow/brown discolouration of dentine.
Amount of bone remodelled each year in adults
25% of trabecular bone remodelled each year
3% of cortical bone remodelled each year
~10% of total bone remodelled each year
Five phases of bone remodelling
– Activation – Resorption – Reversal – Formation – Quiescence
How can growth factors be released in bone remodelling?
Embedded in bone, released during bone resorption.
Recruit, activate osteoblasts to begin making new osteoid over resorbed bone.
Osteoclastogenesis
Upstream pro-resorptive cytokines promote stromal cell RANKL (membrane associated or soluble).
RANKL stimulates osteoclastic precursors (in conjunction with M-CSF) to differentiate into mature osteoclasts
Factors regulating bone remodelling
1-5
1) Parathyroid hormone
2) Oestrogen
3) Glucocorticoids
4) Sequestered cytokines in bone
5) Calcitonin
Parathyroid hormone role
Increased osteoblast activity, increased osteoclast activity
Oestrogen role, with respect to bone
Decreased osteoclast activity
Glucocorticoid effect on bones
Increased osteoclast activity
Decreased osteoblast activity
Calcitonin effect on bones
Decreased osteoclast activity
Effect of dexamethasone on bones
Increases RANKL and decreases OPG
Things regulating serum calcium concentration
1-3
Parathyroid hormone
Vitamin D
Calcitonin
How does PTH increase serum Ca2+?
Increased vitamin D synthesis
Mobilises Ca2+ from bone
Reduces renal Ca2+ excretion
How does calcitonin decrease serum Ca2+?
Decreases osteoclast activity and Ca2+ resorption from bone.
Inhibits Ca2+ resorption in the kidney
Where does calcitonin come from?
C cells of the thyroid gland
Vitamin D synthesis
Cholesterol metabolised in the skin, catalysed by UV exposure.
This results in liver producing calcifediol in the liver.
Calcifediol is metabolised to calcitriol in the kidney.
Calcitriol is the active part of vitamin D
Effect of calcitriol on plasma Ca2+
Increases plasma Ca2+.
Increased intestinal absorption
Decreased renal excretion
Increased osteoclast activity
Blood Ca2+ homeostasis
Thyroid gland detects high Ca2+, releases calcitonin.
Parathyroid glands detect low Ca2+, release PTH.
Disorders of bone
1-5
Hypocalcaemia Hypercalcaemia Hypophosphataemia Hyperphosphateaemia Osteoporosis
What can cause hypocalcaemia?
Vitamin D deficiency
What can cause hypercalcaemia?
Malignancies
What can cause hypophosphataemia?
Nutritional deficiency
What can cause hyperphosphataemia?
Renal failure
Definition of osteoporosis
Reduction in bone mass more than 2.5 standard deviations below the normal for healthy 30 year old woman
Definition of osteopaenia
Reduction in bone mass more than 1-2.5 standard deviations below the normal for healthy 30 year old woman
When is peak bone density?
20s to 30s.
When does bone density begin decreasing?
Age 35-40 (decrease about 0.5-1% per year)
Effect of osteoporosis on bone
Loss of trabeculae and thinning leads to reduced cross-sectional area, so that loads on bone are relatively greater.
Anti-resorptive agents for bone disorders
1-3
Bisphosphonates
Selective oestrogen receptor modulators (SERM)
RANK-L inhibitors
Anabolic agents for bone disorders
1-4
PTH
Oral Ca2+
Oral vitamin D analogues
Calcitonin
Bisphosphonate structure
Enzyme resistant analogues of pyrophosphate (pyrophosphate is essential for binding to bone mineral).
Bisphosphonate mechanism of action
Inhibit binding of osteoclasts to bone surface, promote osteoclast apoptosis.
Inhibit osteoclast recruitment.
Promote osteoclast apoptosis
Inhibit osteoclast binding to bone.
Accumulate at sites of bone mineralisation, stay for long periods
Bisphosphonate administration and side effects
Oral administration daily/weekly
IV administration
Poorly absorbed.
Adverse GIT effects (osteophagitis)
How does oestrogen affect bones?
Decreases osteoclast proliferation, differentiation, activation
Promotes osteoclast apoptosis
Increases life span of osteoblasts and osteocytes
Doesn’t increase bone mass, but maintains mass, slows bone loss.
Problem with oestrogen for slowing bone loss
A lost of side effects, can lead to cancers
Drug replacement for oestrogen (for bones)
Selective oestrogen receptor modulators (SERMS)
Selective oestrogen receptor modulators (SERMS) mechanism
Agonist at oestrogen receptors in bone and cardiovascular tissue
Antagonist at oestrogen receptors in mammary tissue and uterus (decreases cancer risk)
Side effects of SERMS
Increased DVT risk, pulmonary embolism risk
Human MAb that binds RANK-L
Denosumab
Denosumab action
Human MAb that binds RANK-L
Inhibits RANKL activity
Reduces osteoclastic differentiation, survival , activity
Antiresorptive and anabolic drug
Strontium ranelate
Side effects of strontium ranelate
Increased incidence of MI.
For this reason, is a last line of treatment for severe osteoporosis.
Drug based on PTH
Teriparatide
Effect of PTH administration on bones
At low levels, is anabolic.
Long-term, high exposure to PTH leads to bone catabolism.
Common adjunctive therapy for osteoporosis
Oral Ca2+
What is vitamin D administered for?
Deficiency states, EG rickets, osteomalacia, endocrine dysfunction (hypoparathyroidism), chronic renal disease (where calcitriol can’t be produced by kidney)
Effect of calcitonin on bones
Decreases osteoclastic resorption and mobilisation of Ca2+ from bone.
How is calcitonin administered?
Synthetic salmon calcitonin (salcatonin) given as an injection.
What is calcitonin used to treat?
Paget’s disease, hypercalcaemia associated with neoplasia
