Drugs for bone metabolism

Question 1

What are the main cells in bones? role?

Answer 1

Osteoblasts = bone forming cells –> from bone marrow precursors

Osteoclasts = bone resorbing cells (from macros and monocytes

Osteocytes = derive from osteoblasts, embed in bone formation

Question 2

What happens when Ca2+ drops in the body? (general)

Answer 2

parathyroid cells –> synthesise and secrete PTH –> conserve Ca2+

Question 3

What happens when Ca2+ inc in the body? (general)

Answer 3

high plasma Ca2+ —> binding of Ca2+ to CaSR –> activates GPCR –> activates PLC –> inhibits further PTH secretion

Question 4

What is the effect of PTH secretion from the parathyroid on the rest of the body? (kidney, digestive, bone)

Answer 4

Kidney = dec excretion of Ca2+

Gut = inc Ca2+ absorption

Bone = mobilisation of Calcium from bone

Question 5

What is the effect of calcitonin on bone?

Answer 5

Produced by thyroid gland in response to Ca2+, dec rate of bone turn over

- bind to receptors on osteoclasts --> Inhibit bone resorption
- Inhibits resorption of Ca2+ in PCT of kidney

Question 6

What is the natural antagonist of the actions of PTH and VIT D?

Answer 6

Calcitonin

Question 7

What are the indications for Ca2+ use and what are some ADRs?

Answer 7

Indications = Ca2+ def, adjuvant for osteoporosis, osteomalacia, rickets, acute hypocalcaemia and hypocalcaemia tetany

ADRs = belching, flatulence, abdominal distension, constipation, hypercalcaemia, alkalosis, hypophosphatemia

Question 8

How is active vitamin D formed?

Answer 8

7-dehydro-cholesterol + UVB –> Vit D3 (cholecalciferol) —>Vit D3 goes to liver and is made into 25(OH)D3 (calcifediol) –> travels to kidney –> formed into 1,25(OH)2D3 (calcitriol) –> calcitriol enters blood

Question 9

What are the effects of vit D? (available forms)

Answer 9

Reg Ca homeostasis and bone metabolism

Inc intestinal absorption and renal reabsorption of calcium and phosphorus

Promotes bone mineralisation

Available forms = ergocalciferol D2, cholecalciferol D3, calcitriol

Question 10

What are the indications, C/I, effects of cholecalciferol (D3) & ergocalciferol (D2)? (time of action, strength)

Answer 10

Slow onset of 4-8 wks, prolonged duration of action

D3 may be more effective than ergocalciferol in inc and maintaining serum 25(OH)D3

Indications = prevent/tx vit D def due to improper diet or sunlight
- combine w/ bisphosphonates for osteoporosis req Vit d

C/I = renal impairment

Question 11

What are the indications, C/I, effects of Calcitriol? (time of action, strength)

Answer 11

Active vit D metabolite, rapid onset (!-3 days) and short duration <1wk

Indications = hypocalcaemia in hypoparathyroidism, renal dialysis, tx of osteoporosis, prevention of corticosteroid induced OP

ADRs = N/V, constipation, freq urination, headache, thirst

Question 12

What are the relevant bisphosphonates?

Answer 12

*End in -dronate

Pamidronate
Alendronate
Etidronate
Risedronate
Zolidronate

*PACERZ

Question 13

What is the MOA of the bisphosphonates? (indications?)

Answer 13

Bind strongly to bone surface –> inhibit osteoclast ATP dependent enzymes, induce osteoclast apoptosis –> deplete osteoclasts/osteoclast activity

Indications = for postmenopausal OP (1st line), paget’s disease, hypercalcaemia of malignancy

Question 14

What are the ADRs of bisphosphonates?

Answer 14

Oesophagitis = TAKE WITH FULL GLASS WATER 30min BEFORE FOOD, DONT LIE DOWN FOR 30MIN AFTER —> acidic drug
- oesophageal erosions, ulcers (alendronate), gastritis, duodenitis, glossitis, iritis, scleritis, rash

N/V/D/C, muscle pain, osteonecrosis of jaw

Question 15

What jaw related side effect can be seen with bisphosphonate use?

Answer 15

Osteonecrosis of jaw due to IV bisphosphonate

Risk associated w/ dose and type of bisphos, hx of trauma, dental surgery, dental infection

Question 16

What two drugs influence the parathyroid horomone?

Answer 16

Teriparatide

Cinacalcet

Question 17

What is the MOA of teriparatide? (ADRs)

Answer 17

active fragment of human PTH –> promote bone formation and inc BMD

ADRs = N, headache, dizziness, leg cramps, arthralgia, hyperuriciaemia,

Question 18

Which parathyroid hormone drug can only be used for a max of 18 months in a lifetime? Why?

Answer 18

Teriparatide

Due to risk of osteosarcoma

Question 19

What are the indications and C/I for teriparatide?

Answer 19

C/I = paget’s disease, hyperparathyroidism

Indication = postmeno OP, or primary OP in men

Question 20

What is the MOA of cinacalcet? (ADRs)

Answer 20

Inc sensitivity of CaSR on PT gland for Ca2+ —> dec sec of PTH –> dec serum Ca2+

ADRs = hypocalcaemia, N/C, anorexia, dizziness, reduced testosterone, seizures, angioedema

Question 21

What is raloxifene used for? What does it do? (generally)

Answer 21

Used in postmeno OP

ER agonist –> bone mass and lipid

ER antagonist –> other oestrogen receptive in tissues (breast and uterus)

Question 22

What is strontium ranelate used for? What does it do? (generally)

Answer 22

Similar to Ca2+, bone seeking role

- Inc bone formation = inc osteoblast precursor 
- Reduce bone resorption = alter osetoclast ultrastructure, dec resorbing activity 

Indication = severe postmenopausal osteoporosis, severe osteoporosis in men

Question 23

What is Calcitonin/salcatonin used for? What does it do? (generally)

Answer 23

Action = inhibits bone resorption and inc urinary excretion of ca2+

Indication = hypercalcaemia (IV infusion)

Treat for shortest possible time –> long term is associated w/ malignancies

Question 24

What is denosumab used for? What does it do? (generally)

Answer 24

Action = dec bone destruction and inc bone mass and strength
- anti-receptor activator of nuclear factor k B ligand [RANKL] antibody

Indications = post menopausal women w/ OP at high facture risk