Module 4.2.1 (Pharmacology of Osteoporosis) Flashcards Preview

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Flashcards in Module 4.2.1 (Pharmacology of Osteoporosis) Deck (44)
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1
Q

How is calcium maintained?

A

Free fraction is precisely maintained within narrow limits by the actions of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (calcitriol).

Concentration in plasma affects Calcitonin secretion.

2
Q

How is calcium absorbed?

A

Calcium is:

absorbed only in its ionised (Ca2+) form.

present as insoluble salt (in foods and dietary supplements)

released from most calcium salts in ~1h at an acidic pH (in the stomach).

However, Ca2+ may complex with minerals or other selected dietary constituents in the small intestine (more alkaline pH), thus limit calcium bioavailability.

3
Q

How is calcium excreted?

A

Urine & faeces (some via skin – sweat)

Urinary Ca2+ excretion

  • Most is filtered and reabsorbed by the kidney.
  • Decreased by PTH secretion (also in presence of phosphorus, potassium, magnesium and boron).
  • Increase in presence of sodium, protein and caffeine.

Faecal Ca2+ excretion

  • Increase dietary Ca excretion with consumption of fibre, phytate and oxalate; also if Mg is in excess and in people with fat mal-absorbing disorder.
4
Q

What are the 3 main types of bone cells?

A

Osteoblasts

  • are mononucleated, bone building cells; originate from bone marrow
  • secrete collagen and other proteins, as well as ground substance (the extracellular matrix, osteoid, surrounding bone cells) under the influence of PTH, calcitriol and oestrogen.
  • are responsible for mineralization of the osteoid matrix.

Osteocytes

  • are osteoblasts that have been incorporated into bone matrix; important in maintaining the integrity of surrounding bone.

Osteoclasts

  • large, multinucleated cells; function to resorb previously made bone.
  • respond to PTH, calcitriol and calcitonin
  • play an important role in helping maintain normal blood [Ca2+] in time of inadequate calcium intake.
  • Initiate remodelling cycles.
5
Q

What is PTH?

A

is a polypeptide hormone

is the main physiological regulator of Ca2+ in blood

~ secretion from parathyroid chief cells is:

stimulated by decreased in calcium concentration

inhibited when calcium concnetration increases

6
Q

Vitamin d2 and d3 converted invivio to calcitriol

true or false

A

true

-> calcitriol biologically active

7
Q

When is calcitriol released?

A

released in response to an increase in PTH

release:

  • enhances calcium absorption (stimulates uptake across GI mucosa - Calbindin).
  • Increases demineralisation of bone.
  • Increases reabsorption of calcium from kidney.
8
Q

What is calcitonin?

A

Polypeptide hormone

Synthesised in the parafollicular cells of the thyroid gland

  • acts to reduce blood Ca2+ levels, thus opposing the effects of PTH

> stimulates osteoblasts;

>inhibits activity of osteoclasts;

>prevents mobilisation of Ca2+;

> decreases postprandial absorption of Ca2+;

>inhibits calcitriol production;

>diminishes renal Ca2+ re-absorption (ie promotes calcium excretion) –> also Na,Mg and P

9
Q

Summarise what happens when there is low or high calcium int the body

A

low calcium = increased PTH and increased Calcitriol = incerased plasma concentration levels of calcium by:

  • Bone: Increased Ca mobilisation
  • Kidney: Increased Ca reabsorption
  • Intestines: Increased Ca absorption

high calcium = increased calcitonin = decresed plasma concentration of calcium by:

  • Bone: Decreased Ca mobilisation
  • Kidney: Decreased Ca reabsorption
  • Intestines: Decreased Ca absorption
10
Q

What are the drugs used for osteoporosis?

A
  1. Calcium
  2. Vitamin D

o Colecalciferol (vitamin D3)

o Calcitriol

  1. Bisphosphonates
  2. Raloxifene
  3. Teriparatide
  4. Strontium
  5. Denosumab
11
Q

What are the types of calcium salts available?

A

Calcium carbonate (cal-sup, caltrate tabs)

Calcium chloride injection

Calcium citrate

Calcium gluconate injection

Calcium carbonate, calcium lactate gluconate

12
Q

What are the indications for calcium?

A

Calcium deficiency

Adjunctive treatment

> osteoporosis –> fixed dose combination with colecalciferol

> osteomalacia

> rickets

  • Acute hypocalcaemia and hypocalcaemiac tetany
  • Hyperphosphataemia in renal failure
  • Severe hyperkalaemia not due to digoxin toxicity
13
Q

Contraindications for calcium?

A

¾ Hypercalcaemia ¾ Hypercalciuria ¾ Digoxin toxicity

14
Q

Coinsiderations with calcium?

A

Treatment with digoxin – may lead to arrhythmias ¾

Treatment with calcitriol – increased risk of hypercalcaemia ¾

Decreased gastric acidity (eg treatment with PPI) – use products not dependent on gastric acidity for absorption ¾

Interactions eg Iron

15
Q

AE of vitamin D

A

Adverse effects:

Common – Flatulence – Belching – Constipation

Infrequent – Hypophosphataemia – Hypercalcaemia

Note: – IV can cause • Skin necrosis (extravasation) • Irritation

Rare:

Milk-alkali syndrome presents:

Acutely with – Headache – Nausea – Irritability – Weakness • Chronically with: – Uraemia – Alkalosis – Hypercalcaemia – Usually triggered by concomittent vomiting &/or Na bicarbonate ingestion

16
Q

Vitamin D: calcitriol and colecalciferol

MOA

  • Regulate Ca2+ homeostasis & bone metabolism
  • Increased intestinal absorption & renal reabsorption of Ca2+
  • Promote bone mineralisation (due to bigger pool of blood Ca2+ due to increased absorption and reabsorption -> inc mineralisation).
A
17
Q

Indications for vitamin D

A

Treatment of osteoporosis 1, 2

> colecalciferol in combination with alendronate

Prevention of corticosteroid-induced osteoporosis 1

1= calcitriol

2= colecalciferol

18
Q

Vit D3 = colecalciferol

Vit D2 = ergocalciferol

What happens to these two

A

Converted to calcitriol?

19
Q

Compare calcitriol with colecalciferol and ergocalciferol

A

Calcitriol

  • Rapid onset of action (1-3 days) but
  • Short duration of action (< 1 week)
  • Risk of hypercalcaemia – Requires monitoring

Colecalciferol & Ergocalciferol

  • Slow onset (4-8 weeks)
  • Prolonged duration of action (8-16 weeks)

> Colecalciferol may be more effective in raising & maintaining serum [25- hydroxyvitamin D]

> Usually no risk of hypercalcaemia at normal doses (< 2000 units/ day)

20
Q

What are the adverse effects of Vitamin D?

A

Mostly due to effects of hypercalcaemia

Early signs of hypercalcaemia:

  • Nausea
  • Vomiting
  • Constipation
  • Anorexia
  • Apathy –> absence/suppression of passion, emotion or excitement
  • Headache
  • Thirst
  • Sweating
  • Polyuria
21
Q

Considerations for Vitamin D

A

Avoid cholecalciferol & ergocalciferol in severe renal impairment

  • Inability to convert to active form

Calcitriol

  • Can cause hypercalcaemia & hyperphosphataemia in patients with renal impairment

> Must be used cautiously

Treatment with digoxin

  • Increased risk of arrhythmias if hypercalcaemia is present
22
Q

What are examples of biphosphonates?

A

BISPHOSPHONATES Include: ƒ

Alendronate (Fosamax® tabs) ƒ

Clodronate (Bonefos® tab, caps) ƒ

Etidronate (Didronel® tabs) ƒ

Tiludronate (Skelid® tabs) ƒ

Ibandronic acid (Bondronat ®) ƒ

Pamidronate (Aredia® & Pamisol® inj) ƒ

Risedronate (Actonel® tabs) ƒ

Zoledronic acid (Zometa® inj)

23
Q

Indications for Biphosphonates

A
  • Paget’s disease of bone ƒ
  • Prevention and treatment of osteoporosis ƒ
  • Hypercalcaemia of malignancy ƒ
  • Prevention of skeletal-related events in patients with malignancies involving bone

>Bisphosphonates are: • synthetic analogues • completely resistant to hydrolysis • chemically very stable.

24
Q

MOA of biphosphonates?

A
  • are highly –vely charged •
  • form a 3-dimensional structure that can chelate divalent cations (eg Ca2+)
  • concentrate at sites of active remodelling and inhibit bone resorption (prevent hydroxyapatite dissolution) by

> direct inhibitory effects on osteoclasts

> stimualte osteoblast to produce inhibitor (s) of osteoclast

DOES THIS BY

  • BP bind to hydroxyapatite crystals in bone matrix
  • preferentially deposit under osteoclasts
  • Osteoclasts take BP up; metabolise BP to form a toxic analogue of ATP –> induces osteoclast apoptosis (suicide)
  • Some, eg nitrogen containing drugs (alendronate, risedronate), inhibit the production of cholesterol & related lipids essential for osteoclast function —> causes eventual apoptosis
25
Q

A) Second gen biphsphonates?

B) Third gen biphosphonates?

A

A)

  • Alendronate ƒ
  • Pamidronate ƒ
  • Ibandronate

> have a nitrogen group on the side chain

> are 10-100x more potent than 1st generation

B)

  • Risderonate
  • Zoledronic acid
  • Have a nitrogen atom with a heterocyclic ring
  • Upto 10,000x more potent than 1st generation
26
Q

PK of biphosphonates?

A

Usually given orally after O/N fast (but some by IV)

  • Absorbed by passive diffusion in the stomach and upper small intestine
  • Absorption is:

> decreased if the drug is given with Ca, Fe or Mg

–> Ca, Fe or Mg not to be taken within 2h of taking bisphosphonate; at least 30min after alendronate or ibandronate

Prolonged storage in bone –> half life is several years

27
Q

What to give with alendronate and risedronate?

A

Should give Ca2+ & vitamin D supplements with alendronate and risedronate if dietary intake is inadequate.

28
Q

What are CI for biphosphonates?

A

Hypocalcaemia

29
Q

What are precautions of biphosphonates?

A
  • Osteonecrosis of the jaw (ONJ) – dental assessment and complete dental surgical procedures before use of BP.
  • Deterioration of renal function has been reported; avoid use in severe impairment.
  • Women: consider when planning pregnancy (B2) & breastfeeding (B3) no data available thus avoid use or avoid breastfeeding.
30
Q

AE of biphosphonates

A

Common ƒ

Nausea, vomiting, diarhoea, headache, hypocalcaemia, musculoskeletal pain, ƒ IV: flu-like symptoms, hypophosphataemia, ….

Infrequent ƒ

Oesophagitis, oesophageal erosions and ulcers, gastritis, …. ƒ IV: hypertension, hypomagnesaemia, hypokalaemia.

Rare ƒ

Heart failure, renal impairment, ocular inflammation (eg iritis), ONJ, alergic reactions including angioedema ƒ IV: anaphylactic shock

>Iritis causes bulging and inflammation of the iris (the colored part of the eye that surrounds the pupil ) and surrounding white tissue.

31
Q

Strontium (discontinued, why is it in rima lecture?!?!)

A

Adverse effects Common: ƒ Nausea, diarrhoea, headache, ƒ Dermatitis ƒ n [creatine kinase]

Rare: ƒ venous thromboembolism ƒ Peripheral oedema, ƒ Memory loss ƒ Seizures ƒ Stevens-Johnson’s syndrome ƒ DRESS (Drug Rash with Eosinophilia and Systemic Symptoms)

32
Q

MOA of teriparatide?

A
  • is the active fragment of human PTH

– promotes bone formation & n BMD (bone mineral density)

33
Q

Indications for teripatide?

A
  • Postmenopausal osteoporosis
  • Primary osteoporosis in men
  • Corticosteroid-induced osteoporosis

when there is a high risk of fractures and other agents are unsuitable

contraindications

  • pagets disease of bone
  • hyperparathyroidism

Administered SC

34
Q

AE of Teriparatide

A

Common: Nausea • Headache • Dizziness • Hyperuricaemia • Injection site reactions

Infrequent: Hypercalcaemia • Myalgia • Increased ALP

Rare:Allergic reactions including anaphylaxis

35
Q

Why teriparatide got doubts for long term use?

A

Occurrence of osteosarcoma in animal studies

  • Is the most common type of malignant bone cancer
  • Affects mainly the ends of long bones
  • Highest incidence in 10-25 y/o group but can also occur in the elderly
36
Q

MOA of denosumab?

A

Human monoclonal antibody. –

Binds receptor activator of nuclear factor-kappa B ligand (RANK Ligand) preventing activation of RANK receptor. –

Results in decreased formation and activity of osteoclasts, thus reduced bone resorption.

> RANK Ligand is produced by bone cells and is a key mediator of bone resorption.

37
Q

Indications of denosumab?

A

Indications

Postmenopausal osteoporosis – Increase BMD in men with osteopenia receiving androgen deprivation therapy for non-metastatic prostate cancer. –

Prevention of skeletal-related events due to bone metastases from solid tumors.

38
Q

Precuations of Denosumab?

A

Hypocalcaemia; inc risk if CrCl <30mL/min.

Pregnancy: category D.

Breastfeeding: no human data

39
Q

Adverse effects of denosumab?

A

Common:

• Eczema • Hypercholesterolaemia

Infrequent • Skin infections

Rare • ONJ • Hypersensitivity (including anaphylactic reaction)

40
Q

How does denosumab work?

A

Tumour cells produce factors that stimulate osteoblasts to secrete RANK Ligand

DENOSUMAB binds RANK Ligand; thus reduces bone resorption

RANK Ligand drives increased formation, function and survival of osteoclasts; thus increases bone resorption

41
Q

Raloxifene MOA and indications?

A

MOA

  • Increases BMD in postmenopausal women but decreases estrogen
  • Selective oestrogen receptor modulator.

> Oestrogen agonist – bone mass and lipid

> Oestrogen antagonist at other oestrogen-receptive tissues (eg breast and endometrium)

Indications

  • Postmenopausal osteoporosis
  • Invasive breast cancer in high-risk postmenopausal women.
42
Q

Precautions for raloxifene?

A

Venous Thromboembolism (VTE) –

Contraindicated in pregnancy (category X) and breastfeeding.

43
Q

Adverse effets of raloxifene?

A

Adverse effects:

Common: • Hot flushes • Peripheral oedema • Sleep disorders

Infrequent: • VTE

44
Q

Sumamry

A
  • Cholecalciferol (+/- Ca)
  • Calcitriol (cautiously whilst monitoring)
  • BPs and Sr are the most commonly used but long term use is of concern

> plus Ca & Cholecalciferol?

  • Other drugs available all with precautions and some serious side effects