Module 4.2.1 (Pharmacology of Osteoporosis) Flashcards
How is calcium maintained?
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.
How is calcium absorbed?
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.
How is calcium excreted?
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.
What are the 3 main types of bone cells?
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.
What is PTH?
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
Vitamin d2 and d3 converted invivio to calcitriol
true or false
true
-> calcitriol biologically active
When is calcitriol released?
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.
What is calcitonin?
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
Summarise what happens when there is low or high calcium int the body
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
What are the drugs used for osteoporosis?
- Calcium
- Vitamin D
o Colecalciferol (vitamin D3)
o Calcitriol
- Bisphosphonates
- Raloxifene
- Teriparatide
- Strontium
- Denosumab
What are the types of calcium salts available?
Calcium carbonate (cal-sup, caltrate tabs)
Calcium chloride injection
Calcium citrate
Calcium gluconate injection
Calcium carbonate, calcium lactate gluconate
What are the indications for calcium?
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
Contraindications for calcium?
¾ Hypercalcaemia ¾ Hypercalciuria ¾ Digoxin toxicity
Coinsiderations with calcium?
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
AE of vitamin D
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
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).
Indications for vitamin D
Treatment of osteoporosis 1, 2
> colecalciferol in combination with alendronate
Prevention of corticosteroid-induced osteoporosis 1
1= calcitriol
2= colecalciferol
Vit D3 = colecalciferol
Vit D2 = ergocalciferol
What happens to these two
Converted to calcitriol?
Compare calcitriol with colecalciferol and ergocalciferol
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)
What are the adverse effects of Vitamin D?
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
Considerations for Vitamin D
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
What are examples of biphosphonates?
BISPHOSPHONATES Include:
Alendronate (Fosamax® tabs)
Clodronate (Bonefos® tab, caps)
Etidronate (Didronel® tabs)
Tiludronate (Skelid® tabs)
Ibandronic acid (Bondronat ®)
Pamidronate (Aredia® & Pamisol® inj)
Risedronate (Actonel® tabs)
Zoledronic acid (Zometa® inj)
Indications for Biphosphonates
- Paget’s disease of bone
- Prevention and treatment of osteoporosis
- Hypercalcaemia of malignancy
- Prevention of skeletal-related events in patients with malignancies involving bone
>Bisphosphonates are: • synthetic analogues • completely resistant to hydrolysis • chemically very stable.
MOA of biphosphonates?
- 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
A) Second gen biphsphonates?
B) Third gen biphosphonates?
A)
- Alendronate
- Pamidronate
- 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
PK of biphosphonates?
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
What to give with alendronate and risedronate?
Should give Ca2+ & vitamin D supplements with alendronate and risedronate if dietary intake is inadequate.
What are CI for biphosphonates?
Hypocalcaemia
What are precautions of biphosphonates?
- 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.
AE of biphosphonates
Common
Nausea, vomiting, diarhoea, headache, hypocalcaemia, musculoskeletal pain, IV: flu-like symptoms, hypophosphataemia, ….
Infrequent
Oesophagitis, oesophageal erosions and ulcers, gastritis, …. IV: hypertension, hypomagnesaemia, hypokalaemia.
Rare
Heart failure, renal impairment, ocular inflammation (eg iritis), ONJ, alergic reactions including angioedema 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.
Strontium (discontinued, why is it in rima lecture?!?!)
Adverse effects Common: Nausea, diarrhoea, headache, Dermatitis n [creatine kinase]
Rare: venous thromboembolism Peripheral oedema, Memory loss Seizures Stevens-Johnson’s syndrome DRESS (Drug Rash with Eosinophilia and Systemic Symptoms)
MOA of teriparatide?
- is the active fragment of human PTH
– promotes bone formation & n BMD (bone mineral density)
Indications for teripatide?
- 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
AE of Teriparatide
Common: Nausea • Headache • Dizziness • Hyperuricaemia • Injection site reactions
Infrequent: Hypercalcaemia • Myalgia • Increased ALP
Rare:Allergic reactions including anaphylaxis
Why teriparatide got doubts for long term use?
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
MOA of denosumab?
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.
Indications of denosumab?
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.
Precuations of Denosumab?
Hypocalcaemia; inc risk if CrCl <30mL/min.
Pregnancy: category D.
Breastfeeding: no human data
Adverse effects of denosumab?
Common:
• Eczema • Hypercholesterolaemia
Infrequent • Skin infections
Rare • ONJ • Hypersensitivity (including anaphylactic reaction)
How does denosumab work?
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
Raloxifene MOA and indications?
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.
Precautions for raloxifene?
Venous Thromboembolism (VTE) –
Contraindicated in pregnancy (category X) and breastfeeding.
Adverse effets of raloxifene?
Adverse effects:
Common: • Hot flushes • Peripheral oedema • Sleep disorders
Infrequent: • VTE
Sumamry
- 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
