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SEM3: PATH30210 Endocrine Health/Disease > PHARM 3: Osteoporosis, Calcium Disorders and Parathyroid Disorders > Flashcards

PHARM 3: Osteoporosis, Calcium Disorders and Parathyroid Disorders Flashcards

1
Q

Three principal hormones regulate calcium and phosphate homeostasis and their origin?

A

Parathyroid hormone (PTH) (Chief cells of parathyroid gland)

Active metabolite of vitamin D (1,25-dihydroxy vitamin D) (Calcitriol) made in kidney

Calcitonin (perifollicular cells of the thyroid gland)

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2
Q

________ stimulates the production of the active metabolite of vitamin D (1,25-dihydroxyvitamin D) (calcitriol) in the ________

A

PTH stimulates the production of the active metabolite of vitamin D (1,25-dihydroxyvitamin D) (calcitriol) in the kidney

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3
Q

___________ stimulates intestinal absorption of phosphate and calcium

A

Calcitriol (1,25(OH)2D)) stimulates intestinal absorption of phosphate and calcium

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4
Q

_________ and __________ suppress the production of PTH

A

Calcium and Calcitriol (1,25(OH)2D) suppress production of PTH

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5
Q

__________ promotes bone formation stimulating the differentiation of osteoblasts and ___________ promotes resorption by stimulating the proliferation and differentiation of osteoclasts.

Continuous vs. Pulsaitle Secretion?

A

Calcitriol (1,25(OH)2D) promotes bone formation stimulating the differentiation of osteoblasts and PTH promotes resorption by stimulating the proliferation and differentiation of osteoclasts.

Continuous PTH = bone resorption
Pulsatile PTH = bone formation

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6
Q

_______________ and ______________ both promote renal retention of calcium

A

Calcitriol (1,25(OH)2D) and PTH both promote renal retention of calcium

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7
Q

___________ promotes renal phosphate excretion whereas ____________ promotes renal reabsorption of phosphate

A

PTH promotes renal phosphate excretion whereas Calcitriol (1,25(OH)2D) promotes renal reabsorption of phosphate

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8
Q

Calcitonin MOA?

A

Released by perifollicular C-cells of the thyroid gland in response to high Ca 2+:

  • Binds receptors on osteoclasts to decrease reabsorption of Ca2+
  • Increases renal excretion of Ca2+
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9
Q

What is secreted by perifollicular cells of the thyroid gland in response to high Ca 2+?

A

Calcitonin

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10
Q

What increases calcitonin levels?

A

High Ca2+
Gastrin
Glucagon
Epinephrine

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11
Q

Calcitonin vs. PTH?

A
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12
Q

Significance of RANKL?

A

RANKL binds RANK receptor on Macrophages and promotes differentiation into Osteoclasts
=>INCREASES Bone Reabsorption (Decreases Bone Mass)

Mice Deficient in RANKL Have ‘Stone Bone’ (Osteopetrosis)

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13
Q

Causes of Hypercalcemia?

A

Hyperparathyroidism
Cancer
Chronic Kidney Disease

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14
Q

Causes of Hypocalcemia?

A

Hypoparathyroidism
Vitamin D deficiency
Chronic renal failure
Malabsorption

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15
Q

Primary versus Secondary Hyperparathyroidism?

A

Primary: spontaneous overproduction of PTH)

Secondary: primarily attributable to chronic kidney disease (kidneys fail to activate vitamin D => failure to negative feedback on PTH production)

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16
Q

Symptoms of Hyperparathyroidism?

A

Painful Bones (increased resorption=> Increased osteoclast activity=> increased risk of osteoporosis )
Renal stones
Abdominal groans
Psychic moans

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17
Q

Therapies for hyperparathyroidism?

A

Therapies aimed at inhibiting osteoclast activity (overlap with osteoporosis medications)

  • Cinacalcet: prevents PTH release from parathyroid by binding to the calcium receptor
  • Bisphosphonates: Promotes osteoclast apoptosis and inhibits the cholesterol biosynthetic pathway
  • Surgery (95% success rate) but life-long replacement with vitamin D/Calcium will ensue.
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18
Q

Diagnosis of Hyperparathyroidism?

A

Measuring albumin-adjusted serum calcium

Measuring parathyroid hormone

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19
Q

Osteopenia vs. Osteoporosis?

A

Osteopenia is 1-2.5 standard deviations below the mean peak bone mass

Osteoporosis is defined as osteopenia that severe enough to cause fracture (at least 2.5 standard deviations below the mean bone mass)

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20
Q

Risk Factors for Osteoporosis?

A

Hormonal influences –menopause
Steroid hormone use

Also:
Reduced physical activity (weight bearing)
Nutrition (calcium deficiency, vitamin D deficiency)
Genetics (LRP4 mutation)

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21
Q

Diagnosis of Osteoperosis?

A

Fracture Risk Assessment Tool (FRAX): Combines Bone mineral density (BMD) with clinical risk factors to predict the 10-year risk of fracture. Useful as a decision to treat tool

22
Q

Treatment of Osteoporosis?

A

Bisphosphonates (1st: Etidronate disodium; 2nd: Alendronate, Ibandronate, Tiludronate and Pamidronate; 3rd: Risedronate, Zoledronic Acid)

Anti-RANKL antibody (Denosumab)

Selective estrogen receptor modulators (SERMs)

Calcitonin mimetics (fortical and miacalcin)

PTH (Teriparatide)

23
Q

MOA of Bisphosphonates?

A

Bisphosphonates are antiresorptive medicines i.e. they slow the break down of bone tissue (impair osteoclasts)

Pyrophosphate analogs.

24
Q

First Generation Bisphospahte (Dosing/MOA)?

A

Etidronate disodium (daily dosing, orally administered)

MOA: Non-Nitrogenous bisphosphate is internalized by osteoclasts and converted to ATP Analog that cannot be hydrolyzed => Promotes osteoclast apoptosis

25
Q

Second/Third Generation Aminobisphosphates (Dosing/MOA)?

A

Second generation = contains nitrogen - x10 more potent

Third generation = nitrogen within heterocyclic ring - x10,000 more potent

  • Risedronate given orally once weekly
  • Zoledronic Acid administered IV just once a year

MOA: Promote osteoclast apoptosis and inhibit the cholesterol biosynthetic pathway

26
Q

What is the Bisphosphonate drug holiday?

A

Taking a drug holiday (Ceasing bisphosphonate therapy for ~2 years) is gaining traction in clinical practice

Plateau in bone mineral density in response to bisphosphonates after ~ 5 years of treatment with little increase thereafter.

Discontinuation of therapy has a slow offset effect with minimal decrease in BMD over the next few years.

Fracture risk increases thereafter with peak fracture risk 4-5 years into a drug holiday

27
Q

_______________ (recombinant PTH) used in the treatment of Osteoporosis

Given to those who have not responded/don’t tolerate ________________ (or have severe spinal osteoporosis)

____________ once daily = pulsatile exposure => bone formation results

A

Teriparatide (recombinant PTH) used in the treatment of Osteoporosis

Given to those who have not responded/don’t tolerate bisphosphonates (or have severe spinal osteoporosis)

Subcutaneously once daily = pulsatile exposure => bone formation results

28
Q

__________ is a monoclonal antibody that blocks the actions of RANKL

A

Denosumab is a monoclonal antibody that blocks the actions of RANKL=> Reduces osteoclast proliferation and activation

29
Q

MOA/Indications/Delivery/Contraindications of Denosumab?

A

Denosumab is a monoclonal antibody that blocks actions of RANKL=> Reduces osteoclast proliferation and activation

Approved for treatment of post-menopause osteoporosis, multiple myeloma, bone-metastases

Contraindicated in those with low calcium levels
Given subcutaneously every 6 months (60mg dose): Expensive!!

30
Q

Main concern of Selective Estrogen Receptor Modulators (Roloxifene)?

A

RISK OF BLOOD CLOTS MAIN CONCERN!! – DVT, PE, Retinal Vein TE

31
Q

__________ can effectively slow bone loss post menopause and relieve menopausal symptoms

A

Estrogen replacement can effectively slow bone loss post menopause and relieve menopausal symptoms

Not usually given to treat osteoporosis unless also indicated for menopausal symptoms

32
Q

Guidelines for Hormone Reaplacement Therapy?

A

Estrogen replacement can effectively slow bone loss post menopause and relieve menopausal symptoms

HRT successfully reduced risk of fracture but it is associated with increased risk of DVT

only recommended for short duration (2-5yrs) until menopausal symptoms have been alleviated

Not usually given to treat osteoporosis unless also indicated for menopausal symptom

33
Q

Signs of Hypocalcemia?

A

C-A-T-S

Convulsions
Arrythmias
Tetany
Stridor and Spasms

34
Q

Hypocalcemia Therapeutics?

A

Vitamin D and calcium supplementation

Calcitriol- patients w/ kidney disease who cannot make enough active metabolite

Teriparatide (recombinant human PTH) in rare cases of poor response to calcium and vitamin D

35
Q

Calciferol MOA?

A

Calciferol is vitamin D2 used to treat hypoparathyroidism (decreased functioning of the parathyroid glands), and is also used to treat rickets (softening of the bones caused by vitamin D deficiency) or low levels of phosphate in the blood (hypophosphatemia).

Vitamin D is hydroxylated in the liver to 25-hydroxyvitamin D (Calcifediol)
=>Calcifediol is then converted in the kidney to active form calcitriol (1,25-dihydroxyvitamin D)
==>Calcitriol increases blood calcium (Ca2+) mainly by increasing the uptake of calcium from the intestines

36
Q

2 Types of Calciferol (Vitamin D)?

A

Natural form (Vit D3 = Cholecalciferol): binds better to Vit D transport in the blood
Plant-derived form (Vitamin D2 = Ergocalciferol)

37
Q

________ is given to patients with Hypocalcemia and kidney disease who cannot make enough active metabolite (given orally)

A

Calcitriol given to patients with kidney disease who cannot make enough active metabolite (given orally)

38
Q

Synthetic calcitriol derivative that reduces serum PTH levels
Only modest increases in serum calcium levels observed
Approved for the treatment of patients with hyperparathyroidism and renal failure
Administered by infusion

A

Paricalcitrol

39
Q

Administered orally or IV for hyperparathyroidism secondary to renal failure.

Does not increase intestinal Ca2+ absorption

Does not cause hypercalcemia

A

Doxercalciferol

40
Q

Potent suppressor of PTH and useful in patients with primary or secondary (due to renal failure) hyperparathyroidism

Long-term use has been associated with hypercalcemia

A

22 Oxacalcitrol (maxacalcitrol)

41
Q

Topical administration for the treatment of Psoriasis

Minimum effects on systemic calcium levels

A

Calcipotriene

42
Q

Therapeutic Uses of Vitamin D/Metabolites?

A

Hypocalcemia:

  • Vitamin D deficiency (rickets)
  • Hypoparathyroidism
  • Renal disease
  • Malabsorption
  • Osteoporosis

Primary Hyperparathyroidism: Paricalcitrol and 22-oxacalcitrol suppress PTH and are useful for the treatment of secondary

43
Q

Vitamin D metabolites (____________ and _________) suppress PTH and are useful for the treatment of Secondary/Primary Hyperparathyroidism

A

Vitamin D metabolites (Paricalcitroland 22-Oxacalcitrol) suppress PTH and are useful for the treatment of Secondary/Primary Hyperparathyroidism

44
Q

Drug/MOA/Indication of Calcium Mimetics?

A

Cinacalcet prevents PTH release from Parathyroid by binding to the calcium receptor (CaSR)

Indication: Used in the treatment of secondary hyperparathyroidism (kidney disease) or primary hyperparathyroidism

45
Q

Secondary drugs affecting Calcium Homeostasis?

____________________ Reduce renal excretion of Ca2+

____________________ increase renal Ca2+ excretion

Glucocorticoids:

  • Stimulates ___________/inhibits _______
  • Reduces _____________ absorption
  • Stimulates ________ release and increases _____________excretion
A

Thiazide diuretics Reduce renal excretion of Ca2+

Loop diuretics (furosemide) increase renal Ca2+ excretion

Glucocorticoids:

  • Stimulates osteoclasts/inhibits osteoblast
  • Reduces intestinal calcium absorption
  • Stimulates PTH release and increases urinary calcium excretion
46
Q

____________________: Increased but disordered structurally unsound bone associated with severe bone pain that occurs in late adulthood

Stages:

  1. __________________
  2. ___________________
  3. ____________________

Diagnosis/Therapy?

A

Paget Disease: Abnormal breakdown of bone followed by abnormal bone formation (turnover increased ~50 fold). New Bone is bigger but weaker and filled w/ new blood vessels

Stages:

  1. Initial Osteolytic stage
  2. Mixed Osteoclastic-Osteoblastic stage
  3. Quiescent Osteosclerotic Stage (too much bone deposited => deformation)

Diagnosis

  • Elevated Serum Alkaline Phosphatase (SAP- BLOOD TEST)
  • Elevated Urinary Hydroxyproline

Bisphosphates (Antiresorptive) First Line - Daily for 6 months

47
Q

First line of treatment for patients with hyperparathyroidism, osteoporosis, and Paget’s disease?

Generations?

A

Bisphosphonates:

1st generation (Etidronate Disodium) induces osteoclast apoptosis

2nd and 3rd generations (contain nitrogen) also inhibit the cholesterol biosynthetic pathway.

48
Q

Pulsatile exposure to __________increases bone formation while continuous exposure promotes bone resorption (_______________link)

A

Pulsatile exposure to Teriparatide (recombinant human PTH) increases bone formation while continuous exposure to PTH promotes bone resorption (Hyperparathyroidism-Osteoporosis link)

49
Q

________________ and __________________ are associated with protection against osteoporosis but the risk of DVT outweighs the benefit.

__________________ appear to be safer for alleviation of menopausal symptoms but still not indicated alone for prevention of osteoporosis in absence of menopausal symptoms

A

Selective Estrogen Receptor Modifying Agents and Oral HRT are also associated with protection against osteoporosis but risk of DVT outweighs the benefit

Transdermal patches appear to be safer for alleviation of menopausal symptoms but still not indicated alone for prevention of osteoporosis in absence of menopausal symptoms

50
Q

Side Effects/ Contraindications of Bisphosphates?

A
  • Poor oral absorption (1-3%): Recommended to take on empty stomach
  • Esophageal irritation and erosion (recommended to sit up after taking them for 30mins)
  • Not recommended for people with severe kidney disease –kidney function tests recommended before commencement of therapy
51
Q

Indications for Bisphosphonates/Aminobisphosphates?

A

Paget Disease: Increased but disordered structurally unsound bone

Osteoporosis: osteopenia severe enough to cause fracture (2.5 standard deviations below mean bone mass)

52
Q

Hypercalcemia Treatment Associated with increased risk of malignancies, since taken off the market?

A

Calcitonin Mimetics (Fortical and Miacalcin)

SEM3: PATH30210 Endocrine Health/Disease (25 decks)

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