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Pharma 2- Semmelweis > B-28. Agents affecting bone mineral homeostatsis (calcium, vitamin D, parathyroid hormone, calcitonin, etc.). Pharmacotherapy of osteoporosis. > Flashcards

B-28. Agents affecting bone mineral homeostatsis (calcium, vitamin D, parathyroid hormone, calcitonin, etc.). Pharmacotherapy of osteoporosis. Flashcards

1
Q

3 main hormones controling bone mineral homeostasis

A
  1. Vitamin D
  2. Fibroblast Growth Factor 23
  3. Parathryoid Hormone
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2
Q

What is the process of Vitamin D activation starting with the skin?

A

7-dehydrocholesterol → cholecalciferol via UV in skin → calcifediol via liver 25-OHation → calcitriol (1,25-OH vitamin D) via kidney 1-OHation

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3
Q

Vitamin D actions

A
  • Vitamin D actions: overall ↑ serum Ca and Pi
    • ↑ Ca / Pi absorption from GI tract
    • ↑ RANKL production by osteoblasts
    • ↑ FGF-23 release from bone
    • ↓ Ca / Pi excretion from kidney
    • ↓ PTH production by parathyroid
    • Immune effects: receptors on lymphocytes and APCs regulate immune function; ↓ vitamin D is assoc. with autoimmunity + ↑ infections
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4
Q

Fibroblast Growth Factor 23 is released from what? Actions?

A

Fibroblast Growth Factor 23 - released from osteocytes; overall ↓ serum Pi

  • FGF-23 actions:
    • ↓ Pi reabsorption in kidney ( → ↑ excretion)
    • ↓ 1-α hydroxylase in kidney → ↓ vitamin D
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5
Q
  • Parathyroid hormone
    • Overall effect
    • Drug derivative
    • Physiological downregulation of PTH
A

Parathyroid Hormone - overall ↑ Ca and ↓ Pi in serum

  • an 84 AA hormone with a 34 AA active peptide (active peptide available as teriparatide drug)
  • on parathyroid cells senses serum calcium level: ↑ Ca++ → ↓ PTH release
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6
Q

PTH mainly stimulates

A
  • PTH stimulates:
    • Osteoclast/-blast differentiation from monocytes / stem cells, respectively
    • production by osteoblasts, which binds RANK on osteoclasts, activating them and thus bone resorption + subsequent remodeling by osteoblasts
    • 1-α hydroxylase in kidney → ↑ vitamin D production
    • Phosphate excretion in kidney
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7
Q

Osteoblast aslo produce what? What is it’s function? Short term PTH action leads to?

A
  • Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor for RANKL which binds and inactivates it, balancing RANKL activation of osteoclasts
    • Short-term PTH action results in more OPG than RANKL action → more osteosynthesis; repeated short-term PTH → net bone mass increase
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8
Q

Secondary hormones in bone homeostasis

A
  1. Calcitonin
  2. Glucocorticoids
  3. Estrogens
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9
Q

Calcitonin function? Is it more physiologically or pharmacologically important?

A
  • Calcitonin
    • From thyroid parafollicular cells; results in ↓ serum Ca/Pi by inhibiting osteoclasts; long-term inhibition of both bone resorption + formation; less physiologically important, but can be used pharmacologically
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10
Q

Glucocorticoids effects? Leads to long term?

A

Glucocorticoids - ↓ absorption + ↑ excretion of Ca → ↓ bone formation

Long-term → osteoporosis

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11
Q

Estrogen effects on bones?

A

Estrogens- prevent post-menopausal bone loss via ↓ PTH action and ↑ calcitriol

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12
Q

Non-nitrogen Bisphosphonate drugs (3)

A
  1. Etidronate
  2. Clodronate
  3. Tiludronate
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13
Q

Nitrogen Bisphosphonate drugs (5)

A
  1. Zolendronate
  2. Pamidronate
  3. Alendronate
  4. Ibandronate
  5. Risedronate
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14
Q

Bisphosphonates general MOA?

A

Bisphosphonates: most effective inhibitors of bone resorption

  • MOA: pyrophosphate (PPi) analogs → bind to bone minerals, then taken up by + inhibit osteoclasts
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15
Q

Non-nitrogen bisphosphonates MOA?

Nitrogen bisphosphonates MOA

A
  • Non-nitrogen BPh: incorporate into ATP and have a cytotoxic effect
  • Nitrogen BPh: inhibits farnesyl PPi synthase + thus the mevalonate pathway
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16
Q

Main effect of bisphosphonates lead to? Nitrogen or non-nitrogen bisphosphonates are used more often?

A
  • Lead to ↓ bone turnover, initial ↑ bone mineral density + later stabilized bone mineral homeostasis
  • Nitrogen-containing drugs (ex: alendronate) used more now than earlier non-nitrogen Bphs (ex: etidronate, the first BPh)
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17
Q

Indications of bisphosphonates

A
  • Osteoporosis
  • Hypercalcemia- via hyper-PTH or malignant lytic lesions
18
Q

Side effects of osteoporsis

A
  • Side Effects:
    • Upper GI effects - reflux, esophagitis w/ ulcers (w/ oral admin; prevent w/ hydration + sit upright)
    • Mandibular Osteonecrosis - rare; mostly with IV admin
    • Hypocalcemia- via osteoclast inhibition; transient + more with IV admin
19
Q
  • SERMs
    • Drug name?
    • MOA?
    • Indication?
A
  • SERMs - Raloxifene
  • MOA: estrogen agonist in bone; antagonist in breast, uterus
  • Indication: use in osteoporosis patients not tolerant to BPhs
20
Q

Synthetic PTH

A

Teriparatide

21
Q

What is the antibody used in osteoporsis?

A

Denosumab

  • MOA: anti-RANKL monoclonal antibody
22
Q

Calcimimet drug? MOA? Use?

A
  • Cinacalcet
    • Activates calcium sensing receptor (CaSR)
    • In the parathryoid gland by activating CaSRs will inhibit PTH secretion
    • Clinical use: secondary hyperparathyroidism (in chronic kidney disease), parathryoid carcinoma
    • CaSR antagonist might be used to stimulate intermittent PTH secretion in osteoporosis
23
Q

Nonhormonal agents affecting bone mineral homeostasis (4)

A
  1. Cinacalcet
  2. Thiazide diuretics
  3. Fluoride
  4. Strontium ranelate
24
Q

Thiazide diuretics effect in bone homestsis

A

Thiazide diuretics - ↑ PTH-mediated Ca resorption; ↓ hypercalciuria / stones

25
Q

Fluoride diuretics effect in bone homestsis

A

Fluoride - stabilizes hydroxyapatite; promotes bone growth + improves Ca balance (but no ↓ in fractures!)

26
Q

Strontium Ranelate in bone homeostasis

A

Strontium Ranelate - ↓ bone resorption via osteoclast apoptosis → ↑ bone formation (EU, not US)

27
Q

Calcitonin MOA and Indication

A

Calcitonin

  • MOA: directly inhibits osteoclasts → ↓ resorption → ↓ serum Ca; also ↑ renal Ca excretion
  • Indication:
    • Osteoporosis- 2nd line to ↓ resorption
    • Severe hypercalcemia - as in malignant lytic bone lesions
    • Paget’s disease -
  • Side Effects:
    • Hypocalcemia
28
Q

Endogenous drug given in osteoporosis due to deficiency in most people?

A

Vitamin D

29
Q

Osteoporosis definition

A
  • Definition: a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture
30
Q

Bone T score

A
  • 1 SD: normal
  • -1 – 2.5 SD: osteopenia
  • Below -2.5 SD: osteoporosis
  • Below -2.5 SD + at least one vertebral fracture: severe osteoporosis
31
Q

Risk factors for osteoporosis

A
  1. Genetic factors
  2. Environmental factors: smoking, alcohol, physical inactivity, thin habitus, low body weight < 58kg, low calcium intake and little exposure to sun light
  3. Menstrual status: meonpause < 45 year, previous amenorrhea
  4. Drug therapy: glucocorticoids, antiepileptic drugs (phenytoin), excessive substitution therapy with thyroxine, hydrocortisone, anticoagulants, heparin, dicoumarin derivatives
  5. Endocrine (hyperparathyroidism, thyretoxicosis), GI (malabsorption), rheumatologic, hematologic disease
32
Q

Treatment strategy of postmenopausal osteoporosis. Main point?

A
  • The main direction of therapy is the inhibition of the increased osteoclast activity
  • A substance truly stimulating bone formation did not reach yet the clinical practice
34
Q

Treatment options for osteoporosis

A
  1. Hormone substitution therapy (for women)
  2. Selective estrogen receptor modulators (SERM) (for women)
  3. Denosumab
  4. Bisphosphonates
  5. Parathyroid hormone (PTH 1-34=Teriparatide)
  6. Vitamin D intake
  7. Thiazide diuretics
35
Q
  • Hormone substitution therapy
    • What does menopause do to the bones?
    • How does hormone substitution therapy work?
    • What risks are increased iwth treatment?
A
  • Hormone substitution therapy
    • The menopause induces accelerated bone loss the first 4-5 years, which is followed by a linear decrease, above 75 years of age bone loss becomes accelerated again
    • Hormone replacement therapy (HRT) increases BMD, decreased bone turnover and the number of bone fractures
    • It is effective until administered
    • Estrogen (combined with progestin if the uterus is intact) increases risk of breast cancer, may enhance the risk of cardiovascular disease

Prolonged HRT is not recommended anymore

36
Q

Selective estrogen receptor modulators (SERM) drugs

A
  1. Raloxifen
  2. Tamoxifen
37
Q

SERMs effect

A
  • Act on the estrogen receptors
    • In some organs they act as agonists, while in others as antagonists
  • In the treatment of osteoporosis those SERMs have clinical importance which are
    • Agonists: in the bones
    • Antagonists: in the breast and uterus
38
Q

Do SERMs increase the cardiovascular risk?

A
  • SERMs do not increase the overall cardiovascular risk but increase significantly the risk of thromboembolism
39
Q

Raloxifen

  • Efficacy?
  • Risks?
  • Protects against what kind of fractures?
A
  • Efficacy on the bones is equal to that of estrogen
  • The thickness of endometrium, breast pain, vaginal bleeding, hot flushes, did not increase compared with placebo
  • Imposes the same increased risk for venous thromboembolism as estrogen
  • Protects against spine fractures but not hip fractures (unlike bisphosphonates, denosumab and teriparatide protect against both)
40
Q

Parathyroid hormone drug? MOA?

A
  • Teriparatide is the first 34 amino acids of the PTH
  • PTH stimulates both bone resorption and bone formation
41
Q

Continuous and intermittent treatment difference and similarities?

A
  • Continuous and intermittent treatment stimulates bone formation equally, however:
    • Continuous treatment leads to persistent increase of PTH level and relatively larger bone resoprtion
    • Daily small doses lead to minimal bone resoprtion and substantial bone formation
42
Q
  • Vitamin D drugs
A
  • Vitamin D intake
    • Vitamin D3 (cholecalciferol)
    • Vitamin D2 (ergocalciferol)
    • Active forms of vitamin D
      • a-hydroxyvitamin D3 (1a-hydroxycalciferol)

1,25-dihydroxyvitamin D3 (1,25 dihydroxycholecalciferol)

Pharma 2- Semmelweis (43 decks)

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