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Drug Action II > Block 5: Bone, Calcium Homeostasis and Osteoporosis > Flashcards

Block 5: Bone, Calcium Homeostasis and Osteoporosis Flashcards

1
Q

What regulates Ca in blood?

A

Bone, PTH, Vitamin D

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2
Q

99% of Ca2+ is found in?

A

Hydroxypatite crystals in bone

Free, ionized Ca2+ is active

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3
Q

What is the importance of phosphorous?

A

Essensial for bone, ATP, cAMP

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4
Q

What components co-regulates Ca2+ and Phosphorous?

A

1, 25-dihydroxycholecalciferol increases Ca2+ absorption
PTH increases calcium absorption and decreases plasma phosphate in kidneys
Fibroblast growth factor-23 (FGF23) inhibits renal phosphate reabsorption

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5
Q

Falling blood Ca2+ levels signal ___, while Rising blood Ca2+ levels trigger ____?

A

Falling blood Ca2+ levels signal the parathyroid glands to release PTH degrading bone matrix

Rising blood Ca2+ levels trigger the thyroid to release calcitonin that deposits calcium salts in bone

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6
Q

What are cells of a parathyroid gland?

A

Chief cells: Secretes parathyroid hormone
Oxyphil cells: involved in energy production or storage

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7
Q

PTH action when there is low blood Ca2+?

A

PTH increases plasma Ca++ and decreases plasma phosphate
Bone: Increases osteoclast number & activity to increase Ca++ resorption of bone
Kidney: Stimulates Ca2+ reabsorption in the distal tubule of the kidney, decreasing urine Ca2+ excretion
Liver: PTH acts to stimulate synthesis of 1, 25-(OH)2-vitamin D

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8
Q

How does phosphorous levels change in response to Ca2+?

A

See increased phosphate release due to PTH actions at the intestines and bone, but a net decrease in plasma levels due to the effects of PTH on the kidney

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9
Q

How is PTH levels regulated?

A

The dominant regulator of PTH is plasma [Ca2+] and the secretion of PTH is inversely related to [Ca2+]

Low plasma Ca2+ concentrations stimulate PTH release
High plasma Ca2+ concentrations inhibit PTH release

no direct control of PTH with phosphate

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10
Q

What is calcitonin?

A
  • Decreases plasma calcium levels by parafollicular cells (C cells) of the thyroid gland
  • Inhibits osteoclast motility and activity
  • Inhibits bone resoprtion
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11
Q

What is the function of vitamin D?

A
  1. Heterodimerizes with RXR (DNA recognition sequences)
  2. Support circulating calcium concentrations by calbindin and increased expression of calcium channels TRPV 5/6
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12
Q

What are the main regulators of calcium concnetration into the interstitial space?

A

PMCA1b (Calcium active transporter) and NCX (the sodium calcium exchanger)

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13
Q

Deficiencies in Vitamin D?

A

Rickets, Osteomalacia, Osteoporosis

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14
Q

How is Vitamin D synthesized?

A
  1. 7-dehydrocholesterol is photo converted in the skin by ultraviolet radiation to cholecalciferol or vitamin D3
  2. First hydroxylation occurs in liver to yield 25-hydroxycholecalciferol
  3. 25-hydroxycholecalciferol is transported to the kidney and through PTH stimulation, is hydroxylated to 1,25-dihydroxycholecalciferol (1,25-(OH)2D3; Calcitriol) which is the active and most potent metabolite of Vitamin D
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15
Q

Role of Vitamin D in the bone?

A

Stimulates release of Ca by osteoblasts causing them to release RANKL activating osteoclasts promoting bone mineralization and regrowth

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16
Q

What is the cause of hypocalcemia? Sx?

A

Damage to parathyroid during thyroid surgery, vitamin D deficiency, or CKD
Sx: Progressive, Hyperexcitability

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17
Q

What is the cause of hypercalcemia? Sx?

A

Often due to tumor in PT gland
Sx: Depressed CNS and muscle, hypercalcemic crisis

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18
Q

What is the function of bone?

A
  1. Structural support
  2. Locomotion
  3. Protects vital organs
  4. Depot of ions
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19
Q

What is cortical/compact bone?

A

Forms the dense outer shell of the adult skeleton

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20
Q

What is Trabecular or Cancellous Bone?

A

Spongy, honeycombed (20% of bone)

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21
Q

What is diaphysis?

A

The shaft of a long bone containing medullary cavity of marrow

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22
Q

What is epiphysis?

A

Ends of a long bone

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23
Q

What is the epiphyseal plate?

A

Growth plate made of cartilage

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24
Q
A
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25
Q

What is the periosteum?

A

Membrane that covers bone and the site of ligament and tendon attachment

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26
Q

What are the hormones associated with bone growth during youth?

A

Infancy: Epiphyseal plate activity is stimulated by growth hormone & IGF-1
Puberty: Testosterone and estrogen

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27
Q

What are the major cell types of bone?

A

Osteoblasts: Bone forming cells
Osteocytes: Mature bone cells
Osteoclasts: (bone resorption) Secrete acids and proteases that dissolve the bone matrix and stimulates binding of osteoblast-generated RANKL to the RANK surface receptor on osteoclasts

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28
Q

Describe bone formation?

A
  1. Osteoblasts synthesize and extrude collagen
  2. Collagen fibrils form arrays of an organic matrix called the osteoid
  3. Formation of Hydroxyapatite Crystals: Ca10(PO4)6(OH)2
    * Dependent on Vitamin D and regulated by PTH
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29
Q

What is the difference between resoption and remodeling?

A

Resorption: Destroys entire matrix of the bone and diminishes bone mass to extract calcium
Remodeling: Endocrine signals to resting osteoblasts generate paracrine signals to osteoclasts and precursors

30
Q

Describe the process of bone resorption and remodeling?

A
  1. Parathyroid hormone (PTH), shear stress, and transforming growth factor-β (TGF-β) induce osteoblast precursors to express the osteoclast differentiation factor RANK-ligand (or RANKL)
  2. RANKL binds to RANK, a receptor expressed on osteoclast precursors
  3. The RANKL–RANK binding, together with other factors such as macrophage colony stimulating factor (M-CSF), cause osteoclast differentiation
  4. As mature osteoclasts resorb bone, matrix-bound factors such as TGF-β, insulin-like growth factor-1 (IGF-1), other growth factors, and cytokines are released
  5. These liberated factors stimulate osteoblast precursors to develop into mature osteoblasts, which begin to refill the resorption cavities excavated by the osteoclasts
31
Q

What is osteoporosis?

A

Abnormal loss of bone, predisposing patient o increased risk of fractures
* Decreased peak bone mass and accelerated bone loss

32
Q

What is the cause of postmenopausal osteoporosis?

A

Estogen deficiency increases activation and prolongs maturation of osteoclasts increasing vertebral compression fractures and wrist fractures risk

33
Q

What are the common RF of male osteoporosis?

A
  1. Smoking
  2. Low body weight
  3. Age
  4. GCC use
  5. androgen deprivation therapy
  6. Testosterone def
34
Q

What increases risk of disability and death due to osteoporosis?

A

hip fractures

35
Q

What are sx of osteoporosis?

A

Most patients are asymptomatic:
1. Pain
1. Immobility
1. Shortened stature
1. Fractures
1. Kyphosis
1. Lordosis

36
Q

How do you diagnose osteoporosis?

A

Measurement of Bone Mineral Density (BMD) using dual energy X-ray absorptiometry (DEXA scan)

37
Q

What is a Central and peripheral Skeletal BMD?

A

Central: Measures BMD at hip and/or spine
Peripheral: Measures BMD at forearm, heel, and/or phalanges

38
Q

What is the gold standard of osteoporosis diagnosis?

A

Central Dual-Energy X-ray Absorptiometry (DEXA) provides T-score and Z-score

39
Q

What is a T and Z score?

A

T: compare your bone density with that of a young adult
Z: compare your bone density with that of your peer group

40
Q

Calcium carbonate requires an ____ environment?

A

Acidic therefore requires food for absorption

41
Q

What is the active form of vit d? Daily recommended value?

A

Calcitriol: 600-800U

42
Q

Who qualifies for osteopenia/osteoporosis tx?

A

Men and women:
1. Hip or vertebral fracture
2. T-score ≤ -2.5 at femoral neck, total hip or lumbar spine
3. Postmenopausal women and men age 50+ with osteopenia

43
Q

What is first line for osteoporosis?

A

bisphosphonates

44
Q

What is the MOA of bisphosphonates?

A
  1. Binds to hydroxyapatite in bone
  2. Decreases osteoclast activity and inhibits osteoclast proliferation and adherence
  3. Decreases bone resorption

Net effect: Osteoblasts form well-mineralized bone without opposition from osteoclasts

45
Q

How should bisphosphonates be taken?

A

Low PO F therefore should never be administered with food

46
Q

Describe the main chemical component of bisphosphonates?

A

Pyrophosphate compound

47
Q

What are the types of bisphosphonates?

A
  1. Alendronate (Fosamax)
  2. Risedronate (Actonel)
  3. Ibandronate (Boniva)
  4. Zoledronate (Reclast, Zometa)
  5. Etidronate (Didronel): off-label
  6. Pamidronate (Aredia): off-label
48
Q

Zoledronate

Brand, Form, Indication

A

Reclast: IV
* Osteoporosis
* Annual infusion for treatment of osteoporosis.
* Biannual infusions for prevention of osteoporosis

Zometa: IV
* Bone metastases

Reduces vertebral (70%), hip (41%), non-vertebral (25%) fractures

49
Q

Alendronate

Brand, Form, Indication

A

Fosamax, Binosto: PO
Indication: Osteoporosis
* Treatment dose: 10 mg/day or 70 mg weekly
* Prevention dose : 5 mg/day or 35 mg weekly

50
Q

Risedronate

Brand, Form, Indication, Dosing

A

Actonel, Atelvia: PO
Indication: Osteoporosis
Atelvia is taken once weekly, with water 30 minutes before breakfast

51
Q

Ibandronate

Brand, Form, Indication, Dosing

A

Boniva
Form: PO (stand or sit for 1hr after ingestion) and IV infusion
Indication: Treatment and prevention of osteoporosis

52
Q

Pamidronate

Brand, Form, Indication

A

Aredia: IV
Indication: Hypercalcemia of malignancy and bone cancer, Pagets

53
Q

Etidronate

Brand, Indication

A

Didronel
Indication: Pagets

54
Q

What are the medical indicataions for IV BPs?

A
  1. Bone metastasis
  2. Cancer hypercalcemia
55
Q

What is a potent inhibitor of osteoclast activity and provides a bone-specific treatment?

A

Zoledronic acid (Zometa)

56
Q

Bisphosphonates

ADR, DDI, CI, Monitoring

A

ADR:
1. Upset stomach (inflammation and erosions)
2. Musculoskeletal joint pain
3. Bisphosphonate-related osteonecrosis of the jaw (BRONJ)

DDI: Do not co-administer with ANY other medications
CI: Hypocalcemia (correct before therapy)
Monitoring: After 3-5 years a risk assessment should be performed (FDA Warning): may DC if at moderate risk

57
Q

What are the counseling points for Bisphosphonates?

A
  1. Must swallow whole; do not crush
  2. Take first thing in the morning with 6-8 ounces of plain water ONLY before eating
  3. Must sit/stand for at least 1 hour with ibandronate
  4. Stop taking if develop painful swallowing, chest pain or bad heartburn that does not go away
58
Q

What Bisphosphonate formulations can be used in patients with GI or PO intolerance?

A

IV ibandronate and zoledronate

59
Q

What are the types of SERMS?

A

Raloxifene (Evista)
Bazedoxifene + Conjugated estrogens (Duavee)

60
Q

Raloxifene

Brand, MOA, Indication, PiT, ADR

A

Evista
MOA: Estrogen agonist in bone and estrogen antagonist in uterus and breast tissue
Indication: Prevention of osteoporosis in post-menopausal women
PiT: Mostly used by those intolerant to bisphosphonates
ADR: Increases the risk of thromboembolic events (stroke), hot flushes, leg cramps

61
Q

Duavee

Class, Indication, PiT, BBW

A

Conjugated estrogens + Bazedoxifene (SERM)
Indication: Prevention of osteoporosis after menopause
PiT: Only for postmenopausal women who still have a uterus
BBW: Increased risk of dementia in >65YO taking estrogen alone
* Increased VTE and stroke

62
Q

What are the monoclonal antibodies for osteoporosis?

A

Denosumab (Prolia)
Romosozumab (Evenity)

63
Q

Denosumab

Brand, MOA, Indication, CI

A

Prolia, Xgeva
MOA: Human Monoclonal Antibody against RANK Ligand disrupting osteoclast differentiation and function
Indication: Last resort and postmenopausal women with osteoporosis with high fracture risk
CI: Hypocalcemia

64
Q

Describe the Wnt / β-Catenin Signalling Pathway?

A
  1. FZD and co-receptor (LRP5/6)
  2. Wnt activates its signaling pathway leading to β-catenin stimulated gene expression
  3. Bone formation and protein synthesis occurs
65
Q

What is the regulatory pathway of Wnt / β-Catenin Signalling Pathway?

A

Sclerostin: secreted by osteocytes which inhibits bone formation (antagonist_

66
Q

How does sclerostin inhibit the pathway?

A
  1. The chaperone LRP4 presents sclerostin to the Wnt co-receptors LRP5/6, facilitating sclerostin inhibition of Wnt/β-catenin signaling
  2. β-catenin is phosphorylated and then targeted for degradation
67
Q

Romosozumab

Brand, MOA, Onset

A

Evenity
MOA:
* Inhibition of Sclerostin increases bone formation by promoting survival and proliferation of osteoblasts through increased RANKL effects on osteoblasts
* Inhibits the increase in RANKL dependant increases in osteoclast activity, reducing bone resorption

Onset: Bone forming effect wanes after 12 doses
BBW: Increase the risk of MI, stroke, and CV death
CI: CV RF, hypocalcemia
ADR: joint pain, headache, and pain at the site of injection

68
Q

HRT

Indication, MOA, PiT

A

Indication: Prevention of postmenopausal osteoporosis
MOA:
1. Decreases bone resorption
2. Increases Calcitrol concentrations
3. Increases intestinal calcium absorption
4. Preserves cortical and trabecular bone

PiT: Not recommended for routine use due to increased cancer risk

69
Q

Calcitonin

Brand, MOA, PiT

A

Miacalcin, Fortical, Calcimar
MOA: Endogenous hormone released from the C-Cells of the thyroid when serum calcium levels are elevated, inhibiting osteoclastic bone resorption
PiT: Treatment of osteoporosis in women at least 5 years post menopausal with low bone mass and after other medications have failed

70
Q

What are the types of bone formation therapies?

A

Teriparatide (Forteo)
ABALOPARATIDE (Tymlos)

71
Q

Teriparatide

Brand, Class, MOA,

A

Forteo
Class: rHPTH
MOA: Stimulates bone formation by increasing osteoblast number and activity, and depresses osteoclast formation
Efficacy: If and when treatment is stopped, bone density loss can be rapid and alternative agents should be considered to maintain BMD
BBW: Osteosarcoma
CI: Pagets, Radiation, osteoporosis prevention

72
Q

Abaloparatide

Brand, Class, MOA, Warning, ADR

A

Tymlos
Class: sPTHrP analog (PTH-related protein)
MOA: Stimulates bone formation by the selective activation of PTH-1R
ADR: Greater BMD increase and less hypercalcemia than teriparatide, osteosarcoma
Warning: Do not use more than 2 years

Drug Action II (28 decks)

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