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PT 2 > Block 9 - L7- > Flashcards

Block 9 - L7- Flashcards

1
Q

List the disorders of mineral ion homeostasis and bone.

A
  1. Hypo/hypercalcemia
  2. Hypercalcemia of malignancy
  3. Hyperphosphatemia
  4. Hypo/hyperparathyroidism
  5. Paget’s disease of the bone
  6. Osteoporosis
  7. Chronic kidney disease
  8. Rickets and osteomalacia
  9. Vitamin D disorders
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2
Q

List the essential functions of calcium.

A
  1. Skeleton/teeth
  2. Blood coagulation
  3. Vesicle fusion
  4. Critical signaling second messenger
  5. Muscle contraction
  6. Neurological transmission
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3
Q

What is the total calcium body content and where is the vast majroity contained?

A

~1300 g

> 99% contained in bone/teeth

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4
Q

Serum calcium is tightly regulated from ___ mg/dL via absorption, excretion, and mobilization from the skeleton.

A

8.5-10.4 mg/dL

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5
Q

What transporters are involved in maintain Ca2+ at a cellular level of ~100 nM?

A
  1. PMCA (extrudes Ca2+)
  2. Na/Ca2+ exchanger
  3. SERCA (brings Ca2+ into ER)
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6
Q

Walk through the mechanisms regulating daily whole body calcium balance.

A

~1000 mg/day ingested
~800 mg excreted in feces
~300 mg absorbed into the serum (~100 mg endogenous loss in mucosal/biliary secretions and intestinal cell loss) - ~200 mg net

Bone remodeling: ~500 mg accretion and resorption

~200 mg excreted renally (to match net absorption and maintain homeostasis)

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7
Q

What regulates absorption of Ca2+ into the blood?

A

1,25-OH Vitamin D (Calcitrol)

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8
Q

What regulates accretion and resorption of Ca2+ from bone?

A

PTH (also activates renal excretion of Ph ions)

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9
Q

What inhibits bone resorption?

A

Calcitonin

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10
Q

What inhibits renal excretion of Ca2+?

A

1,25-OH Vitamin D (Calcitrol) and PTH

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11
Q

Describe the process of bone remodeling.

A

Osteoblast with RANK-L binds to RANK on an immature osteoclast precursor cell. With MCSF, the osteoclast differentiates and matures. It binds to bone and causes release of Ca2+ and PO4 (increases serum levels).

TGF-beta, IGF-1, growth factors, and cytokines released from resorbed bone stimulate osteoblast differentiation and activity. Osteoblast precursor cells proliferate and differentiate and deposite bone.

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12
Q

What happens in Type I osteoporosis?

A

Loss of trabecular bone due to estrogen deficiency in post-menopausal women (E normally decreases osteoclast function and increases osteoblast function)

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13
Q

What happens in Type II osteoporosis?

A

Loss of cortical and trabecular bone in men and women due to long-term bone remodeling inefficiency, dietary inadequacy, and age-related increase in the parathyroid axis

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14
Q

What are the symptoms of osteoporosis?

A

Bone pain, increased fractures, loss of heigh, stooped posture

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15
Q

What are deficiencies in vitamin D intake or synthesis and what are the symptoms?

A

Rickets/Osteomalacia; bone pain and potentially symptoms of hypocalcemia

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16
Q

What is Paget’s disease of the bone?

A

Disordered sites of bone remodeling caused by increased bone resoprtion and formation

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17
Q

What are the symptoms of Paget’s disease of the bone?

A

Asymptomatic, although bone pain, deformities, and fractures may occur

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18
Q

What is the most common cause of hypercalcemia?

A

Primary hyperparathyroidism (PTH hypersecretion)

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19
Q

What happens in malignancy-associated hypercalcemia?

A

Systemic tumor expression of PTHrP (or calcitriol) or local bone metasteses

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20
Q

What are the symptoms of hypercalcemia?

A

Fatigue, polyuria, polydipsia, anorexia, N/V, abdominal pain, muscle weakness, altered mental status when serum [Ca2+] >12-14 mg/dL

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21
Q

What are common causes of hypocalcemia?

A

Hypoparathyroidism (PTH deficiency), Vitamin D deficiency

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22
Q

What are symptoms of hypocalcemia?

A

Tremor, muscle spasm, tetany, seizures, prolongation of QTc interval

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23
Q

What happens in CKD regarding mineral and bone disorders?

A

Hyperphosphatemia, decreased Vitamin D production, hypocalcemia, increased PTH

Increased bone pain and fractures, calcification of vasculature (increased CVD mortality rates)

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24
Q

List the agents used to treat disorders of mineral homeostasis and bone metabolism.

A
  1. Vitamin D and its analogues
  2. Sevelamer
  3. Bisphosphonates
  4. Denosumab
  5. Raloxifene
  6. Calcitonin
  7. Teriparitide
  8. Cinacalcet
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25
Q

Vitamin D is both synthesized endogenously and available through the diet. Discuss.

A

Vitamin D3 is synthesized in the skin; it is also found in fatty fish, beef liver, dairy products, eggs, and fortified foods.

Vitamin D2 is available from plant sources.

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26
Q

What is another name for Vitamin D3 and D2?

A

D3 - cholecalciferol (pro-hormone)
D2 - ergocalciferol

Both forms require metabolism in the liver and kidney to become active

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27
Q

Describe the synthesis of Vitamin D.

A

UV light converts 7-dehydrocholesterol to D3 in the skin (can also take in D3 and D2). 25-hydroxylase converts it to 25-OH Vitamin D3 (Calcifediol - inactive); PTH increases 1-alpha-hydroxylase, which converts 25-OH D3 to 1,25-(OH)2 Vitamin D3 (Calcitriol), which is active

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28
Q

What is the MOA of 1,25-(OH)2 Vitamin D3 and D2?

A

Agonists at the Vitamin D nuclear receptor transcription factor to promote patterns of gene transcription that influence mineral ion homeostasis.

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29
Q

What are the physiological effects of 1,25-(OH)2 Vitamin D3?

A
  1. Augments absorption of Calcium and Phosphate from the SI
  2. Blocks renal excretion of Ca2+ and phosphate
  3. Blocks production of PTH from the parathyroid gland
  4. Influences bone homeostasis
30
Q

What are the Vitamin D, Calcitriol, and anaologues used in medicine?

A
  1. Ergocholecalciferol (D2)
  2. Cholecalciferol (D3)
  3. Doxercalciferol 1-alpha-OH Vitamin D2
  4. Calcitriol (1,25(OH2) Vitamin D3)
  5. Many other second generation calcitriol analogues
31
Q

Which form of Vitamin D requires only hepatic hydroxylation to be active?

A

Doxercalciferol 1-alpha-OH Vitamin D2

32
Q

What are the clinical uses of Vitamin D?

A
  1. Treatment of nutritional rickets
  2. Treatment of osteomalacia
  3. Prevention and treatment of osteoporosis
  4. Treatment of hypoparathyroidism (must treat with calcitriol and calcium supplementation)
  5. CKD/secondary hyperparathyroidism
33
Q

What are the AE of Vitamin D?

A

Hypercalcemia

34
Q

What are the contraindications of Vitamin D?

A

Administration in the presence of hyperphosphatemia (CKD); can promote metastatic calcification and increase risk of vascular calcification; results in a hypercoagulable state, tissue infarction, and skin necrosis - chronic non-healing ulceration, followed by systemic bacterial infection

35
Q

How can phosphate levels be reduced?

A 
Phosphate-restricted diet
Phosphate binders (prevent intestinal absorption, lowers serum phosphate without effect on Ca2+)
36
Q

What drugs act to decrease serum Ca2+ levels and prevent bone loss by inhibiting osteoclast activity?

A
  1. Bisphosphanates
  2. Raloxifene
  3. Denosumab
  4. Calcitonin
37
Q

List the Bisphosphanates.

A
  1. Alendronate
  2. Pamidronate
  3. Risedronate
  4. Zoledronate
38
Q

What is the MOA of bisphosphonates?

A

All are analogs of pyrophosphate; they have a strong affinity for bone, especially bone surfaces undergoing remodeling. They inhibit farnesyl pyrophosphate synthetase, which is required for protein farnesylation/prenylation. This is improtant for function of many signaling proteins, especially small GTPases that are involved in regulation of the cytoskeleton and other signaling pathways.

By decreases farnesylation/prenylation, cytoskeletal abnormalities occur, leading to detachment of osteoclasts from bone and loss of function - bone resorption and fractures decrease

39
Q

What are the uses of bisphosphonates?

A

Diseases associated with excessive bone resorption

  1. Osteoporosis (first line)
  2. Hypercalcemia
  3. Hypercalcemia of malignancy
  4. Metastatic bone disease (especially tumors of the breast, prostate, and lung)
  5. Osteogenesis imperfecta
  6. Paget’s disease of the bone
40
Q

Discuss the PK of bisphosphonates.

A

Poor absorption, must be taken on an empty stomach, patient must remain upright for ~30 minutes to prevent esophageal irritation, 30% taken up by bone (70% cleared by kidney), max effect 2-4 days post-administration

Drug may persist in bone for the patient’s lifetime

41
Q

What are the AE of bisphosphonates?

A
  1. Upper GI (heartburn, esophageal irritation, esophagitis)
  2. Transient hypocalcemia (should take drug with Calcium and Vitamin D supplements)
  3. Renal impairment
  4. Ocular side effects (rare - blurred vision uveitis)
  5. Osteonecrosis of jaw (rare) - typically following dental proceudre
42
Q

What are the contraindications of bisphosphonate use?

A

Upper GI disease (achalasia, esophageal stricture, esophageal varices, Barret’s)

Discontinue if patient develops esophagitis

CKD

43
Q

What are alternatives to bisphosphonate?

A

Teriparitide, Denosumab, Raloxifene

44
Q

What is the MOA of Raloxifene, a SERM?

A

Estrogen receptor agonist in bone and liver; anti-estrogen in breast and uterus

Inhibits bone loss by selectively influencing gene expression

Decreased transcription of cytokines involved in osteoclast proliferation, differentiation, and activation

Increased osteoclast apoptosis, increased lifespan of osteoblasts and osteocytes

Decreased bone loss, increased BMD, decreased risk of vertebral fractures

45
Q

What are the uses of Raloxifene?

A

Osteoporosis in post-menopausal women

46
Q

What are the AE of Raloxifene?

A

Increased risk of venous thromboembolism

Can worsen vasomotor symptoms

47
Q

What is the MOA of Denosumab, a RANK-L antagonist?

A

Binds to RANKL, prevents its interaction with RANK; this blocks osteoclast differentiation and excessive bone loss

48
Q

What are the clinical uses of Denosumab?

A

Osteoporosis (those with high fracture risk)
Hypercalcemia
Giant cell tumor of the bone

49
Q

What are the AE of Denosumab?

A

Joint/muscle pain
Hypocalcemia
Osteonecrosis of the jaw

50
Q

What are the contraindications of Denosumab?

A

Hypocalcemia

51
Q

What is calcitonin?

A

Hypocalcemia hormone secreted by the parafollicular cells of the PT gland to oppose PTH action

52
Q

When is calcitonin secreted?

A

When serum calcium levels are high

53
Q

What is the MOA of calcitonin?

A

Lowers serum calcium rapidly by binding to receptors on osteoclasts and preventing bone resorption; inhibits renal reabsorption of Ca2+

Net effect - rapid decrease in serum Ca2+ levels

54
Q

What are the clinical uses of calcitonin?

A

Treatment of severe hypercalcemia (>14 mg/dL) - IM/subQ route

Treatment of osteoporosis - nasal route (not first line, other agents are more effective; concern for cancer risk with longterm use)

Treatment of acute bone pain due to an osteoporotic fracture

Paget’s disease of the bone in patients intolerant to bisphosphonates

55
Q

What are the AE of Calcitonin?

A

Rhinitis and epistaxis (nasal route)
Hypocalcemia
Some concern with increased rates of cancer associated with sustained use

56
Q

What drugs influence the PTH pathway?

A

Teriparitide

Cinacalcet

57
Q

What is PTH?

A

Regulator of serum Ca2+ and phosphate levels, secreted from PT gland

58
Q

30% of PTH is secreted ___; 70% is secreted ___.

A

30% - high frequency pulsatile bursts

70% - constant tonic level

59
Q

Discuss the differential effects of PTH on osteoblast function.

A

Intermittent - binds PTH1R, causes osteoblast proliferation and increased bone accrual

Chronic - causes osteoblast RANKL to bind RANK of immature osteoclast precursor cell, leading to mature osteoclasts and increased bone resorption

60
Q

PTH production is tightly regulated by plasma Ca2+ levels. Discuss.

A

When plasma Ca2+ drops, PTH is produced, leading to increased Ca2+ absorption from the GI tract, decreased PO4/increased Ca2+ reabsorption by the kidney, increased hydroxylation of 25-OH Vitamin D to 1, 25-OH Vitamin D, and increased release of Ca2+ and PO4 from bone.

Increased Plasma Ca2+ feeds back and inhibits PTH production.

1,25-OH Vitamin D also inhibits PTH.

61
Q

What is the MOA of Teriparatide?

A

Recombinant N-terminal fragment of PTH that acts as a direct agonist at PTH receptors; delivers intermittent PTh signals that promote bone growth

62
Q

What are the uses of Teriparatide?

A

Osteoporosis in women and men at high risk for fracture, patients with osteoporosis that are unable to tolerate bisphophonates, patients with osteoporosis who have failed other treatments

63
Q

What is the only anabolic agent on the market for the treatment of osteoporosis?

A

Teriparatide

64
Q

What are the AE of Teriparatide?

A

Potential transient hypercalcemia, elevation in serum uric acid, risk of osteosracoma

65
Q

What are the contraindications of Teriparatide?

A

Patients with elevated uric acid levels or a history of gout, history of renal stones, patients with hypercalcemia, patients with increased risk for osteosarcoma (children/adolescents, active malignancy involving bone, Paget’s disease of the bone, unexplained increase in Alk Phos, prior radiation therapy involving the skeleton)

66
Q

What is the MOA of Cinacalcet?

A

Blocks active bone resorption by inhibiting the chronic expression of PTH

Acts allosterically to enhance the sensitivity of the CaSR to serum Ca2+; allows for the suppression of PTH at a lower serum Ca2+ concentration. Since chronic PTH regualtes bone turnover, decreased PTH leads to decreased bone resorption and decreased serum Ca2+/phosphate

67
Q

What are the uses of Cinacalcet?

A
  1. Primary hyperparathyroidism (those unwilling/unable to undergo parathyroidectomy)
  2. Hypercalcemia associated with parathyroid carcinoma
  3. Treatment of secondary hyperparathryoidism due to CKD
68
Q

What are the AE of Cinacalcet?

A

Hypocalcemia

Seizure threshold reduction

69
Q

What are the contraindications of Cinacalcet?

A

Serum Calcium <8.4 mg/dL

70
Q

Discuss the effects of CKD.

A
  1. Decreased phosphate excretion -> hyperphosphatemia, CaPO4 precipitation -> Ca2+ deposition in tissues -> vascular calcification -> CVD
  2. Decreased calcitrol production -> decreased GI calcium absorption -> decreased plasma Ca2+ (also caused by increased Ca2+ deposition in tissues per #1) -> increased PTH synthesis (also caused by decreased calcitrol production) -> hyperparathyroidism -> abnormal bone turnover
71
Q

How is CKD and secondary hyperparathryoidism treated?

A
  1. Sevelamer - reduces hyperphosphatemia in order to diminish risk of metastatic calcification with calcitrol therapy
  2. Calcitrol - treat Vitamin D deficiency due to impaired renal VitD hydroxylation
  3. Cinacalcet - reduce PTH production and attenuate effects of PTH on bone turnover

PT 2 (15 decks)

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