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ENDO II Exam II > Drugs- Agents that affect bone mineral homeostasis (Kinder) > Flashcards

Drugs- Agents that affect bone mineral homeostasis (Kinder) Flashcards

1
Q

raloxifene

A

aka Evista

Selective estrogen receptor modulators

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2
Q

alendronate

A

bisphosphonate

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3
Q

what regulates osteoclast production

A

osteoblast derived cytokines

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4
Q

what is the receptor for activating NF-KB (RANK)

A

an osteoclast protein whose expression is required for osteoclastic bone resorption

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5
Q

what is OPG

A

osteoprotegerin

produced by osteoblasts

acts as a decoy ligand for RANKL.

(1) Under conditions associated with increased bone resorption (estrogen deprivation) OPG is suppressed.

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6
Q

how long does the remodeling of bone cycle take

A

6 months

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7
Q

how does age related bone loss occur

A

vii) If replacement of resorbed bone precisely matched bone removed, remodeling would not change bone mass. However, small bone deficits persist after each cycle and life-long accumulation of these deficits leads to age-related bone loss.

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8
Q

how much Ca is in the diet about and how much is absorbed

A

600-1000 mg/day

100-250 mg absorbed in duodenum and jejunum , excreted in ileum

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9
Q

what percentage of filtered calcium is reabsorbed by the kidney

A

98%

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10
Q

what is the normal extracellular ca

A

8.5 - 10.4 mg/dL

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11
Q

normal extracellular phosphage levels

A

2.5 - 4.5 mg/dL

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12
Q

PTH effects on Ca and PO4

A

increases ca , decreased serum PO4

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13
Q

how does PTH affect bone

A

(1) PTH acts on osteoblasts to induce membrane bound and secreted soluble protein RANKL.
(2) RANKL acts on osteoclasts and osteoclast precursors to increase numbers and activity.
(3) These actions increase bone remodeling.

net effect is increased bone resorption

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14
Q

PTH affects on sclerostin

A

ii) PTH also inhibits production and secretion of sclerostin from osteocytes.
(1) Sclerostin blocks osteoblast proliferation.
(2) Thus, PTH directly increases proliferation of osteoblasts through sclerostin inhibition

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15
Q

PTH effects on kidney

A

iv) In kidney, PTH increases tubular reabsorption of Ca2+ and inhibits reabsorption of PO43-.

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16
Q

PTH effects on vitamin D

A

(1) PTH also stimulates 1,25(OH)2D production.

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17
Q 
PTH effects on:
magnesium
amino acids
bicarb
sodium
chloride
sulfate
A

(2) Other effects: increased reabsorption of magnesium

and increased excretion of amino acids, bicarbonate, sodium, chloride, and sulfate.

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18
Q

what suppresses PTH production

A

i) Calcium-sensing receptor (CaSR) when stimulated by Ca2+ decreases PTH production.
ii) Vitamin D (1,25(OH)2D) also suppresses PTH production.

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19
Q

what is teriparatide

A

i) Synthetic, recombinant human parathyroid hormone (1-34)
ii) MOA: continuous administration of PTH causes bone demineralization and osteopenia; however, intermittent*** PTH (once daily subcutaneous injection) promotes bone growth.

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20
Q

what is the therapeutic use of teriparatide

A

iii) Therapeutic use: women with history of osteoporotic fracture, who have multiple risk factors for fracture, or who have failed (or are intolerant to) other drug therapy. Men with primary or hypogonadal osteoporosis.
(1) Has not been studied beyond two years of use – limit duration of therapy to two years.

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21
Q

what are the ADR’s of teriparatide

A

orthostatic hypotension, hypercalcemia, dizziness, nausea, hyperuricemia, and angina

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22
Q

what are the contraindications for teriparatide

A

CI: Teriparatide therapy is not advised in patients who are at an increased risk of osteosarcoma, such as those with Paget disease of the bone, unexplained elevations of alkaline phosphatase, open epiphyses, or prior radiation therapy involving the skeleton.

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23
Q

what does calcitriol (Vitamin D) do

A

augments intestinal absorption and retention of Ca2+ and PO43-.

increases bone turnover by:

i) Promoting the recruitment of osteoclast precursor cells to resorption sites.
ii) Promoting the development of differentiated functions that characterize mature osteoclasts.
iii) Inducing the synthesis of several proteins that regulate the bone mineralization process, such as RANK ligand and osteocalcin.

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24
Q

MOA of vitamin D analogs

A

i) MOA: increases intestinal absorption of Ca2+ and PO43- as well as bone turnover.

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25
Q

what are the therapeutic uses for vitamin D analogs

A

Prophylaxis and cure of nutritional rickets

Treatment of metabolic rickets and osteomalacia (particularly in the setting of chronic renal failure)

Treatment of hypoparathyroidism

prevention and treatment of osteoporosis

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26
Q

For pt’s who are otherwise healthy and have metabolic rickets OR osteomalacia, what vitamin D analogs should be used

A

(b) For patients who are otherwise healthy, ergocalciferol or cholecalciferol may be used.

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27
Q

For patients with liver disease, that are getting vitamin D analogs for metabolic rickets or osteomalacia, what vitamin D analogs are used?

A

25-hydroxyvitamin D should be used because it does not require hepatic 25-hydroxylation.

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28
Q

for pt’s with kidney disease who are getting treatment for metabolic rickets and osteomalacia , what vitamin D analogs are used?

A

calcitriol - most rapid onset of action, but associated with high incidence of hypercalcemia so follow carefully

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29
Q

what vitamin D analogs do you use for prophylaxis and cure of nutritional rickets

A

(a) The most widely used treatment for vitamin D deficiency consists of vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol), which require metabolic conversion in the liver and kidney to the most active form of vitamin D (calcitriol).

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30
Q

what are the ADR’s of vitamin D analogs

A

hypercalcemia with or without hyperphosphatemia

nausea, vomting

constipation

serious side effects:

  • arryhthmias
  • pancreatitis
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31
Q

Fibroblast growth factor 23

effects on intestine, kidney and bone? net effect?

A

a) Single-chain protein. Inhibits 1,25(OH)2D production and phosphate reabsorption in kidney and can lead to both hypophosphatemia and inappropriately low levels of circulating 1,25(OH)2D
a) Osteocytes and osteoblasts in bone appear to be primary site of production.

Intestine–> Decreased calcium and phosphate absorption by decreased 1,25(OH)2D production

Kidney–> Increased phosphate excretion

bone–> Decreased mineralization due to hypophosphatemia

net effect on serum levels–> Decreased serum phosphate

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32
Q

where does calcitonin come from

A

a) Excreted by parafollicular cells of thyroid; single-chain peptide.

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33
Q

what are the principle effects of calcitonin and what organ systems does it act on?

A

decrease serum calcium and phosphate by actions on bone and kidney.

i) In the bone, inhibits osteoclastic bone resorption. Although bone formation is not impaired initially after calcitonin administration, with time both formation and resorption are reduced.
ii) In the kidney, calcitonin decreases both Ca2+ and PO43- reabsorption as well as reabsorption of other ions including sodium, potassium, and magnesium.

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34
Q

what is the therpeutic use of calcitonin?

A

d) Therapeutic use: disorders of increased skeletal remodeling (Paget’s disease, osteoporosis)

35
Q

what are the ADR’s of calcitonin?

A

e) ADRs: nausea, hand swelling, urticaria, and intestinal cramping (rare).

36
Q

what are the effects of glucocorticoids on calcium

A

a) Antagonize vitamin D stimulated intestinal calcium transport, stimulate renal calcium excretion, and block bone formation. The ultimate effect: decrease in total body calcium stores.

37
Q

what is the therapeutic use of glucocorticoids in terms of calcium control

A

b) Therapeutic use: reversing hypercalcemia associated with lymphomas and granulomatous disease like sarcoidosis (in which unregulated ectopic production of 1,25(OH)2D occurs), or in vitamin D intoxication.

38
Q

what happens with prolonged use of glucocorticoids in adults and children

A

c) Prolonged administration is a common cause of osteoporosis in adults and can cause stunted skeletal muscle development in children.

39
Q

what are the effects of estrogens on bone/calcium

A

a) Prevent accelerated bone loss during the immediate post-menopausal period. At least transiently increase bone in post-menopausal women.

estrogens reduce bone-resorbing action of PTH.

40
Q

what is SERM (Selective estrogen receptor modulator)

A

(selective estrogen receptor modulatory)

serves as a partial agonist in bone but does not stimulate endometrial proliferation in post-menopausal women.

i) Raloxifene retains the beneficial effects on bone while minimizing the deleterious effects on breast, uterus, and cardiovascular system.

41
Q

what is the therapeutic use of raloxifene (evista)

A

ii) Therapeutic use: treatment and prevention of post-menopausal osteoporosis.

42
Q

what are the ADR’s of raloxifene

A

hot flashes, leg cramps, and thromboembolism

(3x risk of deep vein thrombosis and pulmonary embolism).

43
Q

what are the contraindications for use of raloxifene

A

iv) CI: in women with active or past history of venous thromboembolism and women with coronary heart disease or risk factors for major coronary events, including stroke.

44
Q

what are the three secondary hormone regulators

A

Calcitonin
Glucocorticoids
Estrogens

45
Q

alendronate

“dronates”

A

bisphosphonates

46
Q

MOA of bisphosphonates

A

analogs of pyrophosphate in which P-O-P bond replaced with non-hydrolyzable P-C-P bond

i) Their structure responsible for chelating Ca2+, which gives these agents a strong affinity for bone.
ii) Concentrate at sites of active bone remodeling; incorporated into bone until the bone is remodeled and the bisphosphonate is released back into the acid medium.
iii) Decreases the formation and dissolution of hydroxyapatite crystals within and outside the skeletal system. Also, directly inhibits osteoclasts.
iv) Some of the newer agents appear to increase bone mineral density. May be a result of other cellular effects including inhibition of 1,25(OH)2D production and intestinal calcium transport.

47
Q

how should a pt take bisphosphonates

A

on an empty stomach

administer with a full glass of water at least 30 minutes prior to the first meal.

48
Q

what are the adverse effects of Bisphosphonates

A

esophageal and gastric irritation - minimize by taking full glass of water and remaining upright for 30 min

osteonecrosis of jaw (rare, more frequent with high IV doses used in bone mets and cancer induced hypercalcemia)

subtrochanteric femur fractures due to over-suppression of bone turnover

iii) Complications are rare but have led some authorities to recommend a “drug holiday” after 5 years of treatment if clinical condition warrants it (i.e. if fracture risk of discontinuing bisphosphonate is not deemed high).

49
Q

what is Denosumab and what is its MOA

A

fully human monoclonal antibody

MOA:
binds and prevents action of RANKL
i) Mimics the effects of osteoprotegerin, reducing binding of RANKL to RANK and blocking osteoclast formation and activation (osteoclastogenesis).

50
Q

what is the therapeutic use of Denosumab and how do you adminster it?

A

b) Therapeutic use: post-menopausal osteoporosis and some cancers (prostate and breast).
c) PK: administered subcutaneously every 6 months

51
Q

what are the three main ADR’s of Denosumab?

A

i) A number of cells in the immune system also express RANKL suggesting there could be an increased risk of infection associated with use.
ii) Because suppression of bone turnover is similar to potent bisphosphonates, risk of osteonecrosis of the jaw and subtrochanteric fractures may be increased (although this has not been reported in clinical trials leading up to FDA approval).
iii) Can lead to transient hypocalcemia, especially in patients with marked bone loss (and bone hunger) or compromised calcium regulatory mechanisms including chronic kidney disease and vitamin D deficiency.

52
Q

what is the mechanism of action of cinacalcet (Calcimimetic)

A

a) MOA: activates CaSR, which is widely distributed but has greatest concentration in parathyroid gland. Activation leads to inhibition of PTH secretion.

53
Q

therapeutic use of cinacalcet

A

treatment of secondary hyperparathyroidism in chronic kidney disease and vitamin D deficiency.

54
Q

ADR of cinacalcet

A

hypocalcemia

(do not use if initial Ca2+ < 8.4 mg/dL).

55
Q

what are the DDI’s to consider with cinacalcet

A

e) DDI’s: drugs which interfere with calcium homeostasis

those that inhibit cinacalcet absorption (vitamin D analogs, bisphosphonates, calcitonin, glucocorticoids),

or those that interfere with metabolism (P450 inducers and inhibitors).

56
Q

what are the major causes of hypercalcemia

A

thiazide therapy
hyperparathyroidism
cancer

57
Q

what are some less common causes of hypercalcemia

A

hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency and immobilization.

58
Q

what are the 5 main treatment approaches to hypercalcemia

A

Saline diuresis +/furosemide
(1) Most patients with severe hypercalcemia have a substantial component of prerenal azotemia due to dehydration which prevents kidney from compensating for the rise in serum calcium by excreting more calcium in the urine.

Bisphosphonates

Calcitonin

Phosphate –(1) Fastest and surest way to decrease serum calcium but hazardous if not done properly

Glucocorticoids

59
Q

what are the risk associated with IV phosphates

A

sudden hypocalcemia, ectopic calcification, acute renal failure, hypotension.

60
Q

tetany, paresthesias, laryngospasm, muscle cramps, seizures.

A

hypocalcemia

61
Q

what are the major causes of hypocalcemia

A

b) Major causes: hypoparthyroidism, vitamin D deficiency, chronic kidney disease, and malabsorption

62
Q

what is the treatment approach to hypocalcemia

A

Calcium IV, IM or PO

Vitamin D, calcitriol, when rapid action required (raises serum Ca within 24-48 hrs)

63
Q

what is the risk with rapid infusions of calcium for treatment of hypocalcemia

A

cardiac arrhythmias

64
Q

what are the common causes of hyperphosphotemia

A

common complication of renal failure

hypoparathyroidism

vitamin D intoxication

tumoral calcinosis

65
Q

how do you treat primary hyperparathryoidism

A

surgery

vitamin D supplementation in mild deficiency

cinacalcet for secondary hyperparathyroidism

66
Q

what are the treatment options for osteoporosis

x6

A

i) Bisphosphonates
ii) SERMs
iii) Calcium and vitamin D supplementation
iv) Teriparatide
v) Calcitonin
vi) Denosumab

67
Q

first line agents (2) for Paget’s disease

A

calcitonin and bisphosphonates (etidronate, alendronate, risedronate, tiludronate)

68
Q

where is RANK L

A

on the osteoblast

69
Q

where is RANK

A

on the osteoclast

70
Q

what does OPG do

A

suppresses the ability of RANLK to start osteoclast maturation

71
Q

completion of bone resorption is followed by what

A

by preosteoblast invasion

72
Q

what are the biotransformation steps in vitamin D

A

Ultraviolet light in the skin

Hydroxylation in liver (25-hydroxylase)

Hydroxylation in kidney (alpha 1 hydroxylase)

end organ impairment in the kidney? use calcitriol b/c it doesn’t need any further processing

73
Q 
60 year old 
severe inflammatory bowel disease
labs Ca 7
albumin 2.7 
Cr 1.1

suspect- malnutrtion/malabsorption and would like to give an intravenous calcium bolus

what is the pt’s corrected calcium?

what is the treatment approach?

what is the dose for symptomatic hypocalcemia of elemental calcium?

A

4-plasma albumin * 0.8 + serum calcium

So 4 - 2.7 * 0.8 + 7 = 8.04

Treatment:
Calcium (oral) and Vitamin D

oral calcium options:

  • calcium carbonate- preferred
  • calcium citrate- useful if the pt is on proton pump inhibitors or H2 receptor blockers

IV calcium options:
-calcium gluconate- preferred
-calcium chloride- increased risk for tissue necrosis
3x more potent than gluconate

200-300 mg of elemental calcium used is symptomatic hypocalcemia

74
Q

what oral calcium supplement is preferred in pt’s on proton pump inhibitors

A

calcium citrate

75
Q

what is normal vitamin D amounts

A

30-70?

76
Q

65 year old post menopausal
history of HTN

Bone mineral density T scores

  • 2.4 hip
  • 2.6 at spine

should this pt receive calcium and vitamin D supplementation
if so, how much?

A

She definitely needs this !

Amounts of Vitamin for ages:
70 800 vitamin D

Amounts of Ca for ages:
19-50 1000 mg Ca
51-70 years men 1000 mg Ca
51-70 years women 1200 mg Ca
>70 1200 mg Ca

she should receive 1200 mg Ca and 600 mg of Vitamin D

77
Q

supplement that can cause constipation intestinal bloating and excess gas

A

calcium

78
Q

hypotension , hypercalcemia, dizziness ADR

A

teriparatide

recombinant PTH, enhances remodeling

79
Q

nausea and hand swelling

A

calcitonin

80
Q

hypercalcemia, nausea, constipation

enhances intestinal absorption of calcium and phosphate

A

vitamin D

81
Q

what is the drug with the MOA of: Estrogen receptor agonist in bone

ADR?

A

Raloxifene

hot flashes, leg cramps, increased risk for thromboembolism

82
Q

Inhibits osteoclasts, inhibits the dissolution of hydroxyapate

what is this drug and what are the ADR’s

A

Alendronate

esophageal and gastric irritation

osteonecrosis of jaws

atypical femur fractures

83
Q

Hypocalcemia, potential increased risk of infection and osteonecrosis

MOA of this drug?

A

Denosumab

binds and prevents action of RANK L

ENDO II Exam II (8 decks)

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