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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
what are the therapeutic uses for vitamin D analogs
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
26
For pt's who are otherwise healthy and have metabolic rickets OR osteomalacia, what vitamin D analogs should be used
(b) For patients who are otherwise healthy, ergocalciferol or cholecalciferol may be used.
27
For patients with liver disease, that are getting vitamin D analogs for metabolic rickets or osteomalacia, what vitamin D analogs are used?
25-hydroxyvitamin D should be used because it does not require hepatic 25-hydroxylation.
28
for pt's with kidney disease who are getting treatment for metabolic rickets and osteomalacia , what vitamin D analogs are used?
calcitriol - most rapid onset of action, but associated with high incidence of hypercalcemia so follow carefully
29
what vitamin D analogs do you use for prophylaxis and cure of nutritional rickets
(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).
30
what are the ADR's of vitamin D analogs
hypercalcemia with or without hyperphosphatemia nausea, vomting constipation serious side effects: - arryhthmias - pancreatitis
31
Fibroblast growth factor 23 effects on intestine, kidney and bone? net effect?
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
32
where does calcitonin come from
a) Excreted by parafollicular cells of thyroid; single-chain peptide.
33
what are the principle effects of calcitonin and what organ systems does it act on?
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.
34
what is the therpeutic use of calcitonin?
d) Therapeutic use: disorders of increased skeletal remodeling (Paget’s disease, osteoporosis)
35
what are the ADR's of calcitonin?
e) ADRs: nausea, hand swelling, urticaria, and intestinal cramping (rare).
36
what are the effects of glucocorticoids on calcium
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
what is the therapeutic use of glucocorticoids in terms of calcium control
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
what happens with prolonged use of glucocorticoids in adults and children
c) Prolonged administration is a common cause of osteoporosis in adults and can cause stunted skeletal muscle development in children.
39
what are the effects of estrogens on bone/calcium
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
what is SERM (Selective estrogen receptor modulator)
(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
what is the therapeutic use of raloxifene (evista)
ii) Therapeutic use: treatment and prevention of post-menopausal osteoporosis.
42
what are the ADR's of raloxifene
hot flashes, leg cramps, and thromboembolism (3x risk of deep vein thrombosis and pulmonary embolism).
43
what are the contraindications for use of raloxifene
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
what are the three secondary hormone regulators
Calcitonin Glucocorticoids Estrogens
45
alendronate "dronates"
bisphosphonates
46
MOA of bisphosphonates
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
how should a pt take bisphosphonates
on an empty stomach administer with a full glass of water at least 30 minutes prior to the first meal.
48
what are the adverse effects of Bisphosphonates
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
what is Denosumab and what is its MOA
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
what is the therapeutic use of Denosumab and how do you adminster it?
b) Therapeutic use: post-menopausal osteoporosis and some cancers (prostate and breast). c) PK: administered subcutaneously every 6 months
51
what are the three main ADR's of Denosumab?
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
what is the mechanism of action of cinacalcet (Calcimimetic)
a) MOA: activates CaSR, which is widely distributed but has greatest concentration in parathyroid gland. Activation leads to inhibition of PTH secretion.
53
therapeutic use of cinacalcet
treatment of secondary hyperparathyroidism in chronic kidney disease and vitamin D deficiency.
54
ADR of cinacalcet
hypocalcemia (do not use if initial Ca2+ < 8.4 mg/dL).
55
what are the DDI's to consider with cinacalcet
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
what are the major causes of hypercalcemia
thiazide therapy hyperparathyroidism cancer
57
what are some less common causes of hypercalcemia
hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency and immobilization.
58
what are the 5 main treatment approaches to hypercalcemia
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
what are the risk associated with IV phosphates
sudden hypocalcemia, ectopic calcification, acute renal failure, hypotension.
60
tetany, paresthesias, laryngospasm, muscle cramps, seizures.
hypocalcemia
61
what are the major causes of hypocalcemia
b) Major causes: hypoparthyroidism, vitamin D deficiency, chronic kidney disease, and malabsorption
62
what is the treatment approach to hypocalcemia
Calcium IV, IM or PO Vitamin D, calcitriol, when rapid action required (raises serum Ca within 24-48 hrs)
63
what is the risk with rapid infusions of calcium for treatment of hypocalcemia
cardiac arrhythmias
64
what are the common causes of hyperphosphotemia
common complication of renal failure hypoparathyroidism vitamin D intoxication tumoral calcinosis
65
how do you treat primary hyperparathryoidism
surgery vitamin D supplementation in mild deficiency cinacalcet for secondary hyperparathyroidism
66
what are the treatment options for osteoporosis x6
i) Bisphosphonates ii) SERMs iii) Calcium and vitamin D supplementation iv) Teriparatide v) Calcitonin vi) Denosumab
67
first line agents (2) for Paget's disease
calcitonin and bisphosphonates (etidronate, alendronate, risedronate, tiludronate)
68
where is RANK L
on the osteoblast
69
where is RANK
on the osteoclast
70
what does OPG do
suppresses the ability of RANLK to start osteoclast maturation
71
completion of bone resorption is followed by what
by preosteoblast invasion
72
what are the biotransformation steps in vitamin D
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
``` 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?
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
what oral calcium supplement is preferred in pt's on proton pump inhibitors
calcium citrate
75
what is normal vitamin D amounts
30-70?
76
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?
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
supplement that can cause constipation intestinal bloating and excess gas
calcium
78
hypotension , hypercalcemia, dizziness ADR
teriparatide recombinant PTH, enhances remodeling
79
nausea and hand swelling
calcitonin
80
hypercalcemia, nausea, constipation enhances intestinal absorption of calcium and phosphate
vitamin D
81
what is the drug with the MOA of: Estrogen receptor agonist in bone ADR?
Raloxifene hot flashes, leg cramps, increased risk for thromboembolism
82
Inhibits osteoclasts, inhibits the dissolution of hydroxyapate what is this drug and what are the ADR's
Alendronate esophageal and gastric irritation osteonecrosis of jaws atypical femur fractures
83
Hypocalcemia, potential increased risk of infection and osteonecrosis MOA of this drug?
Denosumab binds and prevents action of RANK L

ENDO II Exam II (8 decks)

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