Pharm Bone Active Drugs

Front 1

Paget's dz description

Back 1

chronic, progressive sk disorder
incr size/ no of osteoclasts
local areas of xs bone resorption and formation:
one or many affected bones
new lesions rarely develop in unaffected bones after dx

Front 2

prevalence of paget's dz

Back 2

2nd most common metabolic bone dz (osteoporosis 1st)
~2% of US pop over 55 yo (uncommon before age 40)
15-30% pts w/ FH
most commonly from N european descent

Front 3

what are 2 signaling molecules in response to PTH that the osteoblast uses to stimulate macs (which stim osteoclasts)

Back 3

OPG
RANKL to RANK

(and M-CSF)

Front 4

what kinds of dz's are osteoporosis and paget's dz (generally)?

Back 4

diseases of increased bone resorption

Front 5

2 main categories of osteoporosis drugs?

Back 5

1. anti-resorptive: estrogens, SERMs (raloxifene), calcitonin, bisphosphonates (alendronate, zoledronic acid)

2. anabolic (teriparatide)

Front 6

summary of estrogens and their use for osteoporosis

Back 6

oral and transderm forms
binds nucl ERs
p.o.--1st pass hepatic metab
AE: hypercoag, breast ca, cholestasis
CV dz warning

Front 7

raloxifene (SERM) use for osteoporosis summary

Back 7

oral
binds nuc ERs (agonist: bone and lipid/liver; antag: breast, uterus)
suppresses osteoclast resorption
hepatic metab, fecal excretion
long T1/2 - 32 hrs
AE: hypercoag, hot flashes

Front 8

how does raloxifene work in osteoporosis?

Back 8

suppresses osteoclast resorption

Front 9

how is calcitonin used to tx osteoporosis?

Back 9

tx 5 yr post-meno
subcut, intranasal
binds CT Rs on osteoclasts and kidney
suppresses bone resorption, incr calciuria
onset 15-30 mins
AE: rhinitis, GI, itch

Front 10

summary of bisphosphonate use in osteoporosis

Back 10

binds hydroxyapatite, released by osteoclasts
interferes w/ mevalonate path
suppress bone resorption
long t1/2 (10 yrs in bone!)
poor po absorption (empty stomach)
imprvs periodontal health
AE: hypocalc, esophagitis, jaw osteonecrosis

Front 11

what rxn do bisphosphonates inhibit

Back 11

geranylPP to farnesylPP downstream from HMGCoA in cholesterol synth pathway

Front 12

what's a major problem w/ bisphosphonates?

Back 12

osteonecrosis of the jaw:
maybe due to severe suppression of bone turnover
94% treated w/ zoledronic acid
85% w/ MM or metastatic breast ca
prevented: treat infection before starting BP tx

Front 13

how is teriparatide (PTH) given?

Back 13

daily sc

Front 14

how does teriparatide work?

Back 14

PTH:
binds PTH-1 R on osteoblasts to stim bone formation
pk 30 mins, gone 3 hrs
AE: hypercalcemia, HA, leg cramp
osteosarcoma warning (rats)

Front 15

how is paget's dz managed?

Back 15

bisphosphonates (gold standard)

sc calcitonin (rare)

NSAIDs, COX-2 inhibs, analgesice, opioids (pain relief)
surgery (fractures, deformities, osteoarthritis)

Front 16

what's the best way to prevent dental caries prior to eruption of permanent teeth?

Back 16

fluoride in drinking water

but, xs leads to mottling of tooth enamel

Front 17

mech of fluoride?

Back 17

accumulates in bone and teeth (50%)
anabolic fx on trabecular bone

promotes remineralization of decalcified enamel
inhibs cariogenic microbial process in dental plaque
incr tooth resist to acid

Front 18

when is fluoride indicated?

Back 18

prevents dental caries
rapidly/ 100% absorbed po
renal excretion

Front 19

adverse effects of fluoride

Back 19

nausea, vomit, GI blood loss, arthritis


fluorosis: impaired mineralization

drug interxns w/ Ca and Mg salts and antacids inhib absorption

Front 20

how do glucocorticoids have effects on bone?

Back 20

prednisone:
binds nuc GC R
osteoblast mediated fx: apoptosis and decr bone formation, decr osteoblast precursor, incr PTH, decr Ca absorption, decr urinary Ca reabsorption

indicated as anti-inflamm in multiple conditions

Front 21

adverse effects of prednisone

Back 21

avascular necrosis
lipid/glucose derangement
adrenal insufficiency

Front 22

where does activated 1,25(OH)2 Vit D3 act?

Back 22

nuc R's in intestines (incr Ca absorption), parathyroid glands (incr PTH), osteoblasts (incr bone formation)

Net: decr bone resorption and incr formation

Front 23

adverse effects of vit D3

Back 23

GI bloating, constipation
incr serum and urine Ca/kidney stones

Front 24

how do anticonvulsants effect bones?

Back 24

phenytoin:
osteomalacia and hypocalcemia due to effects on ion ch conductance

Front 25

adverse effects of PPI's

Back 25

diarrhea, HA, abd pain (rare)
incr B12 def risk
incr risk enteric/resp infection

*decr Ca+2 absorption

Front 26

what's the risk of using PPIs in the elderly?

Back 26

59% incr risk of hip fractures after 4 yrs (due to decr Ca+2 absorption from GI), 165% w/ high dose PPI

Front 27

how common is osteoporosis?

Back 27

very common systemic illness
affects >10 million Americans (33 mill at risk)

Front 28

how is bone resorption regulated?

Back 28

1. osteoblast production of RANKL
2. mediated by osteoblast production of osteoprotegrin (decoy R for RANKL)
3. RANKL interxn w/ RANK R's on osteoclast precursors leads to differentiation and bone resorption

Front 29

what's osteoprotegrin

Back 29

decoy R for RANKL produced by osteoblasts

Front 30

how is bone formation regulated?

Back 30

1. coupled to bone resorption
2. regulated by wnt signal path
3. osteoblasts lay osteoid (collagenous matrix)

Front 31

bone mineralization

Back 31

Ca hydroxyapatite deposited by osteoblasts has 3 requirements:
1. adequated serum Ca
2. ad serum Phos
3. active alkaline phos

Front 32

what are some physiologic hormonal regulators of bone

Back 32

1. sex steroid H's
2. PTH
3. 1,25-dihydroxyvitamin D3

Front 33

mech of estrogen in osteoporosis

Back 33

a)Binds to nuclear estrogen receptors (ER- α and ER- β)
b)On osteoblasts, suppresses RANKL production leading to decreased bone resorption

Front 34

mech of SERMS

Back 34

raloxifene:

a)Binds to nuclear estrogen receptors (ER- α and ER- β)
(1) Estrogen agonist effects on bone and lipids.
(2) Estrogen antagonist effects on breast and uterus.

b)On osteoblasts, suppresses RANKL production leading to decreased bone resorption.

Front 35

mech of calcitonin

Back 35

a) Binds to calcitonin peptide receptors present on osteoclasts and kidney.
b) Decreased bone resorption.
c) Increased urine calcium excretion

Front 36

what are bisphosphonates related to?
what are the 4 major drugs approved for osteoporosis?

Back 36

related to pyrophosphate
1. alendronate (fosamax)
2. risedronate
3. ibandronate
4. zolendronic acid (once/yr

Front 37

mech of bisphosphonates

Back 37

a) Binds to calcium hydroxyapatite and released with osteoclastic resorption.
b) Interferes with the mevalonate pathway and protein prenylation leading to osteoclast apoptosis

Front 38

mech of PTH

Back 38

teriparatide:
a) Binds to PTH-1 receptors on osteoblasts.
b) Intermittent elevation of PTH increases bone formation > bone resorption = ANABOLIC effect.
c) Increases c-AMP, IGF-I, FGF-2, TGFβ1 and TGFβ2
d) Increases number of osteoblasts:
(1) Increased recruitment of bone lining cells
(2) Proliferation of osteoblast precursors
(3) Decreases osteoblast apoptosis

Front 39

dental effects of fluorides?

Back 39

a) Promotes remineralization of decalcified enamel
b) Inhibits the cariogenic microbial process in dental plaque
c) Increases tooth resistance to acid dissolution.
d) Brown staining of teeth with excessive fluoride intake.

Front 40

mech of glucocorticoids on bone fx?

Back 40

a) Binds to nuclear glucocorticoid receptors.

b) Osteoblast-mediated effects:
(1) Apoptosis and decreased bone formation.
(2) Decreased osteoblast precursors.

c) Increased PTH:
(1) Decreased calcium absorption.
(2) Decreased urinary calcium reabsorption.

d) Decreased sex hormone production.