Komiskey 10-26-07 Calcium Regulation Ii

Front 1

_____ attach to bone surface, secrete H+ and proteolytic enzymes to dissolve collagen matrix of bone

Back 1

Osteoclasts

Front 2

Osteoclasts attach to bone surface, secrete H+ and proteolytic enzymes to dissolve collagen matrix of bone and release mineral components, including Ca2+, which are released into ____ and picked up by the blood.

Back 2

ECF

Front 3

Osteoblasts deposit a complex calcium/phosphate/hydroxyl
compound, called _____

Back 3

hydroxyapatite

Front 4

_______ = Bone Mineral Density + Bone Quality

Back 4

Bone Strength

Front 5

What are the 3 Diagnostic Categories for Osteoporosis in Postmenopausal Women (WHO Criteria)?

Back 5

Normal: T-score above –1
Low bone mass (osteopenia): T-score between –1 and –2.5
Osteoporosis: T-score at or below –2.5

Front 6

Non-modifiable, Non-BMD Risk Factors for Osteoporosis-Related Fractures

Back 6

Advanced age
History of fracture as an adult
Family history of hip fracture

Front 7

Modifiable, Non-BMD Risk Factors for Osteoporosis-Related Fractures

Back 7

Low body weight/BMI
Smoking
Vitamin D deficiency***
High risk for falls
Excess alcohol intake

Front 8

What are analogues of pyrophosphate that are used to treat osteoporosis?

Back 8

Bisphosphonates

Front 9

All bisphosphonates bind _____ ions

Back 9

calcium

Front 10

Bisphosphonates are toxic to

a) osteoblasts
b) osteoclasts

Back 10

b) osteoclasts

Front 11

Early bisphosphonate drugs (1970s-1990s)

Back 11

etidronate
clodronate

Front 12

characteristic morphological features of apoptotic cell

Back 12

cell condensation
membrane blebbing
nuclear shrinkage
chromatin condensation and fragmentation
formation of apoptotic bodies

Front 13

Apoptosis does or does not cause an inflammatory response?

Back 13

does not

Front 14

Nitrogen-containing Bisphosphonates (1990s-present)

Back 14

pamidronate
alendronate
ibandronate
zoledronate
risedronate

Front 15

The mevalonate pathway is a metabolic pathway present in all eukaryotic cells, and is required for the synthesis of cholesterol and hence other sterol-containing metabolites such as ____

Back 15

vitamin D and bile acids.

Front 16

Nitrogen-containing bisphosphonates inhibit ____ synthase
of the mevalonate pathway

Back 16

FPP

Front 17

______-containing bisphosphonate drugs are potent inhibitors of FPP synthase

Back 17

Nitrogen

Front 18

some bisphosphonates (risedronate, minodronate and zoledronate) have IC50s of 10nM or less. Which has IC50 of 200?

Back 18

Pamidronate (Aredia)

Front 19

FPP synthase is required for the production of farnesyl diphosphate (FPP) and ________ diphosphate (GGPP)

Back 19

geranylgeranyl

Front 20

FPP synthase is required for the synthesis of ______, necessary for
prenylation of small GTPase signalling proteins (eg Ras, Rho)

Back 20

lipids

Front 21

__________ lipids act as membrane anchors

Back 21

Prenyl (farnesyl or geranylgeranyl)

Front 22

Nitrogen-containing bisphosphonates prevent protein _______

Back 22

prenylation

Front 23

Prenylation is required for the correct signaling function
of small ____-ases

Back 23

GTP

Front 24

Loss of prenylated proteins affects morphology of

a) osteoblasts
b) osteoclasts

Back 24

b) osteoclasts

Front 25

Bisphosphonates:
Analogs of pyrophosphate
carbon replaces the central oxygen
greatly increased stability

Give 3 examples

Back 25

Disodium etidronate (Didronel)
Disodium alendronate (Fosamax)
Disodium risedronate (Actonal)

Front 26

Bisphosphonates: Bind to hydroxyapatite crystals, incorporated into bone matrix, taken up by ______

Back 26

osteoclasts

Front 27

Bisphosphonates: Incapacitate osteoclasts and inhibit bone _____

Back 27

resorption

Front 28

Bisphosphonates: Newer, nitrogen-containing BPs inhibit the ______ pathway

Back 28

isoprenoid

Front 29

Bisphosphonates: ________ prenylation of GTP binding proteins

a) increase
b) decrease

Back 29

b) decrease

Front 30

Bisphosphonates:
Experimental studies with rats and primates: alendronate --> bone turnover does what?
a) increases
b) decreases

Back 30

b) decreases

Front 31

Bisphosphonates: clinical uses

Back 31

Paget's disease
Osteoporosis in postmenopausal women
Hypercalcemia associated with malignancy

Front 32

Dose options for Paget's disease

Back 32

5 - 7.5 mg/kg IV etidronate or
40 mg oral alendronate or
30 mg oral risedronate
Daily for 6 months

Front 33

Dose options for osteoporosis

Back 33

10 mg alendronate orally once daily
2.5/5 mg risedronate:
increased bone density
risk of spine, hip, wrist fracture reduced by 50%

Front 34

Dose options for Hypercalcemia associated with malignancy

Back 34

7.5 mg/kg /day etidronate infused in at least 250 ml normal saline over a period of at least two hours
Three successive days for up to seven days
Oral etidronate, 20 mg/kg /day may be started on the day following the last i.v. dose
Continue for 30 to 90 days if serum Ca2+ levels clinically acceptable

Front 35

Bisphosphonates (BPs) are powerful inhibitors of bone ______

Back 35

resorption

Front 36

Bisphosphonates: adverse effects

Back 36

Risk of osteomalacia
at high etidronate doses
10 to 20 mg/kg i.v.
outside therapeutic range
Hypocalcemia
Hypophosphatemia
Local irritation of the upper GI mucosa
esophagitis
esophageal ulcers and erosions
over dosing may also cause:
upset stomach
heartburn
gastritis
GI risk is minimized when the patient takes oral medications with a full glass of water and remains upright for at least 30 minutes after taking it

Front 37

Parathyroid Hormone (PTH) is
Produced in the _____ cells of the parathyroid glands

Back 37

chief

Front 38

Parathyroid Hormone (PTH) is Controlled by plasma Ca2+ levels via ____ receptor

Back 38

Ca

Front 39

PTH is Acts via a G protein coupled surface receptor using ____

Back 39

cAMP

Front 40

Preparation of PTH used clinically:

Back 40

teriparatide acetate

synthetic human PTH 1-34

Front 41

PTH: Clinical uses
What drug is For treatment of osteoporosis in men and postmenopausal women who are at high risk for a fracture
Administered subcutaneously once daily for up to 24 months

Back 41

Teriparatide acetate

Front 42

Daily intermittent administration of Teriparatide acetate increases the number and activity of ______

Back 42

osteoblasts

Front 43

Daily intermittent administration increases the number and activity of osteoblasts
DOes or does not produce bone resorption?

Back 43

does not

Front 44

Daily intermittent administration of Teriparatide acetate increases new bone formation, decreases fracture risk

possibly involves inhibition of osteoblast _____

Back 44

apoptosis

Front 45

Intermittent administration is key; daily infusions of PTH for periods as short as 2 hours --> bone _______, hypercalcemia

Back 45

resorption

Front 46

Teriparatide (Forteo)

Black Box Warning”
In male and female rats, teriparatide caused an increased incidence of _______ that was dependent on dose and treatment duration.

Back 46

osteosarcoma

Front 47

Teriparatide (Forteo)

Long-term use (>2 years) is or is not recommended?

Back 47

is not

Front 48

RANK Ligand Drives an Increase in ______ Activity

Back 48

Osteoclast

Front 49

Selective estrogen receptor modulator (SERM)

Back 49

Raloxifene

Front 50

Bad things about Raloxifene

Back 50

Increased risk of venous thromboembolism
Deep vein thrombosis
Pulmonary embolism
Risk is similar to that reported with hormone replacement therapy

Front 51

Conjugated equine estrogens, various estrogen formulations, ± progestins
“Black Box Warning”

Back 51

Estrogens increase the risk of endometrial cancer
WHI reported increased stroke, deep vein thrombosis, myocardial infarction, invasive breast cancer, pulmonary emboli
Estrogens ± progestins should not be used for prevention of cardiovascular disease of dementia
All forms of estrogen are assumed to carry similar risks

Front 52

FDA-Approved for the Treatment of Postmenopausal Osteoporosis
Bisphosphonates

Back 52

Alendronate
Ibandronate (Boniva)
Risedronate

Front 53

Other
FDA-Approved for the Treatment of Postmenopausal Osteoporosis

Back 53

Calcitonin
Raloxifene
Teriparatide

Front 54

Therapies that Inhibit Bone Resorption

Back 54

Alendronate
Ibandronate
Risedronate
Calcitonin
Raloxifene