Block 3 Vitamin D and Osteoporosis Flashcards Preview

PHS 933 > Block 3 Vitamin D and Osteoporosis > Flashcards

Flashcards in Block 3 Vitamin D and Osteoporosis Deck (149):
1

When/where is PTH secreted from

-- from parathyroid glands
-- in response to decreased Ca or increased PO4

2

What are PTH's effects?

1) bone resorption
2) increase Vit. D synthesis
3) suppress calcitonin release
4) decrease renal Ca excretion

3

When/where is calcitonin secreted?

-- from parafollicular C cells of thyroid
-- in response to increased Ca

4

What are calcitonin's effects?

1) inhibit osteoclast-medited bone resorption
2) increase renal PO4 excretion
3) increase renal Ca excretion

5

What are calcitriol's effects?

1) increase intestinal Ca absorption
2) increase bone resorption AT HIGH LEVELS

6

What is the structure of calcitonin?

32 aa peptide

7

When/where is FGF-23 released?

-- from osteoclasts
-- in response to increased PO4

8

What are the effects of FGF-23?

1) inhibit renal PO4 reabsorption
2) inhibit vitamin D 1a-hydroxylation

9

What hormones are involved in Calcium homeostasis?

1) PTH
2) Calcitonin
3) Calcitriol
4) FGF-23
5) TH, GH, androgen/estrogens, glucocorticoids

10

What is the UL for Ca?

teens: 3g/day
adults: 2.5g/day
elderly: 2g/day

11

What are the RDAs for Ca?

-- adult: 1 g/day
-- 70+, or 50+ woman: 1.2 g/day
-- teens: 1.3 g/day

12

What is the average teenager intake of Ca?

750 mg/day

13

Where is most calcium obtained?

dairy products

14

How is Calcium lost?

300mg/day from bone turnover, increased by loop diuretics
-- half via urine
-- half via feces

15

How is Ca absorbed?

small bowel
1) active Vit.D-dependent transport in proximal duodenum
-- Vit.D boosts 2-fold
-- max 600 mg/day
2) facilitated transport
-- majority of uptake

16

How does phosphate circulate?

NaH2PO4 or Na2HPO4

17

How is PO4 excreted?

in urine

18

How is phosphate absorbed?

Vit.D facilitated active transport
-- 2/3 of intake absorbed
-- PO4 is abundant in food

19

What is the formula for hydroxyapatite? How much of body's PO4 is there?

Ca10.P6.OH2
80%

20

How is Paget's diagnosed?

elevated serum alkaline phosphatase

21

What are the causes of hypercalcemia?

1) primary hyper-PTH
2) familial benign hypercalcemia
3) acute hypercalcemia
4) PTH- or calcitriol-tumors
5) bone resorption tumors
6) granulomatous diseases
7) hypercalcemia of malignancy

22

How is acute hypercalcemia treated? Chronic?

acute
-- IV saline + loop diuretic
chronic
-- bisphosphonates (pam or zole) + calcitonin

23

What are the symptoms of primary hyperparathyroidism?

1) hypercalcemia, osteoporosis, kidney stones
2) osteitis fibrosa cystica
3) fatigue, weakness, depression/confusion, seizures
4) +/- hypophosphatemia

24

How is hyperparathyroidism treated?

parathyroidectomy

25

If you have primary hyperthyroidism, you probably also have...

low vitamin D

26

What causes familial benign hypercalcemia and what is the result?

defunct calcium sensor
-- low renal Calcium excretion
-- PTH might be slightly high

27

How is familial benign hypercalcemia treated?

not treated; it's benign

28

How do granulomatous diseases like TB and sarcoidosis cause hypercalcemia?

excess calcitriol synthesis by mononuclear cells

29

How is granulomatous hyperparathyroidism treated?

1) glucocorticoids (decrease ectopic calcitriol)
2) oral phosphate (to bind Ca)

30

How is hypercalcemia of malignancy treated?

1) decrease dietary Ca
2) increase renal excretion and inhibit bone resorption

31

What are the symptoms of Paget's?

may be asymptomatic
1) bone pain (compressed nerves from vertebral outgrowth)
2) deafness (ossicles)
3) deformed bone

32

What causes Paget's?

unknown
-- maybe measles (paramyxovirus), since it promotes IL-6 and IL-6 stimulates osteoclasts
-- maybe genetic

33

Patients with Paget's are more likely to develop...

osteosarcoma
gout

34

What patients are most likely to get Paget's?

English
-- 2-9% of those older than 50

35

Paget's is due to...

single/multiple foci of bone turnover with 3 stages
-- bone resorption
-- exuberant bone production
-- disorganized, unstable, and deformed bone

36

What is calcitonin used for?

1) Paget's
-- primarily for relief of bone pain due to fracture (analgesic properties)
-- also reduce bone loss and fracture incidence, but BPs more effective
2) hypercalcemia

37

How is calcitonin supplied?

salmon (Miacalcin, Fortical)
-- SQ or IN (IN is approved for osteoporosis)
-- tablet equally effective but not available

38

What are the ADRs of calcitonin?

1) 2x greater cancer risk when used 5+ years post-menopause
2) rhinitis, erythema, excoriation if 65+
3) Ab development leads to loss of efficacy

39

What is the MoA of Cinacalcet?

Calcium receptor agonist
-- once a day

40

When is Cinacalcet used?

primary and secondary hyperparathyroidism

41

What are the effects of cinacalcet?

1) lower [PTH] 15-50%
2) lower Ca and PO4 7%

42

What are the ADRs of cinacalcet?

1) hypocalcemia
2) lower seizure threshold
3) CYP3A4 substrate

43

What causes hypoparathyroidism?

1) removal/injury of parathyroid gland
2) autoimmune
3) genetic deficiency

44

What are the causes of hypocalcemia?

1) hypoparathyroidism (most common)
2) renal osteodystrophy secondary to chronic renal failure
3) dietary insufficiency / malabsorption
4) pseudohypoparathyroidism

45

What are symptoms of hypoparathyroidism?

neuromuscular hyperexcitability
1) tetany
2) anxiety, depression, hallucinations
-- minimal bone effects!

46

How is primary hypoparathyroidism treated?

1) Ca
2) Vit. D
3) synthetic PTH in development

47

What are symptoms of pseudohypoparathyroidism?

1) low calcitriol
2) short stature
3) short metacarpals

48

How is pseudohypoparathyroidism treated?

Ca + Vit D or analogs

49

What causes pseudohypoparathyroidism and what is the result?

1) defects in intracellular PTH signaling = resistance
-- hyperphosphatemia, hypocalcemia
-- low calcitriol level

50

What is concurrent with dietary insufficiency/malabsorption of calcium?

low PO4 and Mg

51

How is renal osteodystrophy secondary to CRF treated?

1) Ca antacids
-- bind PO4
2) low phosphate foods
-- avoid soda, dairy
3) Vit D supplement
-- improve Ca
4) Cinacalcet
-- suppress PTH

52

What causes renal osteodystrophy in CRF?

1) can't excrete PO4
-- high PO4 activates FGF-23
2) can't make calcitriol
-- less Ca absorbed
-- bone resorbed, and Ca ends up in kidney
-- hypocalcemia, hyperphosphatemia

53

half life of D, calcitriol, and 25-hydroxyD

D (4-6h in plasma, 2 mos in body);
calcitriol (15h);
25-hydroxy (15 days)

54

relative affinity for VDBP among D, calcitriol, 25-hydroxy

D less than
Calcitriol less than
25-OH

55

How does Vitamin D enter the circulation?

enters lymph via chylomicrons
or, made from skin
-- slowly transferred to VDBP

56

What constitutes Vitamin D deficiency? What is normal?

25-OH-D less than
20 ng/mL (normal is 40)

57

What is the storage form of VitD?

25-hydroxy/calcifediol
-- transported via VDBP

58

How is calcitriol inactivated?

24-OH in liver by p450
-- results in calcitroic acid

59

What 25OH-D level is associated with hypercalcemia? What is normal?

25OH = 750 nmol/L = 300 ng/mL
-- normal is 250 nmol/L = 100 ng/mL

60

How does 25OH level affect calcitriol?

normally 1000x lower than calcitriol
-- if excessive, can displace to cause excessive Vit. D

61

What constitutes hypervitaminosis D?

elevated 25OH and calcitroic acid (no change in calcitriol!)
-- but, hypercalcemia symptoms due to protein displacement

62

How is 7-dehydrocholesterol turn into cholecalciferol?

UV light
-- stratum basale, spinosum
-- melanin slows formation

63

How much sun is required for enough Vit. D?

10-15 mins/day on face/hands/arms

64

What enzyme converts cholecalciferol to 25-OH?

CYP27C1, CYP2R1 in the liver

65

How is 25-OH converted to 1,25-OH?

CYP27B1 (kidney)
-- activated by PTH

66

What diseases are caused by Vit. D deficiency?

1) rickets

2) osteomalacia

67

What is rickets and what are sxs?

deficient bone mineralization in kids
-- secondary PTH increase
-- bowing of long bones and spine

68

What is osteomalacia and what causes it??

deficient bone mineralization in adults
-- secondary PTH increase
caused by nutritional deficiency or lack of sun exposure

69

How does osteomalacia differ from osteoporosis?

bone formation, not just mineralization, is reduced in osteoporosis

70

What are the clinical features of osteomalacia?

1) bone fx
2) bone pain, tenderness
3) muscle pain, weakness (esp. large proximal muscles)
4) 25-OH less than 8 ng/mL

71

What are risk factors for nutritional rickets/osteomalacia?

1) dark skin
2) elderly
3) obese
4) low vit. D
5) north of SF/Philly

72

What causes Type I Vit. D dependent rickets?

deficiency in 1a-hydroxylase

73

What causes Type II Vit. D dependent rickets?

Vitamin D receptor (VDR) mutations

74

How is type I vit. D dependent rickets treated?

calcitriol or Vit D ANALOGS (must already be activated)

75

How is type II vit D dependent rickets treated?

parenteral Ca and/or hi-dose calcitriol or vit D analogs

76

Vit. D deficiency is linked to these things:

1) all-cause and CV mortality
2) asthma and food/air allergy
3) T1DM risk
4) 3.4x more likely to die of heart failure (the more black, the worse off)
5) CV risk indicators: CRP, IL-6, cell adhesion, O2 stress

77

Vit. D deficiency has one good benefit:

decreased Crohns risk

78

Who should be tested for Vitamin D deficiency?

1) any symptoms or potential causes
2) obese
3) drugs that increase D metabolism
4) drugs that interfere with absorption
5) lots of melaning

79

What drugs increase D metabolism?

antiepileptics: phenytoin, phenobarb, carbamazepine

80

What drugs interfere with D absorption?

- cholestyramine
- orlistat
- colestipol

81

In what populations is D deficiency more common?

1) old men
2) worse with age, BMI, north, inactivity
-- supplements have little impact

82

How does D3 relate to D2?

D3 3-10x more potent with longer duration of action
-- no difference clinically

83

RDA of Vit. D? What if deficient?

600 IU/day (800 if 70+ or overweight
-- 4000 IU/day used to raise Vitamin D?

84

Where is Vitamin D found? How much in a cup of milk?

1) fatty fish
2) mushrooms if UV exposed
3) eggs
4) yeast
5) fortified foods
-- 100 IU/dup milk

85

What is osteopenia? How prevalent?

form of osteoporosis where BMD is 1-2.4 std dev away
-- 50% of women over 50

86

What is osteoporosis? how prevalent?

form of osteoporosis where BMD is 2.5+ std dev away
-- 20% of women over 50

87

What are the clinical findings in osteoporosis?

1) alkaline phosphatase slightly elevated
2) normal Ca, PO4, PTH

88

Where are fractures most common in osteoporosis?

1) wrist
2) femur/hip
3) vertebra

89

What are risk factors for osteoporosis?

1) 40+
2) white
3) thin and sedentary
4) premature postmenopause
5) poor diet, smoke, drink
6) f/h
7) long-term steroid use or low T

90

Describe bone loss in osteoporosis?

E loss accelerates loss
-- increases osteoclast activity
-- decreases # of osteoblasts and osteocytes (the sensors)
lost trabecular and cortical bone

91

Where is trabecular bone found?

spine, hip

92

What are the Vit. D analogs?

good to go
-- paricalcitol, oxacalcitriol
need 25 OH in liver
-- alfacalcidiol, doxercalciferol

93

When are Vit. D analogs indicated?

to suppress PTH release
to prevent renal osteodystrophy

94

What are symptoms of hypercalcemia from Vit. D overdosing?

fatigue, weakness, HA
nausea
soft-tissue calcification
metallic taste

95

How is the interindividual variation in Vit. D analog dosing managed?

monitoring
-- Ca, PO4
avoid Mg antacids
-- lead to hypermagnesia

96

What is the indication for calcipotriene topical cream? What's the efficacy like?

mild-moderate psoriasis
-- 40-50% effective
-- slightly more effective than steroids
-- less likely to relapse

97

Describe the systemic effects of calcipotriene topical?

rapid metabolism and high VDR affinity = no systemic effects

98

How is Calcipotriene used? What about pregnancy?

2 week onset, avoid face
-- QD or BID
Cat C

99

What are the risks associated with HRT?

1) thromboembolism + MI
2) slight breast cancer risk
3) uterine bleeding, breast pain
4) kidney stones

100

How does HRT work for osteoporosis?

1) increases BMD 2-4% in 2 years
2) suppresses IL-6 to promote osteoclast apoptosis

101

What does IL-6 do?

activates osteoclasts

102

Should you recommend HRT for osteoporosis?

no;
but don't D/C, because that leads to hip fx risk regardless of BP use

103

When is Raloxifene indicated?

prevention and treatment of osteoporosis
-- preferred for f/h of breast cancer

104

What is the black box on raloxifene?

increased thromboembolism and stroke risk

105

What are C/I's of raloxifene?

1) concurrent HRT
2) pregnancy
3) f/h of thromboembolism
4) men (safety/efficacy not determined)

106

What is the MoA of Raloxifene?

SERM
1) ER antagonist in endometrium, breast (reduced breast cancer risk)
2) ER agonist in bone
-- reduced vertebral fx w/ Ca + D
-- increases BMD 1-3% w/ 500mg Ca
-- decreases bone resorption in 3 months, lasts for 2 years
3) lowers LDL

107

ADRs of raloxifene.

no significant
no effect on endometrium or bleeding

108

Describe PK of raloxifene.

F= 2% (first pass)
protein-bound, not SHBG tho
t1/2 = 28-32h
hepatic

109

Describe structure of bisphosphonates.

-- 2 PO4 with connecting O replaced by C
-- side chain amine can enhance activity
-- ring-incorporated amine is 10000x potent

110

What are the ring-incorporated bisphosphonates?

risedronate
zoledrenate

111

What is the MoA of bisphosphonates?

1) Ca chelators, incorporated into bone and osteoclasts
2) trigger osteoblast apoptosis
3) decrease hydroxyapatite solubility
4) increase BMD 8% over 2 years
5) anti-cancer effects?
6) reduce colorectal and breast cancer risk

112

What are the simple BPs and what's their MoA?

Etidronate
-- non-hydrolyzable ATP analogs
-- pro-apoptotic

113

What are the amino BPs and what's their MoA?

Alendronate, Risedronate, Zoledronate
-- inhibit isoprenoid synthesis for cholesterol
-- block prenylation of cell signaling
-- block enzymes, esp farnesyl synthase

-- SECONDARY apoptosis

114

What BPs are available orally?

1) Alendronate
2) Risedronate
3) Ibandronate
4) Etidronate
5) Tiludronate

115

What BPs are available parenterally?

1) pamidronate
2) zoledronate

116

What is the indication of BPs?

Paget's & treatment/prevention of osteoporosis:
-- alendronate, risedronate, ibandronate

Paget's only
-- Etidronate, Tiludronate

IV hypercalcemia of malignancy and oral-failure for osteoporosis
-- pamidronate (preferred for Paget's)
-- zoledronate

117

What is the oral BP dosing regimen?

1x daily, weekly (some monthly)
-- 30+ min before breakfast
-- 6-8 oz water
-- remain upright until eating

118

What oral BPs can be taken once monthly?

ibrandronae
risedronate

119

What are administration concerns with BPs?

1) Vit D
-- get to 33+ ng/mL prior
2) renal failure if too fast/too large dose in IV
-- 90+ mg

120

Describe IV dosing BP regimens for the available drugs.

IV infusion w/ vigorous saline hydration due to insolubility and poor F

Pamidronate
4-24 hr infusion q3 month

Zoledronate
15 min infusion q 1 year

121

Describe M and E for BPs.

Renal, no metabolism

122

What are ADRs of bisphosphonates?

1) esophagitis, ulcers, bleeding
2) osteonecrosis of the jaw
3) atypical femur fractures if 5+ yrs use
4) mild-severe bone/joint/muscle pain

123

When do the bone ADRs of bisphosphonates occur?

1) osteonecrosis of jaw following dental surgery
2) atypical femur fx after 5+ years
3) bone/joint/muscle pain (2 week onset, varies from day to 1 year)

124

What are C/I's to BPs?

esophageal disease

125

How can esophagitis be avoided with BPs?

report dysphagia/heartburn
follow dosing regimen

126

What are the indications for Forteo?

severe osteoporosis, including glucocorticoid-induced

127

What is the MoA of Forteo/Terpiaratide?

active PTH segment
-- bone anabolic agent increases bone mass
-- INTERMITTENT administration promotes bone FORMATION

128

When is Terpiaratide contraindicated?

bone cancer risk (Paget's or radiation therapy)

129

What are the ADRs of Terpiaratide and how are they managed?

1) osteosarcomas in rats
-- hyperPTH levels are lower in rats
2) transient orthostasis following injection

limit use to 2 years

130

How is Terpiaratide administered?

SQ inj in thigh/abdomen daily

131

What are the effects of Terpiaratide?

12% bone mass increase (lumbar, femoral neck)
-- 2x effective as alendronate
-- reduced fx incidence
-- coadmin with E or BP is advantageous

132

What is the MoA of Denosumab?

OPG-mimetic, binds to RANKL of osteoblasts
-- inhibits RANK-RANKL binding

133

What are the effects of RANK-RANKL binding?

osteoblast precursor becomes activated

134

OPG stands for...

osteoprotogerin

135

How is OPG secreted?

by osteoblasts
-- increased by estrogen

136

What are the indications for Denosumab? MoA?
What are its effects?

OPG-mimetic mAb
-- indicated for severe osteoporosis
-- decreases vertebral and hip fx

137

What are ADRs of Denosumab?

1) hypocalcemia (20%)
2) infection susceptibility (esp, endocarditis)
3) dermatitis
4) jaw osteonecrosis
5) bone/back/muscle pain

138

How often is Denosumab administered?

SQ q6 months

139

What are C/I's of denosumab?

hypocalcemia

140

What is UL of Vit. D supplementatino?

4000 IU/day (RDA is 600 IU/day)

141

What was odanacatib's MoA?

cathepsin K inhibitor
-- prevented proteolytic activity of ostoclasts

142

What was Ronacaleret's MoA?

Anabolic calcilytic
-- Ca receptor antagonists to cause PTH pulse release

143

Describe effectiveness of Ca supplementation?

only effective if bottom 20th percentile Ca intake
-- does not reduce hip fx risk
-- might slow BMD loss
-- might slow post-menopausal bone loss if prophylactic admin

144

What are the negative effects of Ca supplementation?

-- 20% risk increase of kidney stones
-- 20% risk increase of MI/stroke

145

What is the most readily absorbed form of Ca?

Ca citrate

146

What is the Ca supplementation range for post-menopausal women? Why not over 2g?

1 - 1.5 g/day

over 2g:
-- hypercalcemia, kidney stones
-- no further benefit

147

What happens when Vit D intake exceeds 4 IU /day?

increased cancer risk
hypercalcemia

148

What is the effective dose in osteoporosis for Ca and Vit D combined?

800 IU/d + 1 g/day
-- Vit. D analogs may be 2x as effective as Vit. D

149

What combo treatments are effective for osteoporosis?

1) BP + PTH cyclical therapy
- more effective than either alone

2) BP + PTH concurrent
- no better than PTH alone