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Unit 4 week 3 Flashcards

1
Q

Physiologic roles for calcium:

A

Structural role: major constituent of mineral matrix of bone

Biochemical role: essential regulator of excitation-contraction coupling, stimulus-secretion coupling, blood clotting, membrane excitability, cellular permeability, and other metabolic functions

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2
Q

_______ [Ca2+] out → cells are hyper-excitable

_________ [Ca2+] out → cells are hypo-exitable

A

Decreased [Ca2+] out → cells are hyper-excitable

Increased [Ca2+] out → cells are hypo-exitable

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3
Q

Physiologic roles for Phosphate: (5)

A

1) Structural role: part of mineral matrix of bone
2) High energy compounds
3) Membrane phospholipids
4) Regulation
5) DNA, RNA

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4
Q

Calcium Homeostasis Compartments:

Bone - two influx/efflux paths

A

99% of body calcium, in form of hydroxyapatite

10g in/out per day via osteolytic diffusion in and out of bone

250 mg in/out per day via osteoclastic bone breakdown and reformation

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5
Q

Calcium Homeostasis Compartments:

Intracellular compartment

A

contains 10g of calcium

Cytosolic Ca2+ maintain by intracellular Ca2+ buffers, compartmentalization into ER calcium stores by ATP-Ca2+ pump and Na/Ca antiporter

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6
Q

Calcium Homeostasis Compartments:

Extracellular compartment

A

blood and interstitial spaces (in equilibrium)

Contains 8-10 mg/dL

50% free

10% salts (bicarb, phosphate)

40% bound to albumin

Free Ca2+ levels are the regulated variable

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7
Q

Calcium Homeostasis Compartments:

Kidney

A

Kidney filters 10g of Ca2+/day with 98% reabsorbed

Ca2+ salts and free → filterable by kidney

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8
Q

Calcium Homeostasis Compartments:

Gut

dietary absorption, excretion in feces?

A

Dietary input = 1 g
Feces output = 825 mg

500 mg absorbed in gut
325 mg excreted from serum into feces

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9
Q

PTH actions in general

A

increases plasma calcium, decreased phosphate

**Responsible for short term regulation of blood calcium

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10
Q

PTH actions on Bone (2)

A

1) Rapid increased efflux of labile bone calcium via DIRECT upregulation of osteolytic bone actions

2) Slow effect of increased bone remodeling → increased calcium AND phosphate
- INDIRECT effect via osteoblasts and subsequent upregulation of osteoclasts

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11
Q

PTH actions on Kidney (3)

A

1) INCREASED calcium reabsorption (distal tubule)
2) DECREASED phosphate reabsorption
3) increased synthesis of 1,25 (OH)2 Vitamin D

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12
Q

PTH actions on GI tract (1)

A

indirect via vitamin D → enhance Ca2+ absorption

PTH increases 25-hydroxylase and 1-hydroxylase enzyme activity converting VitD to active form

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13
Q

Calcitonin

A

produced by parafollicular C cells of thyroid

Secreted in response to elevated Ca2+ and in response to gastrin, CCK, secretin, and glucagon

Decreases efflux of labile bone calcium

Used therapeutically to slow down high turnover bone disorders

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14
Q

Vitamin D Synthesis: (3)

A

1) 7-dehydrocholesterol in skin acted on by sunlight → Vitamin D (inert)
2) In liver add hydroxyl group → 25-OH Vitamin D
3) In kidney add hydroxyl group → 1, 25 (OH)2 Vitamin D = ACTIVE form

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15
Q

Types of Vitamin D generated by kidney

A

In kidney add hydroxyl group → 1, 25 (OH)2 Vitamin D = ACTIVE form

Kidney also has 24-hydroxylase activity → 24, 25 (OH)2 Vitamin D = inactive form

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16
Q

Vitamin D is transported in the blood bound to ___________

A

transcalciferin

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17
Q

Vitamin D is responsible for __________ regulation of blood calcium

A

**Responsible for long term regulation of blood calcium

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18
Q

Vitamin D Regulation:

__________ inhibits 1-hydroxylase

_________ increases 1-hydroxylase and 24-hydroxylase activity –> increased _______________ –> increased ________ absorption from the gut

A

1,25 (OH)2 Vitamin D inhibits 1-hydroxylase

PTH increases 1-hydroxylase and 25-hydroxylase activity → increased 1,25 (OH)2 Vitamin D → increased Ca2+ absorption from gut

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19
Q

Vitamin D Regulation:

Decreased phosphate –> increase actions of __________ and decrease actions of ___________ –> increased _________ –> increased _______ absorption from the gut

A

Decreased phosphate →

Increase actions of 1-hydroxylase, decrease actions of 24-hydroxylase

→ increased 1,25 (OH)2 Vitamin D → increased phosphate absorption from gut

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20
Q

Actions of (1,25 OH2) Vitamin D

2

A

1) Interact with nuclear receptors in GI tract to increase synthesis of Calcium binding proteins (CALBINDIN) expressed in the lumen of the intestine AND increase active transport of Ca2+ into enterocyte and out of enterocyte into blood
2) Mobilize bone by sensitizing bone to PTH

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21
Q

Calcium absorption -

Three steps:

A

1) Ca2+ active transport from gut lumen into enterocyte (mostly in duodenum)
2) Binds Calbindin in cell → Ca2+ carried to basolateral side
3) Ca2+ actively pumped out of enterocyte

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22
Q

Is there a limit to calcium absorption?

A

Limited “up-regulation” to compensate for low intake → chronically low intake associated with low bone mass, and high intake associated with high bone mass

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23
Q

5 things that enhance Ca2+ absorption in the gut?

A

1) Increased vitamin D → synthesis of Ca-transport proteins
2) Increased physiologic demand (pregnancy, adolescence)
3) Gastric acidity (release Ca2+ from food matrix)
4) Lactose (maintains solubility)
5) Increased dietary protein → high intake assoc. with high Ca absorbed

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24
Q

7 things that decrease Ca2+ absorption in the gut?

A

1) Vitamin D deficiency (northern latitudes, limited skin exposure, dark pigmentation, elderly)
2) Steatorrhea: unabsorbed fatty acids bind Ca2+ → “soaps”
3) Gastric alkalinity
4) Oxalic acid (spinach)
5) Phytic acid (legumes, soy, corn, wheat)
6) Caffeine (increases Ca2+ urinary excretion)
7) Dietary protein: increases Ca2+ urinary excretion (net neutral because increased absorption)

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25
Key hormonal regulators of calcium homeostasis (3)
PTH 1,25 (OH)2D Calcitonin
26
Metabolism and Homeostasis of Calcium
Serum Ca2+ is maintained in a very tight range at all cost Development of deficiency is a long-term “silent” process because maintenance of serum [Ca] is at expense of bone
27
Most high risk groups for Ca2+ deficiency (4)
1) Premature infants 2) Adolescence 3) Peri-menopause 4) Post bariatric surgery
28
Premature infants and Ca2+:
Preterm infants at risk for “osteomalacia of prematurity” 80% of Ca2+ transfer in third trimester
29
School-Aged Children and Ca2+
higher requirements, and puts children at risk for Ca deficient rickets Studied by Framingham Children’s Study → concluded there is beneficial effect of childhood dairy consumption on adolescent bone status
30
Adolescence and Ca2+
hormonal changes favor Ca absorption/bone deposition 50% of bone mineral mass accrued during adolescence Highest in EARLY puberty
31
After skeletal maturity/”peri-menopause” and Ca2+
high requirements, increased losses, low intake
32
Pregnancy/lactation and Ca2+
physiologic increase in need, NOT dietary increase in need Physiologic responses compensate for increased Ca demand, so no requirement for increased dietary intake
33
Physiologic compensation in Pregnancy vs. lactation
Ca absorption increases during pregnancy During lactation, increased PTH (bone mass lost) and bone mass recovered with post-weaning
34
Dietary and lifestyle factors impacting bone health: (5)
1) **Primary determinant of bone mineral density (BMD) are genetic and intrinsic factors 2) Age - strongest empiric predictor of BMD 3) Nutritional/dietary factors 4) Behaviors/Lifestyle 5) Medications/Medical Conditions
35
Nutritional/dietary factors and bone health (9)
1) Lifetime Ca intake - limited ability to adapt to low Ca intake 2) Protein intake 3) Phosphate intake 4) Vitamin D 5) Vitamin K (cofactor with osteocalcin and other bone forming proteins 6) Sodium intake - high Na+ intake → increased urinary Ca2+ excretion 7) Vegetarian diet (high in fruits/veggies is positive for bone health) 8) Caffeine (increases urinary Ca excretion) 9) Whole diet pattern (e.g. DASH diet)
36
Behaviors/Lifestyle and bone health (3 factors)
1) Exercise (weight bearing): muscle mass directly related to bone mass Mechanosensors in bone stimulate osteoblasts 2) Smoking 3) Alcohol - depresses osteoblasts
37
Medications/Medical Conditions and bone health (3)
Glucocorticoids Chronic illness (associated with malabsorption, chronic systemic inflammation) Hypogonadism (especially low estrogen)
38
Optimizing bone density: (7)
1) Achieve “peak bone mass” when you can (adolescence) 2) Weight bearing activity 3) Maintain good Ca intake over lifetime 4) Avoid excess alcohol and tobacco 5) Minimize practices that enhance calcium loss or bone resorption 6) Maintain healthy diet that supports bone health 7) Supplement when necessary
39
Ca-carbonate vs. Ca-citrate supplements
Ca-Carbonate (Tums): best absorbed WITH meals Ca-Citrate: best absorbed BETWEEN meals
40
Can you over supplement Calcium?
Oversupplentation → increase MI, stroke and death risk
41
DASH diet and calcium
may have benefits to long term bone status Increased dietary Ca intake + higher fruit/veg intake (Mg, VitC) Na+ reduction → decreased urinary Ca2+ Decreased turnover of bone
42
Osteoporosis
compromised bone strength predisposing to risk of fragility fractures
43
Fragility fractures in osteoporosis: 3 common locations
total of 1.5 million/yr Spine (700,000/yr in US) Hip (300,000/yr in US) Wrist (250,000/yr in US)
44
Increased risk of fragility fractures with (4)
age, falls, low bone mass, previous fractures
45
Non modifiable risk factors for osteoporosis (5)
age, race, gender, family history, early menopause
46
Modifiable risk factors for osteoporosis (7)
low Ca or VitD intake, estrogen deficiency, sedentary lifestyle, smoking, excess alcohol, excess caffeine, medications
47
Mechanism of osteoporosis
bone resorption > formation → lose bone mass | BUT low bone mass is NOT always osteoporosis
48
Prevention of osteoporosis (4)
1. Calcium: 1000-1500 mg/day 2. Vitamin D: 1000 units/day 3. Exercise: aerobic and resistance 4. Falls: assessment and prevention
49
Treatment of osteoporosis: 2 strategies
alter bone remodeling 1. Decrease bone resorption 2. Increase bone formation
50
Osteoclasts
use enzymes and acid to break down old bone
51
Activation of osteoclasts
RANK receptor on osteoclast binds RANK-L and stimulates OC | RANK = receptor activator of nuclear factor KB
52
Decay receptor for RANK-L
Osteoprotegerin
53
Osteoblasts
form new bone from osteoid
54
New bone formation
Osteoid calcifies with addition of Ca and PO4 New bone has mechanoreceptors (OSTEOCYTES)
55
Activation of osteoblasts
Wnt Frizzled / LRP-5 B-Catenin activates OBs
56
Inhibition of osteoblasts
Sclerostin inhibits Wnt pathway → inhibit OBs
57
_____ and ____ regulate bone formation and resorption
PTH and 1,25 (OH)- Vit D
58
How does PTH regulate bone formation and resorption?
Stimulate preosteoblast proliferation and differentiation into osteoblasts PTH → inhibit osteocyte production of Sclerostin PTH → stimulate osteoblast expression of RANKL → bind RANK on osteoclast → promote formation of mature osteoclasts
59
Sclerostin
glycoprotein that blocks osteoblast differentiation via inhibition of Wnt signaling pathway
60
Osteoprotegerin (OPG):
“decoy” molecules released by osteoblasts that bind RANKL and prevent activation of RANK receptor
61
Osteomalacia (adults) and Rickets (children):
impaired bone mineralization resulting in soft, weak bones
62
Pathophysiology of osteomalacia/rickets
inadequate Ca x phosphate product for bone mineralization
63
Causes of osteomalacia/rickets
1. Vitamin D Disorders | 2. Phosphate disorders:
64
2 phosphate disorders that cause osteomalacia/rickets
1. Acquired hypophosphatemia | 2. Congenital hypophosphatemia rickets
65
Acquired hypophosphatemia
poor oral intake, renal phosphate wasting
66
Congenital hypophosphatemic rickets
“Vitamin D Resistance Rickets” Renal phosphate wasting Impaired 1,25 (OH)2 VitD Formation
67
Symptoms of osteomalacia
pain, deformities, fractures Pseudofractures (Milkman, Looser’s Lines)
68
Symptoms of rickets
pain, deformities, muscle weakness, short stature Bowing of long bones Flaring ends of long bones Delayed epiphyseal calcification
69
Paget's disease
idiopathic bone condition characterized by excessive/unregulated bone resorption and formation
70
Causes of Paget's disease
development of Paget’s disease requires 1) Genetic enhancement of osteoclast formation/reactivity 2) Chronic paramyxovirus infection that induces changes in osteoclast precursors - Possible link with dog ownership - See paramyxovirus-like inclusions in nuclei + cytoplasm of osteoclasts
71
Clinical features of Paget's: Skeletal
pain, deformity, fractures, osteoarthritis, hypervascularity, acetabular protrusion, osteogenic sarcoma Common sites of involvement: pelvis, skull, vertebrae, femur, tibia
72
Clinical features of Paget's: Neurological
deafness (8th nerve, ossicles), cranial nerve compression by bone, spinal cord compression (vascular)
73
Clinical features of Paget's: Cardiovasclar
atherosclerosis, aortic stenosis, CHF (high output)
74
Clinical course of Paget's
phases of resorption and formation 1. Osteoclastic 2. Osteoclastic/Osteoblastic 3. Osteoblastic
75
Diagnosis of Paget's
1. Remodeling markers elevated 2. Xray fractures very specific 3. Bone scan very specific 4. Bone biopsy occasionally needed
76
X ray features of Paget's
- Osteolytic lesions: “blades of grass” sign in long bones, resorption front in flat bones - Osteosclerotic lesions near lytic areas - Thickened disorganized trabeculae - Thickened, expanded cortex - Expansion of bone size
77
Bone scan finding Paget's
Focal areas of intense uptake
78
Histology of Paget's
increased osteoclast numbers, increased osteoclast nuclei, increase osteoblasts in periphery, disorganized / mosaic / woven bone
79
Actions of PTH (3)
1) Enhance renal reabsorption of Ca 2) Stimulate renal excretion of P 3) Increases bone formation AND reabsorption by stimulating osteoblasts AND osteoclasts 4) Stimulates activation of VitD in kidney
80
Mechanism my which PTH increases bone formation and reabsorption continuous vs. intermittent dosing?
Stimulates RANK with RANKL on osteoclasts to increase bone remodeling and eventually osteoblastic bone formation Increase in bone resorption with CONTINUOUS dose BUT low and INTERMITTENT doses of PTH stimulate formation without increasing bone resorption
81
Primary stimulus for PTH secretion is ___________
hypocalcemia
82
Vitamin D vs. PTH vs. FGF23 vs. Calcitonin effects on Ca and P
PTH: increase Ca, decrease P Vitamin D: increase Ca and P FGF23: decrease P Calcitonin: decrease Ca and P
83
3 direct actions of Vitamin D 1 indirect feedback loop action of Vitamin D
Direct actions: 1) Increases gut absorption of Ca and P 2) Increases bone formation AND reabsorption by stimulating osteoblasts AND osteoclasts 3) Enhance renal reabsorption of Ca and P Feedback loops: inhibit PTH synthesis/release from parathyroid glands
84
Direct and indirect actions of FGF23
Direct actions: Stimulates renal excretion of P Feedback loops: inhibits VitD activation in kidney
85
Calcitonin actions
in pharmacologic concentrations can reduce serum Ca and P by inhibiting bone resorption by osteoclasts 1) Inhibit osteoclastic bone resorption → decreased Ca and P 2) Reduce reabsorption / increase excretion of Ca and P → decreased Ca and P
86
Cholecalciferol vs. Ergocalciferol Vitamin D supplements
Cholecalciferol (VitD3) → less expensive Ergocalciferol (VitD2) → less efficient than D3 in elevating serum 25-OHD3 - use D3 when possible
87
Calcifediol
(25(OH) VitD3) → most useful in patients with liver disease Onset more rapid than VitD3, but shorter half life
88
Calcitriol
(1,25 (OH)2 VitD3) → most useful in patients with decreased synthesis of calcitriol (chronic renal failure, type 1 VitD-dependent rickets) Rapid onset of action Can cause hypercalcemia, kidney stones
89
Dihydrotachysterol
functionally equivalent to 1a-OHD3, requires hepatic 25-hydroxylation to become active Alternative for use in disorders that require calcitriol Rapid onset of action, short duration of action
90
Cinacalcet mechanism? use? (2)
binds allosterically to calcium sensing receptor in parathyroid gland Increases sensitivity of CaSR to Ca2+ → reduced release of PTH Complementary to Vit D and analogs that target VDR Use: secondary hyperparathyroidism and non-surgical option in primary hyperparathyroidism
91
Antiresorptive agents used in osteoporosis (3)
1) Raloxifene-Estrogen: increase production of OPG by osteoblasts - Prevent RANK-RANKL interaction 2) Denosumab: binds RANKL → prevent RANK-RANKL interaction 3) Bisphosphonates and Calcitonin: inhibit bone resorption by osteoclasts
92
Use of Calcitonin
approved for treatment (not prevention) of osteoporosis Not as effective as bisphosphonates or teriparatide Useful if back pain is a problem
93
Estrogens - mechanism?
Increase bone mass as agonist at ERa receptors on osteoblasts and osteoclasts
94
How does estrogen increase bone mass? (3)
1) Regulate osteoblasts: increase synthesis of Type I collagen, osteocalcin, osteopontin, osteonectin, alk phos 2) Decrease number and activity of osteoclasts by altering cytokine signals from osteoblasts 3) Increase osteoblast production of osteoprotegerin (OPG) “decoy” receptor for RANKL → prevent osteoclast activation
95
Osteoprotegrin
“decoy” receptor for RANKL → prevent osteoclast activation
96
Estrogen pharmacologic use
Mechanism: reduce bone resorption via inhibitory effects on osteoclasts -Must give in first 5 years after menopause Progestational agent reduces endometrial carcinoma risk Use: no longer first line for osteoporosis, can be used for prevention in patients without heart disease
97
How does pharmacologic doses of glucocorticoids decrease bone density (3)
1) Lower serum Ca2+ by blocking VitD-stimulated intestinal Ca2+ transport → increases PTH → stimulate osteoclasts 2) Increase production of RANKL by osteoblasts, decrease production of osteoprotegerin → more RANKL binding to RANK → increase bone resorption 3) Suppress osteoblasts
98
Thiazide diuretics used to treat _________ by _____________
hypercalciuria reducing calcium urinary excretion
99
Aldronate, Risedronate, and Zoledronate (IV)
Bisphonphonates
100
Mechanism of bisphosphonates?
Bind active sites of bone remodeling and inhibit osteoclasts | → osteoclast apoptosis and inhibit osteoclast function
101
Use of bisphosphonates
most effective drugs for PREVENTION and TREATMENT of osteoporosis first line for hypercalcemia of malignancy Potent inhibition of osteoclastic bone resorption Can resolve hypercalcemia in 24-72 hrs, lasts for weeks Can prevent postmenopausal vertebral/nonvertebral fractures
102
Adverse reactions of bisphosphonates
GI effects: heartburn, abdominal pain, diarrhea -Esophagitis (stay upright after dose) Severe bone, joint, muscle pain - osteonecrosis of jaw (rare) Contraindications: achalasia, scleroderma esophagus, esophageal strictures
103
Raloxifene
Selective Estrogen Receptor Modulators (SERMs)
104
Selective Estrogen Receptor Modulators (SERMs) use?
reduce risk of vertebral fractures, but less effective than estrogen or bisphosphonates
105
SERMs advantages and disadvantages relative to estrogen
Advantages relative to estrogen: reduce risk of breast cancer and coronary events Disadvantages relative to estrogen: Worsening of vasomotor symptoms (hot flashes) and leg cramps Increased risk of thromboembolic disorders
106
Teriparatide mechanism?
synthetic PTH fragment that stimulates bone FORMATION Intermittent administration of PTH analog increases osteoblast activity and bone formation
107
Teriparatide use?
treatment of severe osteoporosis Use for longer than 24 months NOT recommended daily subcutaneous dose
108
Denosumab mechanism?
ab against RANKL → reduce osteoclast activation, improve bone mineral density
109
Denosumab use?
Dose adjustment in chronic renal disease Use: treatment in patients with high fracture risk
110
Treatment of hypercalcemia (5)
1) Saline diuretics (+/- furosemide) 2) Bisphosphonates 3) Calcitonin 4) Phosphates 5) Glucocorticoids
111
Treatment of hypocalcemia (3)
1) Calcium replacement (acute) 2) Calcium supplementation (chronic) 3) Vitamin D supplementation (chronic)

DEMS (10 decks)

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