Unit 4 week 3 Flashcards
Physiologic roles for calcium:
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
_______ [Ca2+] out → cells are hyper-excitable
_________ [Ca2+] out → cells are hypo-exitable
Decreased [Ca2+] out → cells are hyper-excitable
Increased [Ca2+] out → cells are hypo-exitable
Physiologic roles for Phosphate: (5)
1) Structural role: part of mineral matrix of bone
2) High energy compounds
3) Membrane phospholipids
4) Regulation
5) DNA, RNA
Calcium Homeostasis Compartments:
Bone - two influx/efflux paths
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
Calcium Homeostasis Compartments:
Intracellular compartment
contains 10g of calcium
Cytosolic Ca2+ maintain by intracellular Ca2+ buffers, compartmentalization into ER calcium stores by ATP-Ca2+ pump and Na/Ca antiporter
Calcium Homeostasis Compartments:
Extracellular compartment
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
Calcium Homeostasis Compartments:
Kidney
Kidney filters 10g of Ca2+/day with 98% reabsorbed
Ca2+ salts and free → filterable by kidney
Calcium Homeostasis Compartments:
Gut
dietary absorption, excretion in feces?
Dietary input = 1 g
Feces output = 825 mg
500 mg absorbed in gut
325 mg excreted from serum into feces
PTH actions in general
increases plasma calcium, decreased phosphate
**Responsible for short term regulation of blood calcium
PTH actions on Bone (2)
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
PTH actions on Kidney (3)
1) INCREASED calcium reabsorption (distal tubule)
2) DECREASED phosphate reabsorption
3) increased synthesis of 1,25 (OH)2 Vitamin D
PTH actions on GI tract (1)
indirect via vitamin D → enhance Ca2+ absorption
PTH increases 25-hydroxylase and 1-hydroxylase enzyme activity converting VitD to active form
Calcitonin
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
Vitamin D Synthesis: (3)
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
Types of Vitamin D generated by kidney
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
Vitamin D is transported in the blood bound to ___________
transcalciferin
Vitamin D is responsible for __________ regulation of blood calcium
**Responsible for long term regulation of blood calcium
Vitamin D Regulation:
__________ inhibits 1-hydroxylase
_________ increases 1-hydroxylase and 24-hydroxylase activity –> increased _______________ –> increased ________ absorption from the gut
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
Vitamin D Regulation:
Decreased phosphate –> increase actions of __________ and decrease actions of ___________ –> increased _________ –> increased _______ absorption from the gut
Decreased phosphate →
Increase actions of 1-hydroxylase, decrease actions of 24-hydroxylase
→ increased 1,25 (OH)2 Vitamin D → increased phosphate absorption from gut
Actions of (1,25 OH2) Vitamin D
2
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
Calcium absorption -
Three steps:
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
Is there a limit to calcium absorption?
Limited “up-regulation” to compensate for low intake → chronically low intake associated with low bone mass, and high intake associated with high bone mass
5 things that enhance Ca2+ absorption in the gut?
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
7 things that decrease Ca2+ absorption in the gut?
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)
Key hormonal regulators of calcium homeostasis (3)
PTH
1,25 (OH)2D
Calcitonin
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
Most high risk groups for Ca2+ deficiency (4)
1) Premature infants
2) Adolescence
3) Peri-menopause
4) Post bariatric surgery
Premature infants and Ca2+:
Preterm infants at risk for “osteomalacia of prematurity”
80% of Ca2+ transfer in third trimester
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
Adolescence and Ca2+
hormonal changes favor Ca absorption/bone deposition
50% of bone mineral mass accrued during adolescence
Highest in EARLY puberty
After skeletal maturity/”peri-menopause” and Ca2+
high requirements, increased losses, low intake
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
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
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
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)
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
Medications/Medical Conditions and bone health (3)
Glucocorticoids
Chronic illness (associated with malabsorption, chronic systemic inflammation)
Hypogonadism (especially low estrogen)
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
Ca-carbonate vs. Ca-citrate supplements
Ca-Carbonate (Tums): best absorbed WITH meals
Ca-Citrate: best absorbed BETWEEN meals
Can you over supplement Calcium?
Oversupplentation → increase MI, stroke and death risk
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
Osteoporosis
compromised bone strength predisposing to risk of fragility fractures
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)
Increased risk of fragility fractures with (4)
age, falls, low bone mass, previous fractures
Non modifiable risk factors for osteoporosis (5)
age, race, gender, family history, early menopause
Modifiable risk factors for osteoporosis (7)
low Ca or VitD intake, estrogen deficiency, sedentary lifestyle, smoking, excess alcohol, excess caffeine, medications
Mechanism of osteoporosis
bone resorption > formation → lose bone mass
BUT low bone mass is NOT always osteoporosis
Prevention of osteoporosis (4)
- Calcium: 1000-1500 mg/day
- Vitamin D: 1000 units/day
- Exercise: aerobic and resistance
- Falls: assessment and prevention
Treatment of osteoporosis: 2 strategies
alter bone remodeling
- Decrease bone resorption
- Increase bone formation
Osteoclasts
use enzymes and acid to break down old bone
Activation of osteoclasts
RANK receptor on osteoclast binds RANK-L and stimulates OC
RANK = receptor activator of nuclear factor KB
Decay receptor for RANK-L
Osteoprotegerin
Osteoblasts
form new bone from osteoid
New bone formation
Osteoid calcifies with addition of Ca and PO4
New bone has mechanoreceptors (OSTEOCYTES)
Activation of osteoblasts
Wnt Frizzled / LRP-5 B-Catenin activates OBs
Inhibition of osteoblasts
Sclerostin inhibits Wnt pathway → inhibit OBs
_____ and ____ regulate bone formation and resorption
PTH and 1,25 (OH)- Vit D
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
Sclerostin
glycoprotein that blocks osteoblast differentiation via inhibition of Wnt signaling pathway
Osteoprotegerin (OPG):
“decoy” molecules released by osteoblasts that bind RANKL and prevent activation of RANK receptor
Osteomalacia (adults) and Rickets (children):
impaired bone mineralization resulting in soft, weak bones
Pathophysiology of osteomalacia/rickets
inadequate Ca x phosphate product for bone mineralization
Causes of osteomalacia/rickets
- Vitamin D Disorders
2. Phosphate disorders:
2 phosphate disorders that cause osteomalacia/rickets
- Acquired hypophosphatemia
2. Congenital hypophosphatemia rickets
Acquired hypophosphatemia
poor oral intake, renal phosphate wasting
Congenital hypophosphatemic rickets
“Vitamin D Resistance Rickets”
Renal phosphate wasting
Impaired 1,25 (OH)2 VitD Formation
Symptoms of osteomalacia
pain, deformities, fractures
Pseudofractures (Milkman, Looser’s Lines)
Symptoms of rickets
pain, deformities, muscle weakness, short stature
Bowing of long bones
Flaring ends of long bones
Delayed epiphyseal calcification
Paget’s disease
idiopathic bone condition characterized by excessive/unregulated bone resorption and formation
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
Clinical features of Paget’s: Skeletal
pain, deformity, fractures, osteoarthritis, hypervascularity, acetabular protrusion, osteogenic sarcoma
Common sites of involvement: pelvis, skull, vertebrae, femur, tibia
Clinical features of Paget’s: Neurological
deafness (8th nerve, ossicles), cranial nerve compression by bone, spinal cord compression (vascular)
Clinical features of Paget’s: Cardiovasclar
atherosclerosis, aortic stenosis, CHF (high output)
Clinical course of Paget’s
phases of resorption and formation
- Osteoclastic
- Osteoclastic/Osteoblastic
- Osteoblastic
Diagnosis of Paget’s
- Remodeling markers elevated
- Xray fractures very specific
- Bone scan very specific
- Bone biopsy occasionally needed
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
Bone scan finding Paget’s
Focal areas of intense uptake
Histology of Paget’s
increased osteoclast numbers, increased osteoclast nuclei, increase osteoblasts in periphery, disorganized / mosaic / woven bone
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
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
Primary stimulus for PTH secretion is ___________
hypocalcemia
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
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
Direct and indirect actions of FGF23
Direct actions: Stimulates renal excretion of P
Feedback loops: inhibits VitD activation in kidney
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
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
Calcifediol
(25(OH) VitD3) → most useful in patients with liver disease
Onset more rapid than VitD3, but shorter half life
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
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
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
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
Use of Calcitonin
approved for treatment (not prevention) of osteoporosis
Not as effective as bisphosphonates or teriparatide
Useful if back pain is a problem
Estrogens - mechanism?
Increase bone mass as agonist at ERa receptors on osteoblasts and osteoclasts
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
Osteoprotegrin
“decoy” receptor for RANKL → prevent osteoclast activation
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
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
Thiazide diuretics used to treat _________ by _____________
hypercalciuria
reducing calcium urinary excretion
Aldronate, Risedronate, and Zoledronate (IV)
Bisphonphonates
Mechanism of bisphosphonates?
Bind active sites of bone remodeling and inhibit osteoclasts
→ osteoclast apoptosis and inhibit osteoclast function
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
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
Raloxifene
Selective Estrogen Receptor Modulators (SERMs)
Selective Estrogen Receptor Modulators (SERMs)
use?
reduce risk of vertebral fractures, but less effective than estrogen or bisphosphonates
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
Teriparatide
mechanism?
synthetic PTH fragment that stimulates bone FORMATION
Intermittent administration of PTH analog increases osteoblast activity and bone formation
Teriparatide
use?
treatment of severe osteoporosis
Use for longer than 24 months NOT recommended
daily subcutaneous dose
Denosumab
mechanism?
ab against RANKL → reduce osteoclast activation, improve bone mineral density
Denosumab
use?
Dose adjustment in chronic renal disease
Use: treatment in patients with high fracture risk
Treatment of hypercalcemia (5)
1) Saline diuretics (+/- furosemide)
2) Bisphosphonates
3) Calcitonin
4) Phosphates
5) Glucocorticoids
Treatment of hypocalcemia (3)
1) Calcium replacement (acute)
2) Calcium supplementation (chronic)
3) Vitamin D supplementation (chronic)
