Bone Homoestasis Dr. Pond Flashcards
EXAM 2
Risk factors for Osteoporosis in females
Age: over 50 -> menopause
lower body weight and muscle mass
early menopause: low estrogen
no pregnancy: low estrogen
Risk factors for Osteoporosis in males
-age: over 50
-short statue, thin build
-weak hip muscles
-low tesosterone
Other risk factors
caffeine
depression
low vitamin D and calcium
certain meds
Which medication increases the risk for osteoprosis?
Corticosteroids
-decreases organic matter in bones
-decreases calcium and phosphates in bones
What is the organic matrix in the bone?
Osteoid (95% collagen, 5% ground substance - mixture of proteoglycans)
What is the inorganic matrix in the bone?
-Hydroxyapatite
-other minerals
build on top of organic matrix
Function of Osteoblasts
synthesize Osteoids
-> Hydroxyapatite get deposited on it
Osteoblasts get trapped together with hydroxyapatite in the bone they are forming
->no longer active in bone production -> they become the resident bone cells (osteocytes)
Function of Osteoclasts
Bone resorption
secretes proteases -> breaking down the osteoids
secretes acids dissolves hydroxyapatite
How does PTH affect Ca2+, PO4(3-)?
-increases Ca2+
-decreases PO4(3-)
stimulates the production of active Vitamin D ->
Vitamin D has to be formed into the active form
How does Vitamin D affect Ca2+, PO4(3-)?
-increases Ca2+
-increases PO4(3-)
inhibits the production of PTH -> negative feedback loop to PTH
stimulates FGF-23
How does Fibroblast growth factor 23 affect Ca2+, PO4(3-)?
only decreases PO4(3-)
inhibits production of active Vitamin D -> negative feedback loop to Vitamin D
What is the role of calcitonin?
-decreases Ca2+ in the plasma
-decreases PO4(3-) in the plasma
-> works on osteoclasts -> stimulates resorption and keeps Ca and PO4(-3) in the bone (levels go down in the serum)
other secondary regulators are:
prolactin, growth hormone, insulin, thyroid hormone, glucocorticoids, sex steroids
On which organ does PTH work?
Kidney
increases reabsorption of Ca2+
decreases reabsorption of PO3(-4) -> more excretion
also works in the bones
What is PTH’s effect on the bone?
increasing resorption (bone breakdown) -> it is going to free up Ca and PO (Ca levels go up, PO4(3-) will be exerted)
On which organ does Viramin D work?
The gut
increases absorption of Ca2+
increases absorption of PO3(-4)
through upregulation of their transporters
Kidney:
Vitamin D can also inhibit the urine output of Ca2+ and PO3(-4) –> but that’s a weaker effect
On which organ does FGF-23 work?
in the kidneys:
decreases reabsorption of PO3(-4)
some activity in the bones
On which organ does Calcitonin work?
mainly in the bone
decreases bone resorption -> more Ca2+ and PO3(-4) stays in the bone -> less coming out of the bone into the serum -> decrease Ca2+ and PO3(-4) serum levels
some activity in the kidneys
-> more elimination of Ca2+ and PO4(3-)
How do Ca2+ levels regulate PTH?
high levels of Ca2+ –> decreases PTH
as Ca2+ goes up it actives the Ca-sensitive protease
-> the protease cleaves PTH (peptide hormone) into fragments
as Ca2+ goes up it binds to CaR -> decreases PTH release from the parathyroid gland
How does PO4(-3) regulate PTH?
high Phosphate levels stimulate PTH production
as PO4(-3) goes up it binds to Ca2+ and forms calcium phosphate -> which will reduce free calcium -> there is less calcium binding CaR on the parathyroid gland
-> which will stimulate PTH production
What is the mechanism of PTH’s effect on the bone?
PTH induces RANKL (ligand) from osteoblasts
-> RANKL binds on RANK (receptor) on osteoclast precursor -> activation of osteoclasts -> RESORPTION (bone breakdown)
-> increase in free Ca and PO4(-3)
How does low PTH level affect bone metabolism?
low PTH induces IGF-1 (insulin growth factor)
-> activating osteoblast and bone formation
so PTH can cause bone breakdown - at chronic high dose with RANKL
and thought to cause bone formation - at chronic low dose
Which drug uses PTH’s effect of bone formation?
Teriparatide
-recombinant PTH for osteoporosis
increases bone formation
(mimics low dose of PTH -> stimulates osteoblasts)
-given SC (since it is a peptide)
-approved for use for only 2 yrs (osteosarcoma in rats)
ADE of Teriparatide
joint pain, arthritis, nausea
How does Cinacalcet work?
Calcimimetic - mimics Ca2+ -> binds to CaR
-> inhibits PTH production
-used in hyperparathyroidism
ADE: diarrhea, N/V, hypocalcemia
How is Vitamin D3 called?
CholeCalCiferol (3x C in the name)
-from diet and skin
How is Vitamin D2 called?
ErgoCalCiferol (2x C in the name)
-from plants, yeats, and milk
How is Vitamin D3 produced from our skin?
7-Dehydrocholesterol is stored in our skin
-through UV light converted to Pre-D3
-trough heat converted to CholeCalCiferol
How is Vitamin (D3 and D2) activated?
in the liver converted to 25(OD)D3 (through 25-hydroxylase
then in the kidney to Calcitriol (1,25(OH)2D3) by the 1-alpha-hydroxylase
Which patient population should be supplemented with active Vitamin D instead of Vitamin D3
elderly
renal impaired patients
hepatic impaired patients
-> since it is converted in the liver and kidney
Which enzyme produces the active form of vitamin D?
1-alpha-hydroxylase in the kidney
Molecules that stimulate the production of active Vitamin D
-low Ca2+ and PO4(-3)
-high PTH
-low FGF-23
What are common ADEs of active vitamin D?
-edema
-N/V
-hypercalcemia –> since it increases absorption of Ca and PO4(-3) in the gut
Where is FGF-23 produced?
in the bones by osteocytes and osteoblasts
-> FGF-23 binds to FGF-1 and FGF-IIIc receptors in the presence of Klotho (accessory receptor)
Which organ is involved in the PO4(-3) regulation by FGF-23
Kidney
decreases reabsorption of PO4(-3) -> excreted in the urine
-> Phosphaturia
How does FGF-23 regulate Vitamin D?
inhibitng 1-alpha-hydroxylase in the kidney
What stimulates FGF-23 production
-active vitamin D3 (1,25(OH)2D3)
-low serum phospahte
Where does Calcitonin work?
in the bones and kidneys: decreases Ca and PO4(-3)
-> inhibits bone resorption (osteoclasts)
-> prevents the mobilization of Ca and PO4(-3) so it doesn’t get back into the serum
weak action in the kidney: reduces reabsorption of Ca and PO
Why is resorption actually beneficial to the bones?
Because it is required for bone formation
How do Glucocorticoids contribute to osteoporosis?
-in the bones: block bone formation (uses protein (collagen of the bone) to form glucose
-in the gut: antagonizes Vitamin D-stimulated calcium absorption
-in the kidney: increases Ca2+ excretion
decreases Ca and PO4(-3)
What is the effect of estrogen on the bone?
thougt to reduce bone-resorbing action of PTH,
also dirctly anti-resorptive to the bone
What is the MOA of Bisphosphonates?
-decreases osteoclast bone resorption
inhibits osteoclast activity
inhibits osteoclast survival: alendronate, risedronate
increase osteoclast apoptosis
-bind hydroxyapatite -> protect them from dissolution by acids (from osteoclasts)
-treatment of osteoporosis, hypercalcemia (caused by bone resorption and transfer of released Ca to the bloodstream), cancer (high dose)
How should Bisphosphonates be taken?
-in the morning on an empty stomach, and take a full glass of water - since less than 10% absorbed orally
-remain upright for 30 min (ibandronate - 60 min)
How are Bisphosphonates metabolized?
No metabolism
50% accumulates in the bone: duration of action is not predictive -> remainder excreted unchanged in the urine
What are the ADEs for Bisphosphonates?
GI: diarrhea, nausea, abdominal pain
-esophageal ulcers
-osteonecrosis of the jaw
-potential for esophageal cancer
Contraindicated population
-decreased renal function
-esophageeal disorder (IV formulation works)
-peptic ulcer disease (IV formulation works)
What is the MOA for Denosumab?
RANKL inhibitor -> decreases osteoclasts
-> reduction in resorption
ADE: hypocalcemia, hypophosphatemia (since we inhibit the release of free Ca and PO4(-3)
-serious infections
-osteonecrosis of the jaw
-N/V, diarrhea
-fatigue, backache, headache, pain in limbs
-nasopharyngitis
What is the MOA for Romosozumab?
Sclerostin inhibitor
-increases bone formation
-decreases bone resorption (to a lesser extent)
-short-term use (12 months or less)
What is the role of Sclerostin?
inhibits the precursor of osteoblasts and osteoblasts
-stimulates apoptosis of osteoblasts
What are the serious side effects of Romosozumab?
-MI
-stroke
-cardiovascualr death
-hypocalcemia (some decrease in resorption in free Ca release)
-osteonecrosis of the jaw
The increase of which molecule causes Phosphatuira?
FGF-23
