Hockerman Ca2+ Homeostasis Flashcards
what kind of cells PUT Ca2+ into bones?
osteoBLASTS (building bone)
what do osteocytes do?
are inside bone to control the osteoblasts and osteoclasts
what cells release PO4 and Ca2+ from bone?
osteoclasts
Bone is _____ sensitive: _______ force is detected by cell processes that extend into canaliculi which forms a network involving _______ and ______
load; mechanical; ACTIN; Connexin 43
Parathyroid Hormone:
- is a ________ hormone secreted from parathyroid gland
- it is ____ amino acids long; cleaved from a precursor that is _____ amino acids long;
- what part of the hormone has full activity?
- if ______ is deleted from the hormone - activity is lost
peptide; 84; 115; amino acids 1 - 34; amino acid 1 & 2
The parathyroid’s hormone is in charge of maintain what?
keeping a constant Ca2+ concentration in extracellular serum
what actions does PTH do?
- increase Ca2+ reabsorption from ______
- increase Ca2+ resorption from ______
- increased _____ lost in urine
- increased ______ produced by kidney
collecting tubules; bone; PO4-; Vit. D
what is the first step of Vitamin D Synthesis
7 dehydrocholesterol –> Vitamin D3 (Cholecalciferol) via UV light
Liver’s Role in Vitamin D synthesis - ?
Vitamin D3 –> 25 hydroxyvitamin D3 via Vit D 25- hydroxylase
Kidney’s Role in Vitamin D Synthesis - ?
hydroxylase enzyme (1a or 24) to make 1,25 Vit. D3 or 24,25 Vit. D3
What are the actions of Vit. D
- increased _________ absorption from small intestine
- increases reabsorption of _______
- feedback inhibition of ______
- will have indirect (slow or fast) effects on cells
ca2+/PO4; Ca2+/PO4; PTH; slow
How does Vit. D help with absorption of Ca2+ from intestines
it up regulates TrpV6, Calbindin-D9k; Ca2+ATPase - all of those help Ca2+ go from lumen to the blood
Role of TrpV6 in absorbing Ca2+ from the intestine
Ca2+ channel
Role of Calbindin-D9k in absorbing Ca2+ from the intestine
it is the calcium “chaperone” guides Calcium across the cell
Role of Ca2+ATPase in absorbing Ca2+ from the intestine
pushes Ca2+ out into the plasma from the cell
_______ is released from the thyroid gland and is a negative regulator of serum Ca2+
Calcitonin
How does calcitonin act as a negative regulator of serum Ca2+
- inhibits osteoclastic bone resorption
- increases Ca2+ and PO4 loss in urine (aka less is absorbed)
Calcitonin is triggered to be release by what?
high levels of Ca2+
Explain Paget’s Disease
- UNCONTROLLED OSTEOCLASTIC BONE RESOPRTION AND SECONDARY BONE FORMATION (bone pain/deformities, loss of hearing and hypercalcemia)
Paget’s Disease patients are at risk of having (hypo or hyper) calcemia
Hyper - because hella osteoclastic bone resorption is occurring
Risk Factors for Osteoporosis
Physical inactivity (try weight lifting); age; low Ca2+ intake in early years; long term glucocorticoid
Possible causes for Hypercalcemia
- hyperparathyroidism
- malignant tumors
Hypercalcemia can cause what ?
CNS symptoms (depression, coma)
Hypocalcemia can be caused by what?
- Hypoparathyroidism
- vit. D deficiencies
Hypocalcemia can cause what?
- neuromuscular distrubances
- paresthesias, tetany,
muscle cramps
Different Preparations of Vit. D that are available
- Vit D.3 ( OTC - doesn’t have that 1 or 25 OH) - therefore needs kidney AND liver function
- 25OH Vit. D3 - NEEDS KIDNEY FUNCTION
- 1,25 OH Vit. D3 - does not need function of kidney or liver
Clinical uses for Vit. D
- hypocalemia
- hypoparathyroidism (used as supplement bc usually PTH stimulates Vit. D to be made)
- hyperparathyroidism (secondary to CKD - used as feedback inhibition to have PTH chill)
Bisphosphonates: inhibit bone ______
resorption
Bisphosphonates: MOA - 2 ideas/options
- reduce ________ and ________ of hydroxyapatitie crystals
OR
- disrupt _______, induce _______ and inhibit FPP synthesis in _________
formation; dissolution; cytoskeleton; apoptosis; osteoclasts
Bisphosphonates: Counseling tips
- taken w/ H20
- take 30 min before breakfast (because drug interactions..?)
- gastric irritation (therefore sit up after taking it)
- may cause Hypocalcemia
List all the bisphosphonates
- alendronate
- risendronate
- ibandronate
- zoledronate
- eitdronate
- tiludronate
- pamidronate
What bisphosphonates are approved for Paget’s and cancer (NOT osteoporosis)
- pamidronate
- tiludronate
- etidronate
what bisphosphonates ARE approved osteoporosis
- alendronate
- risedronate
- ibandronate
- zoledronate
MOA of Bisphosphonates:
- ________ of farnesyl pyrophosphate synthase
- disrupts prenylation of proteins in _________
- affects isoprenoid activity and ______ can induced
inhibition; osteoclasts; apoptosis
Second line treatment for Osteoporosis
Estrogens and SERMs
Calcitonin will _______ osteoclast activity and thats why it can be used for ________
osteoporosis (only as alternative for ERT)
side effects of Calcitonin (given as Calcimar or Miacalcin)
urticaria; hand swelling, nausea
Clinical Uses of Calcitonin (given as Calcimar or Miacalcin)
- pagets disease
- hypercalcemia (secondary to malignancy)
- Alt. therapy for osteoporosis (alt. to ERT)
what kind of drug is Forteo?
its the first 34 amino acids of PTH
forteo = ? (generic)
Teriparatide
usually don’t want parathyroid because stimulates resorption of bones BUT forteo can be used to help with osteoporosis - HOW?
- given periodically - and Ca2+ and Vit. D are supplemented
- this will preferentially stimulate osteoblasts NOT osteoclasts
List the components for differentiating osteoclasts
- RANKL
- RANK
- OPG (osteoprotegerin)
Describe how osteoclasts are differentiated
- RANKL (a ligand on an osteoblast) will bind to RANK (a receptor on an osteoclast precursor) - will create an osteoclast
- RANKL can bind to OPG which prevents osteoclast differntiation
Continuous PTH - will lead to….
_____ RANKL and _____ OPG
MORE RANKL and LESS OPG (that means more osteoclast differentiating!
Risk of _______ with Tymlos (abaloparatide) - a PTH related peptide
osteocarcinoma
________ drug is a humanized monoclonal Ab against RANKL - aka will prevent osteoclast precursos from differentiating into osteoclasts
Prolia (Denosumab)
New strategy for Osteoporosis: - drug involving serotonin….
serotonin INHIBITS osteoblast proliferation TPH1 helps serotonin in the gut be made - therefore inhibit TPH1 to decrease serotonin and therefore serotonin too
New strategy for Osteoporosis: - drug involving cathepsin K
cathespin K - is released by osteoclasts and will degrade type 1 collagen in bone = therefore use a cathepsin K inhibitor
Normal Ca2+ plasma level (only Free Ca2+)
1.1 - 1.3 mM
Drug classes listed that affect Ca2+ levels
- loop diuretics (increased Ca2+ excretion)
- Thiazides (decreased excretion)
- PPIs/H2 antagonists (decreased absorption)
- Carbemazepine, isoniazid, theophylline, rifampin (induction of vit. D catabolites
how do loop diuretics affect Ca2+
increase Ca2+ excretion
how do thiazides affect Ca2+
decrease Ca2+ excretion
how do PPIs and H2 antagonists affect Ca2+
decrease absorption
Cinacalcet (Sensipar) is used to treat what?
Hyperparathyroidism
Cinacalcet (Sensipar) binds to _______ on the ______ to inhibit the release of ______
CaR (calcium sensing receptor); PTH gland; inhibit PTH
Cinacalcet (Sensipar) will decrease both ______ and _____ levels
Ca2+ and PTH
