Flashcards in Calcium Homeostasis! Deck (74):
Where is majority of Ca++ stored?
In bone and teeth
Calcium is stored in bone as________
What factors released by osteocytes upregulate osteoblast/Clast activity?
Dentin matrix protein
What factors released by osteocytes down-regulate osteoblast/Clast activity?
What is the role of PTH?
To maintain a constant Ca++ concentration in the ectracellular fluid (serum)
What receptors reabsorb Ca++ from the collecting tubules?
How does PTH regulate calcium?
Increaseding Ca++ reabsorption via TrpV5
Increased Bone resorption (Osteoclast)
Increased PO4 loss in urine
Increased 1,25 (OH)2 D3 prodution in kidney
What receptor in the parathyroid senses Ca levels?
a GPCR (CaR)
What are the steps and enzymes involved in Vit D synthesis?
7-dehydrocholestrol====>UV radiation====>Cholecalciferol(vit D3) ====>Liver (Vit D25-hydroxylase enzyme=====>25 hydroxyvitamin D3====> 1 alpha hydroxylase====> 1,25 Dihydroxy Vit D3 calcitriol.
What is the role of Vit D?
Increase Ca++ and PO4 absorption from the small intestine (via ECaC2/TrpV6)
Feedback inhibition of PTH via 1,25(OH)2D
What cellular transporters are upregulated by Vit D?
What is the role of the Ca++_ATPase?
To enable Ca++ absorption in the intestine
What is the function of Calbindin-D9K?
It binds Ca++ intracellularly after it has been absorbed.
What is the role of calcitonin? Where is it made?
It is a negative regulator of (extracellular Ca++) concentration.
What how does calcitonin regulate serum Ca++ conentration?
It inhibits bone resorption
Increases Ca++ and PO4 loss in urine
What stimulates Calcitonin?
High Ca++ concentration.
What is osteoporosis? What causes it?
Bone mass loss. It is caused by a decrease in estrogen (postmenopaural).(decreased osteoblast activity)
What are the risk factors for osteoporosis?
Low Ca++ intake in early yrs
Long-term glucocorticoid therapy
Give two causes of hypercalcemia
Hyperthyroidism-Increased bone resorption and decreased Ca++ excretion.
Malignant tumors (PTH activity)
What are the major manifestations of hypercalcemia?
CNS symptoms-Depression, coma
What are two causes of hypocalcemia?
VitD deficiencies- Ricketts
How does Vit D work?
It increases absorption of Ca++ and PO4 from gut
What preparation is vitamin D supplement sold as?
How is hypocalcemia and hypoparathyroidism treated?
Vit D+ Ca++
What are the consequences of a Vit D overdose?
Ca++ deposits in the kidney, soft tissues, Hypercalcemia=Coma, Death
What is Paget disease of bone?
Localized bone disorder characterized by increased osteoclast activity followed by increased osteoblast activity causing a "woven bone bone pattern"= More prone to fractures. Ca++ and phosphorus levels are normal!!! May have bone pain, deformity, loss of hearing
How is paget disease of bone (Osteitis deformans) treated?
What do loop diuretics do to Ca++ levels?
Decrease them as they cause and increased secretion of Ca++
What do thiazides do to Ca++ levels?
They cause a decreased secretion of Ca++ (can cause hypercalcemia)
How do loop diuretics work?
They decrease the driving force of Ca++ uptake by inhibition Na+/K+/2Cl (May cause kidney stone)
What do thiazides do to Ca++ levels?
Increase driving force for uptake by inhibiting Na/Cl transporter.
What do PPIs and H2 antagonists do to Ca++ levels in the body?
They cause a decreased absorption of Ca++ by decreasing the acidity of the stomach.
What drugs induce the VitD catabolic P450s?
Carbamezepine, Isoniazid, theophylline, rifampin
How do bisphosphonates work?
Reduce formation and dissolution of hydroxyapatite crystals.
Disrupt cytoskeleton, induce apoptosis, inhibit farnesyl-PP synthesis of osteoclasts.
What are some adverse effects of bisphosphonates?
Musculoskeletal pain, osteonecrosis of the jaw, atypical fractures of femur
What bisphosphonates are used to treat osteoporosis(build bone mass)?
ZARI-Rise Allen b4 Iban ur Zole
What bisphosphonates are used to reduce turnover of Ca++ (cancer and Paget's?
What enzyme is inhibited by bisphosphonates?
Farnesyl Pryophosphate Synthase.
What is the first line treatment for osteoporosis?
What is the second line treatment for osteoporosis?
Estrogens and SERM's (Selective estrogen modulator
Calcitonin, Recombinant PTH (Teriparatide)
How do Estrogens and SERM's treat osteoporosis?
Prevent menopausal bone resorption
Increase osteoblast activity and decrease osteoclast activity.
What estrogens are used to treat osteoporosis?
Name two calcitonin analogs used to treat osteoporosis?
How does calcitonin Tx for osteoporosis work?
Blocks renal absorption of PO4 and Ca++
When is Tx with calcitonin indicated?
What are the side effects of calcitonin Tx?
Urticaria, hand swelling, nausea
What is Teriparatide?
It is a recombinant PTH. Injected sub Q and given with Ca++ and Vit D.
What does Teriparatide do at low concentrations vs high concentrations?
Low= Stimulates osteoblast activity.
High= Stimilate Osteoclast activity.
When is Teriparatide indicated?
Tx for osteoporosis in pts with high risk of fracture.
Where is the PTH receptor found?
On osteoblasts and Kidney
What is the function of RANKL?
It is released by osteoblasts to stimulate osteoclast precursors and enable their maturation/differentiation into .
What is the function of Osteoprotegrin (OPG)?
OPG binds RANKL preventing it from binding to the osteoclast precursors.
What is RANK?
RANK is a receptor activator of NFkB
Continuous PTH infusion causes_______ increase and _________ decrease which causes a __________ in osteoclast activity.
Intermittent infusion of PTH causes a___________ in osteoblast apoptosis and an increase in_______.
What advantage does Teriparatide have over bisphosphonates?
More effective at preventing bone fractures as Teriparatide builds bone at a higher rate than bisphosphonates.
What disadvantage does Teriparatide have over bisphosphonates?
Teriparatide has an increased risk for cancer (Osteosarcoma) and is injected daily. ALSO DO NOT USE FOR MORE THAN 2 yrs.
What is Denosumab? How does it work
Humanized monoclonal Ab against RANKL. It prevents differentiation of osteoclasts. Take W/ Vit D
When is Denosumab used?
For treatment of osteoporosis when bisphosphonates have failed. Used in PM women with fracture history and at a high risk for fractures.
What is Cinacalcet?
Used to treat primary hyperparathyroisim (Parathyroid tumor) and secondary hyperparathyroidism in chronic kidney disease ( Loss of 1,25 (OH)2 Vit D3 production)
What is the MOA of Cinacalcet?
It binds Calcium Sensing Receptor (CaR) - A GPCR on the PTH gland to inhibit release of PTH.
How does Cinaclalcet bind to the CaR?
Allosterically to allow Ca++ to better binf to the CaR and stop PTH release. (Basically fixes a broken receptor)
What effect does Cinaclcet have on serum PTH and Ca++ levels?
It decreases both PTH and Ca++ levels.
Name two Vit D analogs
How does Zamplar and Hectrol work?
Inhibit secretion of PTH with less effect on Serum Ca++ than 1,25(OH)2 Vit D3
When are Zamplar and Hectrol used?
In treating secondary hyperparathyroidism
What is not secreted in urine in chronic kidney disease?
Phosphate. This causes PO4 to combine with Ca++ and precipitate in tissues. causing calcific uremic Ateriopathy
How do phosphate binders work?
Complex with phosphate in the gut preventing absorption.
Name two Phosphate binders
How is Lanthanum different from Sevelamer?
Lanthanum decreases serum PO4 and Ca++ levels. While Sevelamer decreases only serum PO4 levels selectively.
What does serotonin do to osteoblasts?
Serotonin inhibits Osteoblast proliferation.