Calcium homeostasis and regulation

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what drugs affect absorption of vitamin D analogs?

-BAS -supplements

what are the 2 PTH based drugs?

-teriparatide -abaloparatide

what receptor does PTH bind to and what type of receptor is it?

PTHR1 a GPCR

what binds to DNA often in conjunction with RXR and regulates transcription?

calcitriol

what does high FGF23 inhibits via feedback?

calcitriol formation

how is calcitonin used in hypercalcemia?

-there is a desensitization to Ca and calcitonin is more potent

what # amino acids of PTH are actually active in binding the receptor?

#1-34

what CYPs does cinacalcet interact with?

-CYP2D6 inhibitor -CYP3A4 substrate (oxidation followed by glucuronidation)

What are the AEs of bisphosphonates?

-GI upset (acidic) -esophageal irritation -halting turnover may allow accumulation of damage -unusual femur fractures -osteonecrosis of jaw

what are the 4 tx uses of denosumab?

-OP -bone loss secondary to cancer -bone metastasis due to solid tumors -RA

what is the MOA of etelcalcetide?

-PAM of CaSR that increase affinity for calcium (alternative to cinacalcet)

what are the primary hormonal controls of calcium?

-PTH -calcitriol -fibroblast growth factor 23 (FGF23)

what are 3 things that decreased serum calcium leads to?

-PTH secretion -elevated calcitriol -elevated FGF23 (all related)

what are the 2 bisphosphonates to know?

-alendronate -ibandronate

what is the MOA of bisphosphonates?

-analog of pyrophosphate -thus prevents osteoclast-mediated bone resorption by binding to hydroxyapatite (freeze bone turnover, no net gain)

what are the DDIs of bisphosphonates?

-antacids and mineral supplements decrease absorption -NSAIDS increase risk of GI irritation

SAR: what are the 4 features required for cinacalet?

-aromatic hydrophobic ring -methyl amine -2-3 carbon linker -second aromatic hydrophobic ring

what is the MOA of vitamin D based drugs?

-bind and activate the vit D nuclear receptor -activates gene transcription -increased Ca transport

what is the MOA of calcitonin to lower ECF Ca?

-binds calcitonin receptor (GPCR) on osteoclasts and kidneys -this activates AC -releasing cAMP -lowers ECF Ca

where is 99% of calcium stored? in what form?

-bone -as calcium phosphate hydroxyapatitie

what are the secondary hormonal controls of calcium?

-calcitonin -estrogens/androgens -glucocorticoids

a decrease in serum calcium causes an increase in PTH secretion which causes what 3 things?

-calcium release from bone -decreased Ca elimination in kidney -stimulate formation of calcitriol in kidney

what are the CaSR analogs?

-cinacalcet -etelcalcetide

how is calcitriol (active form of vit D) metabolized and excreted? what is its half-life?

-converted to calcitroic acid by 24-hydroxylase -then renally cleared -5-6 h

what is hyperparathyroidism and what disease states cause it?

-elevated PTH -CKD (counteract hyperphosphatemia) -hemodialysis (hypocalcemia) -calcium malabsorption syndrome

what are the 3 ways that PTH restores ECF calcium when it is reduced?

-enhancing Ca release from bone -increase Ca renal reabsorption -stimulate vitamin D activation

what are the 3 tx uses of salmon calcitonin?

-hypercalcemia -paget's disease -OP

decreased serum Ca--> increase PTH--> increase calcitriol-->increase FGF23--> what 1 thing?

-increase phosphate elimination in kidney to maintain Ca/phosphate ratio

decreased serum Ca--> increase PTH--> increase calcitriol--> what 2 things?

-increased intestinal absorption of calcium -stimulates FGF23 release from bone

how does calcitriol maintain ECF Ca? (3 ways)

-increased intestinal calcium absorption -promotes FGF23 release from bone -inhibits PTH synthesis

what effect do bisphosphonates have on the mevalonate pathway?

-inhibit farnesyl pyrophosphate synthase (pathway seems essential for survival of osteoclasts)

what is RANKL secreted by? what is its function?

-osteoblasts -binds to receptors in osteoclast precursors and stimulates differentiation into active osteoclasts

what is sclerostin produced by? and what is its function?

-osteocytes -a marker for cessation of bone deposition (inhibits osteoblastic bone formation)

what are the 4 functions of PTH related peptide (PTHrP)?

-paracrine function -regulates bone formation -short lived effects -mainly anabolic in bone (promotes deposition)

what are the non-calcemic vitamin D analogs for hypeparathyroidism?

-paricalcitol -doxercalciferol

androgens, direct or after aromatization to estrogen, have what 2 effects on bone?

-promote bone deposition -inhibit bone resorption

what are the 3 negative effects of GCs?

-promotes bone resorption -inhibits bone deposition -inhibits intestinal absorption

what is cinacalcet used to treat? (CaSR analog)

-secondary hyperparathyroidism due to renal disease -hypercalcemia due to parathyroid cancer

what is the tx use of etelcalcetide?

-secondary hyperparathyroidism in adults on hemodialysis for CKD

what is the treatment for hyperparathyroidism?

-surpress PTH via enhancing calcium via calcimimetic therapy

how does teriparatide affect OP?

-transient bone deposition (anabolic) via intermittent PTH activating osteoblasts more than osteoclasts but the osteoclasts will eventually catch up

what is the tx use of romosozumab?

-used transiently in women with history of OP -followed with denosumab or bisphosphonate to consolidate gains

what are the tx uses of vit D based drugs?

-vitamin D deficiency -OP (with Ca supplementation) -rickets -osteomalacia -hypoparathyroidism -secondary hyperparathyroidism

how should bisphosphonates be given?

-with water -remain upright for 30 minutes -no food due to poor BA

how long is the bone cycle?

4 months

what constitutively inhibits release of PTH?

CaSR

what is the vit D3 drug? vit D2? active form?

D3-cholecalciferol D2-ergocalciferol active-calcitriol

what is the RANKL antagonist?

Denosumab

what is the dose of cinacalcet limited by?

GI intolerance (nausea)

what does long-term treatment with GCs cause?

OP

what is the MOA of cinacalcet?

PAM of CaSR -thus enhances affinity for calcium -binding Ca will activate CaSR and decrease PTH secretion -decreases serum Ca and phsophate

SAR: what group at R1 and R2 of bisphosphonates improves activity/potency?

R1-OH R2-amino, heterocyclic rings (esp with N)

SAR: what is the most important group of bisphosphonates for binding?

R2

what is secreted by osteoblasts and binds to receptor in osteoclast precursors and stimulates active -clasts?

RANKL

what is the admin route of denosumab? how long can it be used for?

SQ Q6 months -8-10 years has similar safety profile

what is the new synthetic hybrid analog of 1-34 PTH/PTHrP?

abaloparatide

how do you prevent OP?

accumulate sufficient BMD early in life with load bearing exercises

what part of teriparatide acts as an agonist at the PTH-R?

active N terminal fragment

where does calcitriol act? and what does it do here?

agonist at viamin-D receptor

where do glucocorticoids act and what is their action there?

agonists of the glucocorticoid-R

what should teriparatide be followed by to consolidate gains?

bisphosphonates

what does PTH oppose the effects of to stimulate biosynthesis of vitamin D?

calcitonin

what drug is not used as primary treatment in OP due to being less effective and is thus limited to postmenopausal women with spine OP?

calcitonin

what is the 32 amino acid peptide hormone secreted from C cells or parafollicular cells of thyroid gland in response to hypercalcemia?

calcitonin

what is the major divalent cation in the body that is essential for signaling in cells?

calcium

what is the fully human MAB that blocks RANKL function preventing osteoclast differentiation?

denosumab

loss of *X* is the most significant cause of OP in postmenopausal women?

estrogen

what CaSR analog can be delivered during hemodialysis?

etelcalcetide

what inhibits PTH secretion via feedback?

high calcium high calcitriol

what is the non-FDA approved indication for teriparatide?

hypoparathyroidism where Ca/vit D are ineffective

what is the BBW of romosozumab?

increased potential for CV risk

what is the normal function of sclerostin? what does loss of function lead to?

inhibits osteoblastic bone formation -sclerosteosis-excessive abnormal bone formation

what is the BBW of teriparatide?

may increase risk of osteosarcoma (abnormal bone growth)

what is the main role of PTH?

restore ECF calcium when it is reduced

what is the word for excess bone deposition?

osteopetrosis

what is more common in postmenopausal women and a major cause of morbidity in elderly?

osteoporosis

what is the word for bone loss?

osteoporosis

what is RANKL regulated by?

osteoprotegerin

what is the decoy molecule produced by multiple tissues?

osteoprotegerin

what molecule binds RANKL and regulates availability?

osteoprotegerin

what is the disease with abnormal bone deposition and thus abnormal bone growth?

paget's disease

what produces PTH?

parathyroid gland

what is an 84 amino acid peptide hormone?

parathyroid hormone

what is the MAB that has a net bone deposition (stronger than teriparatide)?

romosozumab

what is the sclerostin antagonist?

romosozumab

*X* calcitonin is used because it is 50x more active than human calcitonin

salmon

what is the function of osteoblasts?

stimulate bone deposition (b=build bone)

what is the function of osteoclasts?

stimulate bone resorption (c=cuts bone)

what is the synthetic analog recombinant 1-34 PTH?

teriparatide

how are bisphosphonates metabolized?

they're NOT -excreted or deposited in bone -will accumulate in bone and there is no known method for removal

what is the MOA of abaloparatide?

transient signaling at PTH-R

what is paget's disease?

uncontrolled osteoclastic bone resorption -can cause bone pain, abnormal bone, and hypercalcemia

is cytoplasmic free calcium very low or very high?

very low

Ca binds to *X* leading to activation of *Y* and eventually inhibition of PTH secretion

x-CaSR y-phospholipase C


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