Calcium homeostasis and regulation
what are the 2 PTH based drugs?
-teriparatide -abaloparatide
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 drugs affect absorption of vitamin D analogs?
-BAS -supplements
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
what receptor does PTH bind to and what type of receptor is it?
PTHR1 a GPCR
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 major divalent cation in the body that is essential for signaling in cells?
calcium
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 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 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 main role of PTH?
restore ECF calcium when it is reduced
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