calcium homeostasis and regulation
romosozumab use + BBW
- used transiently in women with history of osteoporosis, followed by denosumab or bisphosphonate to consolidate gains - BBW: increased potential for cardiovascular risk
clinical applications of vitamin D based drugs
- vitamin D deficiency - osteoporosis (with Ca supp) - rickets - osteomalacia - hypoparathyroidism - secondary hyperparathyroidism
bisphosphonates (alendronate, ibandronate) administration
- water, remain upright for 30 mins - without food because bisphosphonates have poor bioavailability
denosumab AE
- RANKL expressed in other immune cells: potential for immunosuppression - reduced bone turnover potential concern
denosumab admin and use
- SC q6 months - long term use: 8-10 year use similar safety profile to short term - favorable benefit/risk - use: osteoporosis, bone loss secondary to cancer, bone metastasis due to solid tumors, RA
glucocorticoids
- regulation by glucocorticoids - GC acts as agonists of the glucocorticoid-R - prototypic steroid hormone receptor - overall negative effect (promotes bone resorption, inhibits bone deposition, inhibits intestinal absorption) - glucocorticoid therapy SE (long term: osteoporosis)
abaloparatide in osteoporosis
- selective anabolic effect - strong protection against fractures - mechanism: transient signaling @ PTH-R
cholecalciferol, ergocalciferol and calcitriol (active form)
- 1-25 (OH)2 D3 active form preferred - fast onset: 12h, and steady state (72-96 h)
calcitonin general
- 32 aa peptide hormone secreted from C cells or parafollicular cells of thyroid gland in response to hypercalcemia
bisphosphonates (alendronate, ibandronate) side effects
- GI upset (acidic) - esophageal irritation - halting turnover may allow accumulation of damage - unusual femur fractures - osteonecrosis of jaw
vitamin D DDI
- absorption of many vitamin D analogs may be affected by bile acid sequestrates and supplements
osteoporosis prevention
- accumulate sufficient BMD early in life: load bearing exercises
calcitriol MOA
- agonist of vit-D receptor - member of nuclear receptor superfamily - binds to DNA often in conjunction with RXR and regulates transcription
etelcalcetide MOA
- allosteric modulator of CaSR that increased affinity for calcium - peptide analog agonis
etelcalcetide therapy
- alternative to cinacalcet - can be delivered during hemodialysis - use: secondary hyperparathyroidism in adults on hemodialysis for CKD
bisphosphonates (alendronate, ibandronate) DDIs
- antacids and mineral supplements decrease absorption (calcium salts are cleared) - NSAIDS increase risk of GI irritation
vitamin D MOA
- bind and activates vitamin D nuclear receptor. activates gene transcription and leads to calcium transport
cinacalcet MOA and use
- binds allosteric site (PAM of CaSR) - does not activate on its own - enhances affinity for calcium - binding of calcium will activate receptor and decrease PTH secretion and lower calcium and phosphate serum (used in treatment of secondary hyperparathyroidism due to renal disease and hypercalcemia due to parathyroid cancer)
secondary hormonal control of calcium homeostasis
- calcitonin - estrogens/androgens - glucocorticoids
vitamin D metabolism
- calcitriol is converted to calcitroic acid by 24-hydroxylase - calcitroic acid readily cleared - half life of calcitriol: 5-6h
PTH secretion
- calcium release from bone - decreased elimination in kidney - stimulate formation of calcitriol in kidney
vitamin D based drugs
- cholecalciferol, ergocalciferol and calcitriol - paricalcitol, doxercalciferol
osteoprotegerin
- decoy molecule produced by multiple tissues - binds RANKL and regulates availability
osteoporosis pathophysiology
- decreased bone density - balance tilted toward bone resorption - more common in postmenopausal women - major cause of morbidity in elderly
calcitonin (salmon) in hypercalcemia
- desensitization to calcium is a protein - requires high doses of calcitonin but still safe
hyperparathyroidism - treatment to suppress PTH
- enhance calcium mediated inhibition of PTH in parathyroid glands (calcimimetic therapy)
calcitriol effects on intestinal transport
- gene transcription and new protein synthesis of calcium transport components lead to increase in Vmax
feedback in calcium homeostasis
- high calcium inhibits PTH secretion - high calcitriol inhibits PTH secretion - high FGF23 inhibits calcitriol formation
elevated calcitriol causes
- increased intestinal absorption of calcium - stimulates FGF23 release from bone
calcitriol maintains ECF calcium by...
- increased intestinal calcium absorption - promotes FGF23 release from bone - inhibits PTH synthesis
elevated FGF23
- increased phosphate elimination in kidney - to maintain appropriate calcium/phosphate ratio
teriparatide in osteoporosis
- intermittent PTH activates osteoblasts more than osteoclasts - transient bone deposition (anabolic) - osteoclasts eventually catch up - followed by bisphosphonates to consolidate gains
estrogens
- loss most significant cause of osteoporosis in postmenopausal women
calcium functions
- major divalent cation in the body, essential signaling role in cells - serum calcium is kept in a narrow range - cytoplasmic free calcium is very low - 99% in bone: structural support and exchangeable reservoir of calcium. present as calcium phosphate hydroxyapatite - 1% in intracellular fluid - 0.1-0.2% ECF (40% bound to proteins, 10% complexed, 50% ionized)
calcitonin (salmon) in osteoporosis
- not used as primary treatment, less effective than other drugs - effects in postmenopausal women limited to spine
PTH related peptide (PTHrP)
- paracrine function - regulates bone formation - short lived effects - mainly anabolic in bone - promotes deposition
primary hormonal control of calcium homeostasis
- parathyroid hormone (PTH) - calcitriol (vit D) - fibroblast growth factor 23 (FGF23)
non-calcemic analogs of hyperparathyroidism
- paricalcitol - doxercalciferol
sclerostin
- produced by osteocytes - a marker for cessation of bone deposition. inhibits osteoblastic bone formation
decreased serum calcium leads to.... (3 things)
1. PTH secretion 2. elevated calcitriol causes 3. elevated FGF23
teriparatide in hypoparathyroidism
NOT FDA approved but effective in cases where Ca/vit D supply are ineffective
hyperparathyroidism - info
PTH is elevated in certain disease states: - CKD: counteract hyperphosphatemia - hemodialysis: hypocalcemia (increases PTH) - calcium malabsorption syndromes (increased PTH)
bisphosphonates (alendronate, ibandronate) SAR
R1: hydroxyl group improves activity R2: greatly affects potency - amino substitution = higher potency - heterocyclic rings, especially with nitrogens further increase potency - this group is most important for binding
control of bone remodeling
RANKL osteoprotegerin sclerostin
bisphosphonates (alendronate, ibandronate) MOA
analog of pyrophosphate - rapidly deposited in bone - mimics of pyrophosphate, PCP break is not hydrolyzable - prevent osteoclast-mediated bone resorption; are "bone seeking" and bind to hydroxyapatite slow formation and dissolution of hydroxyapatite crystals - freeze bone turnover - no net gain effects on mevalonate pathway: inhibit farnesyl pyrophosphate synthase - specific to amino bisphosphonates (decrease osteoclasts) - pathway seems essential for survival of osteoclasts
calcitonin MOA
binds to calcitonin receptor, GPCR, on osteoclasts and kidneys - binding results in activation of adenylate cyclase --> release cAMP - salmon calcitonin: 50x more active than human calcitonin
osteoporosis
bone loss
secondary hormonal control
calcitonin glucocorticoids androgens estrogens
CaSR analogs drugs
cinacalcet etelcalcetide
how are calcium and phosphate in bone and cycle length
constantly deposited and released - cycle: 4 months
RANKL antagonist
denosumab
androgens
direct or after aromatization to estrogen - promote bone deposition - stimulate bone deposition - inhibit bone resorption
osteopetrosis
excess bone deposition
cinacalcet SAR
four features are required, an aromatic ring, a methyl amine, 2-3 carbon linker and a second aromatic hydrophobic ring
denosumab MOA
fully human monoclonal antibody; blocking RANKL function prevents osteoclast differentiation
calcitonin (salmon) uses
hypercalcemia paget's disease osteoporosis
regular sclerostin function
inhibits osteoblastic bone formation - loss of function mutations in sclerostin lead to sclerosteosis - excessive bone formation (abnormal)
calcitonin effects + pharm
lowers ECF calcium - opposes PTH - inhibits release of Ca from bone - reduces renal reabsorption: affects calcium and other ions minor role in normal conditions since excess or deficiency has little effect pharmacologic doses cna have effects beneficial in certain disease
parathyroid hormone (PTH) - main role/MOA
main role: restore ECF calcium when it is reduced - binds to PTHR1 receptor, a GPCR - directly affects calcium homeostasis by enhancing calcium release from bone, increase calcium renal reabsorption and stimulate vitamin D activation - parathyroid gland is extremely sensitive to changes in calcium serum levels. calcium binds to CaSR leading to activation of phospholipase C and eventually inhibition of PTH secretion - opposes effects of calcitonin and stimulates biosynthesis of vitamin D
paget's disease
misdeposition; bone deposition is abnormal; bone growth is abnormal as a result
abaloparatide general
new synthetic hybrid analog of 1-34 PTH/PTHrP. several modifications including an unnatural amino acid
bisphosphonates (alendronate, ibandronate) metabolism
not metabolized; excreted or deposited in bone - amount in bone accumulates with use and no known method for removing drug
calcitonin (salmon) in paget's disease
oncontrolled osteoclastic bone resorption - may cause bone pain, abnormal bone and hypercalcemia
cinacalcet metabolism and limitations
oxidation followed by glucuronidation - limited by GI intolerance (nausea), P450 DDIs (CYP2D6 inhibitor, CYP3A4 substrate)
parathyroid hormone (PTH) - half life and synthesis
peptide hormone: 84 amino acid - produced in parathyroid gland - biosynthesized as a preprohormone (115 aa) and cleaved to a pro hormone (90 aa) and then to mature 84 aa secreted form. a 34 aa n-terminal fragment is also active - PTH has a short half life
parathyroid hormone (PTH) - release
released in response to low calcium - CaSR constitutively inhibits release - vitamin D also inhibits release - phosphate stimulates release: activate by losing suppression
sclerotin antagonist drug
romosozumab
romosozumab MOA
sclerostin blocker - humanized monoclonal Ab, binds and inhibits sclerostin (inhibits the inhibition of osteoblasts) - caused net bone deposition (net effect stronger than teriparatide)
RANKL
secreted by osteoblasts and binds to receptor in osteoclast precursors and stimulates differentiation into active -clasts - regulated by osteoprotegerin
osteoblasts
stimulate bone deposition
osteoclasts
stimulate bone resorption
teriparatide admin + BBW
subQ, short half life. BBW: may increase risk of osteosarcoma
teriparatide MOA
synthetic analog recombinant 1-34 PTH. it is an active N terminal fragment of PTH that acts as an agonist of the PTH-R
PTH based drugs
teriparatide abaloparatide