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