13 - Calcium/bone affecting agents

RANK RANKL interactions

RANKL is a ligand that binds RANK on osteoclasts to promote osteoclast maturation to boost bone resorption. Normally, osteoblasts secrete osteoprotegrin as a decoy receptor to bind RANKL. If RANKL is relatively greater than OPG, then bone resorption is favored

Canonical Wnt/Beta catenin signaling

In osteoblast lineage cells, Wnt, Frizzled, and LRP5/6 bind together to shut down something called GSK-3Beta which allows Beta-catenin to be produced and enter the nucleus to transcribe osteoblast maturation genes + increase OPG + decrease RANKL expression

How does sclerostin play a role in Wnt pathway?

It is secreted by osteocytes to block the triplet of Wnt, Frizzled, and FRP5/6 from binding, meaning that GSK-3Beta stays alive to keep on destroying B-catenin

Parathyroid hormone main actions(4)

1. Increases Ca2+ absorption

2. Increases phosphate excretion

3. Stimulates 1 alpha hydroxylase to turn 25 hydroxyvitamin D to 1,25 dihydroxyvitamin D which boosts both calcium and phosphate gut absorption

4. Will favor bone resorption if chronically elevated and leads to hypercal. but intermittent PTH will actually boost bone formation

Teriparatide

• What is it?

• Administration

• Purpose

• Recombinant PTH

• SC injection

• Utilizes the intermittent PTH effect to promote bone formation in osteoporosis

Abaloparatide

• What is it?

• Administration

• Purpose

• PTH related protein(PTHrP) analog

• SC injection

• Utilizes the intermittent effect of PTH to promote bone formation, but it’s even stronger than Teriparatide

How can vitamin D help with osteoporosis and CKD associated secondary hyperparathyroidism?

1. Osteoporosis: Vitamin D allows for calcium and phosphate to be absorbed, meaning that the body won’t have to release PTH to boost calcium amounts and resorb bone and weaken it further

2. CKD assc. secondary hyperPTH: In CKD, kidneys can’t turn 25 hydroxyvitamin D to 1,25 dihydroxyvitamin D, meaning that we can’t absorb calcium and excrete phosphate properly, so in response to low Ca2+, we release PTH chronically, leading to bone resorption excessively over time, so we give calcitriol directly to stop this

Calcitonin

• Usual function

• Treatments(2)

• Detects high serum calcium and inhibits osteoclasts to stop resorption, thus stopping more Ca2+ released into blood

• Treats acute hypercalcemia by reducing Ca2+ released and treats osteoporosis by reducing resorption(but not really that common)

Estrogen effect on bone

Favors bone formation via suppressing resorption

Raloxifene

• What is it?

• Function

• ADR

• An estrogen agonist

• Increases OPG, decreases RANKL, triggers osteoclast apoptosis → Prevents osteoporosis

• Venous thrombosis

Who should we use raloxifene on and why?

On post menopausal women because they have less estrogen and it also helps reduce breast cancer chance

How does prolonged use of glucocorticoids affect bone and how can we use glucocorticoids in treatment related to calcium?

• Can cause osteoporosis

• In cases of hypercalcemia due to malignancy

Bisphosphonate function and naming

• Triggers osteoclast apoptosis while also increasing OPG and decreasing RANKL

• -dronate

Alendronate, Pamidronate, Zoledronic acid

• Function

• Administration

• Purpose

• ADR

• Bisphosphonates, so inhibits bone resorption

• Aledronate is oral, Pamidronate and Zoledronic acid are IV

• To treat osteoporosis

• Esophagitis(oral) so we have to take it with water

Cinacalcet

• Drug type

• Function

• Uses(2)

• Calcimimetic

• Binds calcium sensing receptors at an allosteric site to boost sensitivity and trick the PTH gland in thinking that we have more calcium than we do, which lowers PTH

• Secondary hyperparathyroidism in end stage renal disease, Primary hyperparathyroidism

Calcium isn’t taken alone now, it’s taken with ___

Vitamin D(Calcitriol)

Calcium

• Reasons to take it orally and IV

• Oral calcium ADRs(4)

• IV calcium ADRs(2)

• Prevent osteoporosis(orally) treat severe hypocal(IV) and severe hyperK(IV) as a protective mechanism for the heart

• Oral: Constipation(because calcium slows motility), nephrolithiasis(because calcium forms kidney stones), hypercalcemia, cardiovascular risk(because it can calcify blood vessels?)

• IV: Tissue necrosis and arrhythmias(Shortens QT int.)

Denosumab

• What is it/how does it work?

• Administration

• Use cases

• Nuance

• Monoclonal antibody that binds RANKL(basically it acts like OPG) → shuts down resorption

• SC injection

• Osteoporosis

• Once it clears, RANKL is no longer suppressed and can rebound, so we have to give bisphosphonate

Romosozumab

• What is it/how does it work?

• Administration

• Use cases

• Contraindication(2)

• It is anti-sclerostin which allows for the Wnt LRP Frizzled complex to form and inhibit GSK 3 beta and allow for beta-catenin to proliferate

• SC injection

• Osteoporosis

• Myocardial infarction and stroke

Thiazide and furosemide relation to calcium

1. Thiazide: Acts on DCT and blocks NCC which keeps sodium in tubule, water follows → diuretic(If NCC is blocked, there’s less sodium in tubular cells, making a larger gradient where NCX on the basolateral side exchanges more sodium into cell and Ca2+ out to blood → Hypercalcemia in blood)

2. Furosemide: Acts on the TAL, blocks NKCC2 → more sodium in tubule, water follows → diuretic(Normally, NKCC2 reabsorption leads to K+ being put back out again via ROMK which makes the urine side more positively charged, which means Ca2+ wants to avoid the fellow positive charge and squeezes through cells and back into blood. But with NKCC2 blocked, there’s less potassium leak out, so Ca2+ stays in lumen → Hypocalcemia in blood)

Why do we get hyperphosphatemia in CKD and how do phosphate binders help?

• Because we are able to excrete less phosphate due to impaired renal cells, and so phosphate binders will stay in lumen and reduce the amount of phosphate we can absorb

What are the first line treatments if…

• Acute hypocalcemia

• Chronic hypocalcemia

• IV calcium

• Oral calcium

Summary of osteoporosis drug classes

• Teriparatide

• Abaloparatide

• Estrogen/SERM

• Calcitonin

• Romosozumab

• Denosumab

• Teriparatide: Bone forming via being a PTH analog for pulsatile dosing

• Abaloparatide: Bone forming, similar to teriparatide

• Estrogen/SERM: Anti-resorptive, decreases RANKL and increases OPG

• Calcitonin: Anti-resorptive, directly inhibits osteoclast but is weaker, used mostly in hypercal.

• Romosozumab: Bone forming via being anti-sclerostin and lets Wnt complex form

• Denosumab: Anti-resorptive by binding RANKL

First and second line osteoporosis treatment

• Bisphosphonate then denosumab

Post-menopausal osteoporosis treatment

• Raloxifene