Calcium Therapeutics

Secondary Hyperparathyroidism: Renal-osteodystrophy

-Due to renal damage there is a high amount of PO4 in blood (binding to Ca) resulting in -Total calcium in the blood is a little elevated because we have the calcium that is bound to PO4. We usually excrete the PO4 and reabsorb the calcium but in renal disease we see the opposite (retention of PO4 and excretion of calcium)

Cushing's syndrome

-Due to tumor making glucocorticoid or patient on high dose of chronic glucocorticoid -Glucocorticoids affect calcium absorption in GI tract and calcium reabsorption in kidneys

Doxercalciferol

-For those with *renal disease* -Already comes with the OH on the 1st carbon -This drug doesn't cause an increase in uptake of calcium in the gut. -This drug suppresses PTH synthesis and secretion.

Calcium regulation - Blood calcium low in primary hyperparathyroidism

-Liver doesn't need PTH so you can still make 25-OH VitD3 in liver -PTH regulates the enzyme that adds the 1-OH in kidney, so we can't do this -Since we have no active vitamin D3, we can't uptake calcium from the gut -Normally our PTH would go to the bone and increase osteoclast activity but in this case we can't do that either -*Overall net effect is low blood calcium (hypocalcemia)*

Primary Hyperparathyroidism

-Most common cause of hypercalcemia is having a *tumor* in the Parathyroid gland -This is seen in older women -Solitary parathyroid adenoma

Teriparatide (Forteo)

-PTH analog -Chronic PTH as seen in primary and secondary hyperparathyroidism → results in bone resorption -If you give *PTH in pulse* you see *tremendous bone building* -Can't be taken orally because it is a peptide, it must be given as an injection

Hyperparathyroidism

-Pumps out a lot of unregulated PTH -PTH goes to the bone and activates osteoclasts to break down calcium causing *hypercalcemia* -This can lead to osteoporosis -This is why you don't give parathyroid hormone to just anyone because they can be hypercalcemic and have osteoporosis

Hypercalcemia due to autoimmunity

-Some autoimmunity results in bone resorption/liberating free calcium -When it comes to autoimmunity you want to *first treat initial problem*

Cinacalcet (Sensipar)

-Used to treat *secondary hyperparathyroidism* -Oral calcimimetic -Mimics calcium, thereby triggering the calcium sensing receptors in the parathyroid epithelium and turning off PTH secretion

Lumen

-Where calcium is absorbed from your food -Calcium is taken up here -Very little calcium is taken up by the *paracellular route*

2nd/3rd generation bisphosphonates

-ie: aminobisphosphonates. -Interfere with osteoclast cholesterol formation -Cells undergo apoptosis

Denosumab: In depth

1. Starts with a crack in bone 2. There's a signal that we need to repair the bone 3. Pre-osteoblasts get out of bloodstream 4. Osteoblasts replicate 5. Osteoblasts make RANK-L 6. Yellow thing is the osteoclast, which has a receptor for RANK-L. So osteoclasts binds to the osteoblasts, forming an activated osteoclast 7. Osteoclasts make a mega cell that has multiple nuclei and will digest the bone 8. Denosumab blocks the binding of pre-osteoclasts to the osteoblasts

Hypocalcemia therapeutics

1. Vitamin D with or without calcium (chronically) - Calcium salts such as carbonate, lactate, gluconate, phosphate, citrate or hydroxyapatite. 2. Calcium salts given by IV - Used in *sever hypoglycemia* (tetany) - Must be given slowly

Romosozumab

1. Bone is in good shape. no crack. "quiescent bone surface" secretes a factor called *sclerostin* - Resting bone: Sclerostin is produced 2. Sclerostin inhibits osteoclast activity and growth of osteoblasts so that you do not have bone turnover - The resting bone wants to stay rested... So it secretes sclerostin to not have bone turnover. but, this *suppresses the growth of osteoblasts* - So *Romosozumab* will target sclerostin and allow *osteoblasts to build bone* 3. Romososumab is an antibody *against sclerostin* that promotes *osteoblast growth* - Drug is currently in phase 3

Diseases of calcium homeostasis: Hypercalcemia

1. Hyperparathyroidism 2. Hyperthyroidism 3. Addison's disease 4. Tumors

Diseases of calcium homeostasis: Hypocalcemia

1. Malabsorption of Vitamin D 2. Calcium deficiency 3. Liver or renal disease 4. Surgical removal of parathyroid glands

Diseases of calcium homeostasis: Disorders that disrupt Ca++ deposition in bone

1. Osteoporosis 2. Paget's disease 3. Osteomalacia-rickets 4. Cushing's syndrome

Patients with renal osteodystrophy have: A. Reduced excretion of phosphates B. Increased reabsorption of calcium C. Reduced vitamin D D. High free blood calcium

Answer A: Reduced excretion of phosphates

Which of these is directly regulated by parathyroid hormone? A. Activation of calcium transporters in GI B. Activation of osteoclasts C. Thyroid hormone secretion D. Conversion of 7-dehydrocholesterol to cholecalciferol

Answer B: Activation of osteoclasts

Vitamin D stimulates: A. Formation of bone mass B. The excretion of calcium from the kidney tubule C. Uptake of Ca++ from the GI tract D. Synthesis of parathyroid hormone

Answer C: Uptake of Ca++ from the GI tract

Malabsorption of Vitamin D

Not absorbing enough vitamin D even though get enough from the diet

Metabolic estrogen effects: Bone

Osteoblasts and osteoclasts express estrogen receptors as well as androgen receptors

Parathyroid glands produce _____.

PTH

When you have sufficient vitamin D, it feeds back and suppresses _____ synthesis and secretion.

PTH

Calcium deficiency

Plain dietary deficiency of calcium

Why is thyroid *ablation* the preferred procedure compared to thyroid removal?

The iodine used in thyroid ablation is not taken up by the parathyroid glands or C cells.

There are 4 parathyroid glands that sit on the _____.

thyroid

Loop diuretics for acute Hypercalcemia

• *Inhibit Na+/K+/2Cl- transporter-action* • If this transporter is inhibited, there will be no K+ secretion • This means there won't be a membrane potential • So the reabsorption of Mg/Ca will be inhibited • So *Ca will be excreted in the urine*

Secondary hyperparathyroidism: How can we reverse this?

• Agents that reduce phosphorus absorption • Sevelamer - Phosphorus binding matrix - Inhibits both PO4 and cholesterol uptake - Binds to ions and stays in the lumen. It's not absorbed into systemic circulation, *it stays in the gut*.

Therapeutics for Osteoporosis

• Antiresorptive: Counters the breakdown of bone - Bisphosphonates - Estrogen, Selective estrogen receptor modulators (SERM) → agonist in bone. - Calcitonin → only works for a few days - Parathyroid hormone analog (Teriparatide) - Denosumab (antibody towards RANK-L) - Romosozumab (antibody towards sclerostin)

Paget's disease

• Bones have a disorganized structure. • More common in elderly - Doesn't usually occur before the age of 65 • Signs and symptoms: - Bone pain - Bone deformity - Elevated alkaline phosphatase • Treat with *bisphosphonates*

Other options for osteoporosis

• Combination therapy - Additive effects happen in combination therapy • Exercise - Weight bearing, attenuates bone loss - Astronauts have problems with their bones because they get no weight bearing exercise

Secondary Hyperparathyroidism (Renal Example)

• Defect is not in the gland • Instead of reabsorbing calcium, we're going to excrete calcium → we end up seeing low free calcium - A lot of calcium is protein bound or bound to phosphates; normally we have a regulatory control on the amount free v amount bound to protein or phosphates • Retain phosphates → normally phosphates are excreted but in renal disease our mechanisms fail to recognize free calcium because we have so much more phosphates

Secondary Hyperparathyroidism (Renal Example): Parathyroid gland regulation

• GPCR for calcium • We have sufficient free calcium, calcium binds to GPCR → Sends signal and we stop secreting PTH - In renal disease the regulator sees low free calcium because of excess PO4 → then it says I need to make more PTH and secrete it (*hyperparathyroidism*) - This PTH goes to the bone and causes the release of calcium. - In some patients the CaPO4 gets so high that it precipitates in their skin (hard nodules) - So we'd expect *hypercalcemia* (cause we're looking at free calcium) but *our body thinks it is hypocalcemia*

Therapeutics: Primary hyperparathyroidism (or other causes of severe hypercalcemia)

• Hypercalcemia can be life threatening - Often dehydrated: *Fluid resuscitation* (IV fluids) - Loop diuretics, *but* with IV fluids first - Calcitonin: Inhibits bone resorption and puts the high blood Ca into the bones - IV-bisphosphonates (eg. fosamax): Given IV here, as they absorb slowly when given orally

Secondary Hyperparathyroidism

• Low circulating calcium stimulates release of PTH as part of a normal response. • Why is the free calcium low? - *Chronic renal insufficiency*

Denosumab

• Monoclonal Antibody • Pre-osteoblasts make *Rank-L* - Rank-L binds to *Rank receptor* causing *osteoclasts* to resorb bones • *Denosumab* binds to RANK-L to stop stimulation of osteoclast activity/maturation

Thick ascending limb of the Loop of Henle: Normal Function

• Na+/K+/2Cl- transporter-action: Reabsorption here causes *K secretion* • Loss of K+ on the lumenal/urine side leaves the membrane on that side *hyperpolarized* • The loss of Cl- from the cell into the blood (on the blood membrane side) leaves the membrane on that side less negative • So *there's a positive potential on the lumenal side and a less negative potential in the blood side* • This potential drives reabsorption of Mg2+/Ca2+ through the paracellular junctions. • Thus, *Ca2+ is reabsorbed*

Primary hyperparathyroidism

-Defect in is the in the gland -Remove the gland to fix the problem

Addison's Disease

-*Adrenal insufficiency* -If you don't have a corticosteroid to bind and activate a mineralocorticoid receptor for sodium uptake you also don't take up water -This causes *blood volume contraction* -This means that the concentration of calcium will now be higher

Raloxifene and SERMs

-*Agonist* in bone -*Antagonist in breast* -Increases in bone density less than bisphosphonates -Reduced risk for fractures = to other agents. -Increase in hot flashes.

Calcitonin

-*Less effective* than other types of antiresorptives -Can't use it for a long time due to "*calcitonin escape*" (long term use results in GPCR desensitization) -Made by *C cells* in the thyroid -Treats osteoporosis but it is *not a prophylactic* -Protects against fractures as well as other but less increase in bone mass -*Nasal spray* -*Salmon calcitonin* is more stable and potent

Ergocalciferol

-*Vitamin D2* -From plant sterols -More likely to find this in OTC preparations -When people have chronic hypocalcemia, they can be given this vitamin D2 and their body is able to make enough of the active form

1,25-dihydroxycholecalciferol

-An active molecule -used for patients who have their entire parathyroid gland taken out, so if you maintain proper diet, this should be sufficient. -More of the chronic kind of hypocalcemia. -This comes in as an injection and also oral dosage. -Also known as *Calcitriol*

Tetany

-Basically your threshold for muscle activation is lowered when you have hypocalcemia and so the muscle contracts [calcium is not there to sit on Na channels so the Na channels open easier] -Emergency Situation -IV *must* be given slowly because you could have (fallen blood pressure) hypotension due to vasodilation (calcium stimulates the *release of nitric oxide* which can cause vasodilation) -Be careful we don't give a bolus which can cause *arrhythmias*

Calcitonin Escape

-Calcitonin will stop working after a few days -Makes it not viable as a chronic treatment

Acute Tetany: Calcium salts

-Calcium gluconate is preferred -Calcium chloride is not given for renal disease because it's an acidifying salt and blood pH will be impacted because kidneys won't be able to manage the ions/solutes

Vitamin D Upregulation: Calbindin-D

-Calcium is picked up here almost like a merry-go-round -Goes around until it's picked up by *PMCA1b* or *NCX1*

Kidney Disease

-Cholecalciferol must be activated by adding on 2 hydroxyl groups -Kidney adds *1 hydroxyl* -If your liver fails, you can't make active Vitamin D -This will lower the amount of calcium taken up in the GI tract

Liver Disease

-Cholecalciferol must be activated by adding on 2 hydroxyl groups -Liver adds *25 hydroxyl* -If your liver fails, you can't make active Vitamin D -This will lower the amount of calcium taken up in the GI tract

Renal osteodystrophy

-Creates imbalance between calcium and phosphates in the blood stream -Phosphate, being high in the blood binds to free calcium -Parathyroid senses low calcium and secretes PTH -PTH acts on bone, to release calcium -However, phosphates bind the calcium...etc.

1st generation bisphosphonates

-Cytotoxic ATP analogs -Interfere with energy production in the mitochondria -The drug is converted into a toxic metabolite -This happens inside of the osteoclasts, resulting in osteoclast apoptosis

Osteomalacia (in adults)

-Decalcification of bone -Called *rickets* in children -Sometimes due to lack of Vitamin D -Osteomalacia means *softening of bones*

Bisphosphonates: Info

-Decrease fracture risk by 30-60% -Increase bone mass by 6-10%. -Oral forms [cheapest] must be taken after a fast, on an empty stomach; wait 1 hour before a meal. *Can't lay down*

Glucocorticoids: Cause osteoporosis and lower blood calcium

-Decrease uptake of calcium in the -Increase excretion of calcium in the kidney -However, *glucocorticoids cannot be used for acute hypercalcemia* -Remember other things glucocorticoids do

Bisphosphonates: Results

A: osteoporotic bone B: Bone with some bisphosphonates C: Bone after 30 months of Bisphosphonates [gets denser, shown with the dark shades] the bone is denser but not everything is repaired there.

Tumors

Activates osteoclasts through *large secretion of cytokines*

Metabolic estrogen effects: Osteoclasts

Estrogen *decreases* the number and the activity of osteoclasts

1,25 dihydroxy D3 binds to its receptor (in the nucleus) to alter _____.

Gene expression

Metabolic estrogen effects: Osteoblasts

Has these effects

Zoledronic Acid

IV bisphosphonate that only has to be taken once a year

Removal of sections of the GI might cause what?

It could cause hypocalcemia because you might absorb less calcium.

What would be a reason that all four parathyroid glands are removed at once?

Thyroid removal

Vitamin D Upregulation: TRPV5/6

Transporter on the lumen side that calcium enters through

There are cells mixed in with thyroid epithelium called "C cells" which make _____.

calcitonin

We take vitamin D as a nutrient but it also behave as a _____.

hormone