Agents Affecting Bone Mineral Homeostasis Flashcards
Drug List for Calcium Regulating Hormones Categories?
A. Parathyroid hormone B. Calcitonin C. Vitamin D agents D. Bisphosphonates E. Calcium Sensing Receptor Mimetics (calcimimetics) F. Various forms of calcium supplements G. Fluoride
Parathyroid hormone Drugs?
- teriparatide, hPTH(1-34)
2. full length hPTH(1-84)
Calcitonin Drugs?
- Synthetic human calcitonin hCT
2. Natural calcitonin from salmon
Vitamin D agents
- cholecalciferol = Vitamin D3 (fish liver oils)
- ergosterol
- ergocalciferol (after irradiation) = Vitamin D2
- 25-OH cholecalciferol
- calcipotriol
- dihydrotachysterol (reduced Vitamin D2 , DHT)
- paricalcitol
- 22-oxacalcitriol
- calcitriol
Bisphosphonates agents?
First Generation 1. etidronate Second Generation 2. alendronate 3. pamidronate 4. ibandronate Third Generation 5. risedronate 6. tiludronate 7. zoledronate
Calcium Sensing Receptor Mimetics (calcimimetics)
cinacalcet
Regulation of Calcium Homeostasis is controlled by 3 calcitropic hormones?
– Parathyroid hormone, PTH
– Calcitonin
– Calcitriol, the active form of Vitamin D
– Coordination of these 3 hormones controls the
concentration of Ca2+ in blood.
Pools of Calcium in the Body
Intracellular calcium: 100 nM to greater than 1 μM.
Calcium in blood and extracellular fluid: 1 mM.
Bone calcium: Vast majority of body calcium.
Plasma calcium is tightly regulated at:
2.5 mM = 5 mEq/L = 10 mg/dl
Components of Plasma Calcium:
– 40 % protein-bound (albumin)
– 10 % complexed (citrate, phosphate)
– 50 % diffusable, ionic calcium or “free
calcium” (Ca2+ = 1 mM)
Three major sites of action for blood calcium
regulation:
– Bone.
– Gastrointestinal tract.
– Kidney.
Bone. Calcium and phosphate in the blood are in
equilibrium with the?
Hydroxyapatite of bone. This allows resorption of bone calcium into blood.
Gastrointestinal tract. Total dietary intake of
calcium is?
About 1,000 mg per day. Excretion in feces is 900 mg per day.
Kidney. Excretion of calcium by the kidney is?
.
About 100 mg per day
Parathyroid Hormone (PTH) Functions to?
Increase plasma Ca2+
Parathyroid Hormone (PTH) is synthesized by and acts on?
Synthesized by parathyroid glands 3 major actions: – Increases bone resorption Ca2+ – Increases kidney reabsorption Ca2+ – Increases active form of Vitamin D
Calcium-Sensing Receptor are?
(G protein-coupled receptor)
Activation of the calcium sensor has two major signal-transducing effects:
- Activation of phospholipase C, which leads to generation of the second messengers diacylglycerol and inositol trisphosphate.
- Inhibition of adenylate cyclase, which suppresses intracellular concentration of cyclic AMP.
What allows both PTH- and Calcitoninsecreting cells to respond to extracellular calcium, and where is it found?
Calcium-Sensing Receptor (G protein-coupled receptor)
In both parathyroid glands and parafollicular cells of thyroid.
The calcium sensor is also expressed in?
Several cell types in the kidney, osteoblasts, a variety of hematopoietic cells in bone marrow, and in the
gastrointestinal mucosa.
Where is Calcitonin synthesized and what is its function and major actions?
Synthesized by parafolicular cells of thyroid and
Functions to decrease plasma Ca2+.
3 major actions:
– Decreases bone resorption
– Decreases kidney reabsorption
– Decreases active form of Vitamin D
In general, calcitonin opposes PTH actions.
Calcitonin also synthesized in other tissues?
Including the lung and intestinal tract.
Where is Calcitriol synthesized and what is its function?
The active form of Vitamin D and Functions to increase plasma Ca2+. Synthesized in skin and blood
Calcitriol most important physiological action?
Increases calcium uptake from GI
Calcitriol additional pharmacological actions include?
Increases kidney reabsorption (pharmacologic dose)
Increases bone resorption (pharmacologic dose)
This is paradoxical, but true, and increasing doses
promote even more resorption. Calcium can
reverse this effect.
Things that can cause a loss of Calcium Homeostasis?
Estrogen deficiency (postmenopausal osteoporosis) Glucocorticoid excess Growth hormone deficiency Insulin deficiency Primary hypoparathyroidism Cancer
Low Calcium is detected by?
Detected by parathyroid, causing increased
PTH synthesis.
Increased PTH then causes?
Increased absorption of calcium by kidney
Increased synthesis of Calcitriol
Increased resorption of bone
More calcitriol results in increased GI absorption of calcium
High Calcium detected by?
Detected by parafolicular cells of the thyroid, causing increased Calcitonin synthesis.
Increased Calcitonin then causes?
Decreased synthesis and secretion of PTH
Decreased resorption of bone (opposing PTH)
Shift to inactive form of Vitamin D
Decreased PTH causes increased excretion of calcium
Hypoparathyroidism diseases?
Autoimmune disease rare, more common from thyroid surgery or parathyroid cancer. Very serious but treatable
Bioengineered hPTH now available for treatment of?
Hypoparathyroidism
short half-life (peptide).
Hypoparathyroidism most common treaatment?
More commonly treated with Vitamin D, with or without dietary supplements of calcium.
What is Teriparatide and what is its mechanism?
hrPTH 1-34 directly stimulates bone formation
Excess endogenous PTH causes bone resorption
Exogenous PTH in low doses increases bone formation without stimulating resorption.
Teriparatide can be used for?
Important for women with osteoporosis after bisphosphonate therapy
The function of Fibroblast Growth Factor 23 (FGF23) and it is produced by?
FGF23 inhibits production of 1, 25-(OH)2D3.
Thus opposes PTH in kidney
Produced by osteoclasts and osteoblasts
Calcitonin Mechanism of Action
Binds to plasma membrane receptor
Decreases ruffled border surface area on osteoclasts
Not a global inhibitor of PTH
Has direct renal effects
Main Therapeutic uses of Calcitonin?
Hypercalcemia (as from Hyperparathyroidism)
Paget’s disease (bone remodeling disorder)
Now used in treatment of osteoporosis
Calcitonin very effective for?
- Short term treatment Hypercalcemia (as from Hyperparathyroidism). Prednisone can be used (takes 1 to 2 weeks)
- Paget’s disease (bone remodeling disorder)
- Now used as injection and nasal spray treatment for osteoporosis
With long-term use of Calcitonin?
Antibody development occurs (even with hCT)
Calcitriol is synthesised by and is the most important?
(1,25-Dihydroxy-D3)
Synthesized by the skin & Transported in the blood.
Most important calcium-regulating hormone and most important for therapeutics
Calcitriol Mechanism of Action
Stimulates Ca2+ and phosphate absorption in the small intestine
Induces synthesis of calbindin (family of Ca2+
binding proteins)
Binds to transcription factor to increase mRNA, protein synthesis
Has additional effects to increase uptake of Ca2+ from intestine.
Major Uses of Calcitriol in Therapeutics
Prophylaxis and cure of nutritional rickets
Treatment of metabolic rickets and osteomalacia
Treatment of hypoparathyroidism
Prevention and treatment of osteoporosis
What is Cholecalciferol and what is it found in?
= Vitamin D3
Found in fish liver oils. Takes effect in 12 to 24 hours.
Remains in lipid stores for months.
Ergosterol is similar to?
cholesterol
Ergocalciferol is?
(after irradiation) = Vitamin D2
25-OH Cholecalciferol is
Vitamin D2
What is Calcipotriol & what is it more effective than?
Analog of Calcitriol used in treatment of Psoriasis topical. More effective than glucocorticoids.
What is Dihydrotachysterol & how effective is it?
Reduced Vitamin D2 , (DHT). It is 0.002 times as active as calcitriol, but more effective in high doses.
Dihydrotachysterol (DHT) now used in treatment of?
OSTEOPOROSIS either by Injection and nasal spray
Paricalcitol reduces?
PTH secretion
22-Oxacalcitriol supresses?
PTH gene expression.
Bisphosphonates are?
Nonhydrolyzable analogs of inorganic pyrophosphate
Bisphosphonates work by & are used to treat?
Inhibitors of bone resorption
First used in Paget’s disease
Effective in treatment of osteoporosis
Two Bisphosphonates that are not effective orally?
The drugs etidronate and pamidronate are not effective in management of hypercalcemia but a 4 to 24 hr infusion is effective in lowering calcium for several weeks.
Etidronate, alendronate, & risedronate used in?
Paget’s disease
Alendronate used for?
Osteoporosis
Etidronate, alendronate, & risedronate are absorbed and taken with?
All are absorbed very poorly in the intestine & must be taken after an overnight fast with a full glass of water. No food for 30 minutes. Now have weekly dosage form.
Alendronate Potency?
10-100X
Risedronate Potency?
1,000-10,000
Serious complication of bisphosphonates therapy?
Osteonecrosis of the Jaw
80% of cases follow dental extraction.
Many cases are complicated by infection.
Mainly in patients with cancer after prolonged therapy.
Much more common with 3rd generation drugs.
Glucocorticoids are a common cause of?
Osteoporosis in adults by antagonize Ca uptake in intestine. Useful in reversing lymphoma-induced hypercalcemia
Estrogens are good for (blank), but increase the risk of (blank)?
Effective in preventing osteoporosis, but replacement therapy trials have shown increased risk of thrombosis.
Bisphosphonates have been demonstrated to prevent?
Cancer treatment induced bone loss.
Calcimimetics function?
Calcium Sensor Receptor Mimetics bind to the Calcium Sensor Receptor (CaSR)
Cinacalcet mechanism?
Binds allosterically to CaSR and allows PTH suppression at lower [Ca2+]. Effectively lowers circulating PTH.
Cinacalcet approved for?
Hyperparathyroidism in patients with parathyroid carcinoma.
Fluoride Potential agent in preventing?
Osteoporosis
Fluoride uses?
Long used for dental caries prevention
F – binds Calcium. Can be used to prevent blood clotting.
Fluoride Toxicity:
Osteosclerosis (hydroxyapatite replaced by fluoroapatite), mottled enamel (fluorosis).
