Osteoporosis - Sharma

What are the physiological effects of PTH in regulating calcium homeostasis? (Bone)

1. High PTH increases the expression and secretion of RANKL from osteoblasts

2. RANKL promotes osteoclast formation → bone reabsorption and calcium release (short term)

What are the physiological effects of PTH in regulating calcium homeostasis? (Kidney)

Decreases phosphate transporter (NaPi-IIa) expression in distal tubular cells and thus reduces phosphate reuptake

Increases calcitriol synthesis by increasing CYP27B1 activity

What are the physiological effects of PTH in regulating calcium homeostasis? (Vitamin D dependent indirect effects)

Calcitriol causes increased calcium reabsorption from tubules and absorption of dietary calcium from small intestine

Overall, PTH affects homeostasis by [__] plasma calcium and [__] plasma phosphate.

Increasing, decreasing

What are the physiological effects of calcitonin in regulating calcium homeostasis?

1. Acts on G protein receptors

2. Increases cAMP → cAMP inhibits osteoclast activity

3. Decrease in plasma calcium

4. inhibits bone reabsorption

5. Physiological antagonist to PTH

What are the physiological effects of vitamin D in regulating calcium homeostasis? (Bone)

1. Osteoblasts (not osteoclasts) have vit D receptors

2. Calcitriol acts on osteoblasts to produce cytokines that activates osteoclasts to reabsorb calcium from bone matrix. Promotes osteoblasts to deposit calcium

3. Net effect of vit D = bone mobilizing action

What are the physiological effects of vitamin D in regulating calcium homeostasis? (Kidney & Intestine)

Kidney: increases calcium reabsorption from renal tubules

Intestine: increases absorption of calcium from intestinal epithelium

Both:

• Increases expression of calcium binding protein → calbindin

• Increases expression of TRPV ion channels

What is osteoporosis?

Skeletal system disease characterized by low bone mass and micro architectural disruption.

Results in fracture with minimal trauma

WHO definition: bone density below -2.5 standard deviation of young healthy adult of the same sex

What are the primary causes of osteoporosis?

1. Aging

2. Possibly menopause and andropause

What are the secondary causes of osteoporosis?

1. Endocrine abnormalities

2. Liver and Kidney diseases

3. Malignancies

4. Malnutrition

5. GI diseases

6. Genetic diseases

What endocrine abnormalities often cause secondary osteoporosis?

1. Hyperthyroidism

2. Hyperparathyroidism

3. Adrenal disorders

4. Pituitary disorders

How do liver and kidney diseases cause secondary osteoporosis?

impairs vit D synthesis

What GI diseases can causes secondary osteoporosis? How do they cause it?

1. Celiac disease, Crohn’s disease

2. Impairs calcium absorption

What genetic diseases can cause secondary osteoporosis?

1. Osteogenic imperfect

2. Turner’s syndrome

3. Down syndrome

4. Marfan’s syndrome

What are the drugs used in treatment of osteoporosis?

Antiresorptive (decrease bone resorption)

1. Bisphosphonates

2. Denosumab

3. Estrogen/progestins & SERMs

4. Calcitonin

Anabolic (stimulate bone formation)

1. PTH analogs

2. Romosozumab

What is the MOA bisphosphonates?

MOA:

1. Binds to bone mineral and gets deposited on bone surface

2. Enter into osteoclasts during bone resorption process

3. Non-nitrogen containing (1st gen) gets converted into non-hydrolysable ATP and induce osteoclast apoptosis

4. Nitrogen containing BPs inhibit farnesyl pyrophosphate synthase and inhibit cholesterol synthesis (which is essential for osteoclast survival) and also induces osteoclast apoptosis

What is the SAR bisphosphonates?

SAR:

1. 1st Gen (clodronate, etidronate, tiludronate): minimally modified side chain or a chlorophenol group (Least Potent)

2. 2nd Gen (pamidronate, alendronate, ibandronate): contain a nitrogen containing alkyl side chain (10-100 times more potent)

3. 3rd Gen (resedronate, zolendronate): contain a nitrogen containing heterocyclic ring (10,000 times more potent) → FDA approved

What is the MOA of denosumab?

Reduces the binding of RANKL to RANK on osteoclast precursors cell surface and blocks osteoclast formation and activation

What is the SAR of denosumab?

Monoclonal antibody against RANKL

What is the MOA of estrogen?

Activation of estrogen receptors:

1. Decreases production of RANKL

2. Increases the production of OPG (reduces osteoclastogenesis)

3. Decreases production of several cytokines which are potent stimulators of osteoclast formation (IL1 & 6, TNF-α, and M-CSF)

4. Increases TGF-α and FAS-FAS ligand, which increases osteoclast

   apoptosis

5. Net result = decrease in bone resorption

What is the MOA of SERMs (raloxifene)?

1. Binds to estrogen receptors

2. Produces agonistic effect in bones, but antagonistic effect in breast and uterus (less risk of breast cancer)

3. AKA mixed estrogen receptor agonist/antagonist

What is the MOA of calcitonin?

Activates G protein receptors in osteoclasts → increases cAMP to inhibit osteoclast motility and activity → inhibition of bone resportion

What is the MOA of PTH analogs? (teriparatide & abaloparatide)

With intermittent/low doses: promotes osteoblast multiplication and bone formation

Causes osteoblasts to release RANKL to act on osteoclast to increase bone resorption and reform new and stronger bone

What is the MOA of romosozumab?

1. Sclerostin is a soluble glycoprotein secreted by osteocytes

2. Sclerostin inhibits osteoblast formation and mineralization

3. Romosozumab binds to sclerostin → increases osteoblast functions and bone mass