Cook - Bone Mineral Drugs

Question 1

Teriparatide (hPTH)

Answer 1

• Short half-life; INJECTABLE subcu (daily)
• Exogenous PTH in low doses directly stimulates bone formation w/o stimulating resorption
• Important for women with osteoporosis after bisphosphonate therapy
• May stimulate IGF-1
• AEs: hypercalcemia and hypercalciuria
• REMEMBER: excess endogenous PTH causes bone resorption

Question 2

What 3 calcitropic hormones control Ca in the body?

Answer 2

• PTH
• Calcitonin
• Calcitriol (active form of Vitamin D)
• Coordination of these 3 hormones controls Ca concentration in the blood

Question 3

Where is the Ca in the body? How much?

Answer 3

• Tightly regulated: 2.5mM = 5mEq/L = 10mg/dL
• IC: mostly in mito and ER (fluctuates greatly)
• Blood and ECF: 40% protein-bound, 10% complexed (citrate, phosphate), 50% diffusable, ionic, or free Ca
  1. Ionized, free Ca in this compartment almost always 1mM (concentration of phosphorous in the blood about the same)
• Bone: vast majority -> 99% in mineral phase, and 1% in pool that can rapidly exchange with EC Ca

Question 4

What are the 3 major sites of action for blood Ca regulation?

Answer 4

• BONE: Ca and phosphate in blood are in equilibrium w/hydroxyapatite of bone -> allows resorption of bone Ca into blood
• KIDNEY: excretion of Ca by kidney about 100mg/d
• GI TRACT: total dietary intake about 1,000mg/d, and 900mg/d excreted in feces

Question 5

Why do we only absorb about 10% of the Ca we consume each day?

Answer 5

• Low bioavailability bc absorbed in brush border of the duodenum only (via Vitamin D regulation)
• Not an active transport system (facilitated diffusion) because Ca moving down the conc gradient (from bowel to IC)
• If you get too much Ca in the cell, it will apoptose because mitochondria take it up
• Vitamin D stimulates production of calbindin inside the cell, which binds Ca to prevent cellular damage
• What is regulating Ca uptake is how much that cell can hold

Question 6

How much Ca and Vitamin D needs to be consumed each day?

Answer 6

This is controversial, and no one really agrees about these

Question 7

What is the primary action of Vitamin D?

Answer 7

Uptake of Ca

Question 8

Describe how PTH, Vit D, Calcitonin, and FGF23 affect Ca/P in bone, kidney, and GI tract (image).

Answer 8

Question 9

Briefly describe the actions of 1,25-OH₂D (image).

Answer 9

Question 10

What mediators are important in osteoclast/blast activity (image)?

Answer 10

Question 11

What are the 3 major actions of PTH?

Answer 11

– Synthesized by parathyroid gland, and functions to INC plasma Ca

1. INC bone resorption
2. INC kidney resorption
3. INC active form of Vit D

Question 12

How does the Ca-sensing receptor work?

Answer 12

• Activation has 2 major signal-transducing effects:
  1. Activation of phospholipase C, leading to generation of 2nd messengers: diacylglycerol and inositol triphosphate (G_Q)
  2. INH of adenylate cyclase, suppressing IC concentration of cAMP
• Allows both PTH and Calcitonin-secreting cells to respond to EC Ca
• In both parathyroid glands and parafollicular cells of thyroid
• Also expressed in several cell types in kidney, osteoblasts, and a variety of hematopoietic cells in bone marrow and GI mucosa

Question 13

Cinacalcet

Answer 13

• Activates CaSR by INC sensitivity (CALCIMIMETIC)
  1. Binds allosterically to CaSR and allows PTH suppression at lower Ca
• DEC PTH (effectively lowers circulating PTH)
• Allows parathyroid gland to stop PTH production at lower Ca levels
• This is for hyperparathyroidism (NOT osteoporosis) in pts with parathyroid carcinoma

Question 14

What are the 3 major actions of Calcitonin?

Answer 14

• Synthesized by parafollicular C cells of thyroid gland, and functions to DEC plasma Ca
  1. DEC bone resorption
  2. DEC kidney reabsorption
  3. DEC active form of Vit D
• In general, Calcitonin opposes PTH actions
• Also synthesized in lung and intestinal tract

Question 15

Calcitriol

Answer 15

• Active form of Vit D -> functions to INC plasma Ca
• Synthesized in skin and transported in blood
• Most important physiological action:
  1. INC Ca (+ phosphate) uptake from GI tract -> induces synthesis of Calbindin by binding to transcription factor to INC mRNA and protein synthesis (nuclear receptor)
• Other actions:
  1. INC kidney reabsorption (pharma dose)
  2. INC bone resorption (pharmacologic dose): paradoxical, but true, and INC dose promotes more resorption (Ca can reverse this effect)

Question 16

What are 6 things that can lead to a loss of Ca homeostasis?

Answer 16

• Estrogen deficiency (post-menopausal osteoporosis)
• Glucocorticoid excess
• Growth hormone deficiency
• Insulin deficiency
• Primary hyperparathyroidism
• Cancer

Question 17

What is the body’s response to low Ca?

Answer 17

• Detected by parathyroid, causing INC PTH synthesis, which causes:
  1. INC absorption of Ca by kidney
  2. INC synthesis of Calcitriol -> INC GI absorption of Ca
  3. INC resorption of bone

Question 18

What is the body’s response to high Ca?

Answer 18

• Detected by parafollicular C cells of thyroid, causing INC Calcitonin synthesis, which causes:
  1. DEC synthesis and secretion of PTH -> INC excretion of Ca
  2. DEC resorption of bone (opposing PTH)
  3. Shift to inactive form of Vitamin D

Question 19

How is PTH synthesized?

Answer 19

• Goes through Golgi (can’t take these orally bc they would be digested)

Question 20

What is the MOA of PTH?

Answer 20

• Binds plasma membrane receptor
• Activates adenylate cyclase -> INC cAMP
• cAMP activates protein kinases
• INC urinary cAMP, a test for parathyroid function

Question 21

Hypoparathyroidism? Tx?

Answer 21

• Autoimmune disease rare; more common from thyroid surgery or parathyroid cancer
• Very serious, but treatable
• TX: hPTH (Teriparatide): short half-life -> daily, injectable form
  1. More comonly treated with VIt D, with or w/o dietary Ca supplements

Question 22

Raloxifene

Answer 22

• Selective estrogen receptor modulator (SERM): for prevention and treatment of OSTEOPOROSIS in post-menopausal women (ORAL)
  1. Partial agonist effect on bone
• Antagonist effects in breast tissue, and reduces incidence of breast cancer in F at very high risk
• No estrogenic effects on endometrial tissue
• AEs: hot flushes (an antagonist effect) and INC risk of venous thrombosis (an agonist effect)

Question 23

Denosumab

Answer 23

• MAb to RANKL
• Subcu 60mg dose/6 mos
• Blocks stimulation of osteoclast formation by RANKL and DEC osteoporosis
• INC bone mass in pts w/breast or prostate cancer
• At least as effective as the bisphosphonates
• Could be INC risk of infection due to RANKL’s role in the immune system

Question 24

FGF-23

Answer 24

• INH production of 1,25-OH₂D₃, opposing PTH action in the kidney
• Produced by osteoclasts and blasts

Question 25

Synthesis of calcitonin (image)

Answer 25

Question 26

What is the MOA of Calcitonin?

Answer 26

- Binds to plasma mem receptor, and _DEC ruffled border surface area on osteoclasts_ 1. Osteoclasts start from monocytes, and merge (several nuclei), but one side of cell has ruffled, brush border that lays down bone, resorbs Ca - Not a global INH of PTH - Has direct renal effects

Question 27

Calcitonin therapeutics

Answer 27

- Acts through calcitonin receptors to INH resorption of bone - Used in tx of osteoporosis and Paget's -\> very effective for short-term tx 1. Ab devo with long-term use (even w/hCT) - Subcu injection or intranasal - Can get rhinitis with the nasal spray

Question 28

How is calcitriol synthesized (image)?

Answer 28

- He said we don't need to memorize all of this

Question 29

What are the major uses of Calcitriol in therapeutics?

Answer 29

- Prophylaxis and cure of nutritional ricketts - Treatment of metabolic ricketts and osteomalacia - Treatment of hypoparathyroidism - Prevention and tx of osteoporosis

Question 30

Cholecalciferol/Ergocalciferol

Answer 30

- **Cholecalciferol**: Vitamin D₃ 1. Found in fish and liver oils, and takes effect in 12 to 24 hours 2. Remains in lipid stores for months - **Ergocalciferol**: Vitamin D₂ - Regulate gene transcription via Vit D receptor to produce the effects of Calcitriol - Used to tx Vit D deficiency - Oral admin; require metabolism in liver and kidney to active forms - _AEs_: hypercalcemia, hyperphosphatemia, hypercalciuria

Question 31

Ergosterol

Answer 31

- Plant form of Vit D -\> similar to cholesterol

Question 32

Calcipotriol

Answer 32

- Analog of Calcitriol - Used in _tx of psoriasis_ -\> more effective than GCS

Question 33

Dihydrotachysterol

Answer 33

- Reduced Vit D₂, DHT - 0.002x as active as Calcitriol, but more effective in high doses - Now used in tx of OSTEOPOROSIS - Injection and nasal spray

Question 34

Paricalcitol

Answer 34

- Analog of Calcitriol used for mgmt of 2^o hyperPTH in pts with CKD - Reduces PTH via different mechanism than Cinacalcet (agonist for the Vit D receptor

Question 35

22-Oxacalcitriol

Answer 35

Suppresses PTH gene expression

Question 36

Bisphosphonates basics

Answer 36

- Nonhydrolyzable analogs of inorganic pyrophosphate -\> INH of bone resorption 1. Bind to bone, killing osteoclasts - First used in Paget's, but effective in tx of osteoporosis - Oral Etidronate and Pamidronate are NOT effective in mgmt of hypercalcemia, but 4-24 hr infusion effective in lowering Ca for several weeks - Can cause esophageal irritation and osteonecrosis of the jaw

Question 37

Which bisphosphonates are used for Paget's? Osteoporosis? How are they taken?

Answer 37

- _Paget's_: Etidronate, Alendronate, risedronate - _Osteoporosis_: Alendronate - All absorbed very poorly in intestine -\> must be taken after overnight fast with full glass of H₂O 1. No food for 30 minutes - Now have weekly dosage form (newer forms are more potent) - Most common side effect is **esophageal irritation** 1. Osteonecrosis of the jaw also possible

Question 38

Name the bisphosphonates (incl. gens).

Answer 38

- 1st gen: Etidronate (Paget's) - 2nd gen: 10-100x more potent 1. Pamidronate 2. Aledronate (osteoporosis, Paget's) 3. Ibandronate - 3rd gen: 1,000-10,000x more potent; used to prevent cancer metastases to bone 1. Risedronate (Paget's) 2. Zoledronate

Question 39

What is a serious complication of bisphosphonate therapy?

Answer 39

- Osteonecrosis of the jaw: 1. Bone under the teeth exposed, often painfully 2. Swelling, loosening of teeth 3. Surgical correction makes lesions worse 4. 80% of cases follow dental extraction 5. Many cases complicated by infection 6. Mainly in pts w/cancer after _prolonged tx_ 7. **Much more common w/3rd-gen drugs** - Some pts started having breaks in their femur (at the strongest point because this bone is very brittle; will not bend, but break) - Very effective drugs, but only for a certain period of time -\> can’t take these for more than 5 years

Question 40

How does bone mineral density change with menopause? Mediators (graph)?

Answer 40

- Estrogen: effective in preventing osteoporosis 1. Replacement therapy trials have shown INC risk of thrombosis

Question 41

How do GCS affect bone?

Answer 41

- Common cause of osteoporosis in adults - Antagonize Ca uptake in intestine - Useful in reversing lymphoma-induced hypercalcemia

Question 42

Plicamycin

Answer 42

- AB used for Paget's disease and hypercalcemia in the past - Don't think we need to know this one

Question 43

Strontium ranelate

Answer 43

- Used in Europe for osteoporosis (like a bisphosphonate) - Blocks differentiation of osteoclasts and promotes apoptosis - Also promotes bone formation - INC bone mineral density and DEC fractures - Don't think we need to know this one

Question 44

Fluoride

Answer 44

- Dental carries prevention: associated w/mottled enamel, but high resistance to decay - F- binds Ca, and can be used to prevent blood clotting - Potential agent in preventing osteoporosis - Toxicity: osteosclerosis (hydroxyapatite replaced by fluoroapatite), mottled enamel (fluorosis)