B-28. Agents affecting bone mineral homeostatsis (calcium, vitamin D, parathyroid hormone, calcitonin, etc.). Pharmacotherapy of osteoporosis.

Question 1

3 main hormones controling bone mineral homeostasis

Answer 1

1. Vitamin D
2. Fibroblast Growth Factor 23
3. Parathryoid Hormone

Question 2

What is the process of Vitamin D activation starting with the skin?

Answer 2

7-dehydrocholesterol → cholecalciferol via UV in skin → calcifediol via liver 25-OHation → calcitriol (1,25-OH vitamin D) via kidney 1-OHation

Question 3

Vitamin D actions

Answer 3

• Vitamin D actions: overall ↑ serum Ca and Pi
  
  • ↑ Ca / Pi absorption from GI tract
  • ↑ RANKL production by osteoblasts
  • ↑ FGF-23 release from bone
  • ↓ Ca / Pi excretion from kidney
  • ↓ PTH production by parathyroid
  • Immune effects: receptors on lymphocytes and APCs regulate immune function; ↓ vitamin D is assoc. with autoimmunity + ↑ infections

Question 4

Fibroblast Growth Factor 23 is released from what? Actions?

Answer 4

Fibroblast Growth Factor 23 - released from osteocytes; overall ↓ serum Pi

• FGF-23 actions:
  
  • ↓ Pi reabsorption in kidney ( → ↑ excretion)
  • ↓ 1-α hydroxylase in kidney → ↓ vitamin D

Question 5

• Parathyroid hormone
  
  • Overall effect
  • Drug derivative
  • Physiological downregulation of PTH

Answer 5

Parathyroid Hormone - overall ↑ Ca and ↓ Pi in serum

• an 84 AA hormone with a 34 AA active peptide (active peptide available as teriparatide drug)
• on parathyroid cells senses serum calcium level: ↑ Ca⁺⁺ → ↓ PTH release

Question 6

PTH mainly stimulates

Answer 6

• PTH stimulates:
  
  • Osteoclast/-blast differentiation from monocytes / stem cells, respectively
  • production by osteoblasts, which binds RANK on osteoclasts, activating them and thus bone resorption + subsequent remodeling by osteoblasts
  • 1-α hydroxylase in kidney → ↑ vitamin D production
  • Phosphate excretion in kidney

Question 7

Osteoblast aslo produce what? What is it’s function? Short term PTH action leads to?

Answer 7

• Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor for RANKL which binds and inactivates it, balancing RANKL activation of osteoclasts
  
  • Short-term PTH action results in more OPG than RANKL action → more osteosynthesis; repeated short-term PTH → net bone mass increase

Question 8

Secondary hormones in bone homeostasis

Answer 8

1. Calcitonin
2. Glucocorticoids
3. Estrogens

Question 9

Calcitonin function? Is it more physiologically or pharmacologically important?

Answer 9

• Calcitonin
  
  • From thyroid parafollicular cells; results in ↓ serum Ca/Pi by inhibiting osteoclasts; long-term inhibition of both bone resorption + formation; less physiologically important, but can be used pharmacologically

Question 10

Glucocorticoids effects? Leads to long term?

Answer 10

Glucocorticoids - ↓ absorption + ↑ excretion of Ca → ↓ bone formation

Long-term → osteoporosis

Question 11

Estrogen effects on bones?

Answer 11

Estrogens- prevent post-menopausal bone loss via ↓ PTH action and ↑ calcitriol

Question 12

Non-nitrogen Bisphosphonate drugs (3)

Answer 12

1. Etidronate
2. Clodronate
3. Tiludronate

Question 13

Nitrogen Bisphosphonate drugs (5)

Answer 13

1. Zolendronate
2. Pamidronate
3. Alendronate
4. Ibandronate
5. Risedronate

Question 14

Bisphosphonates general MOA?

Answer 14

Bisphosphonates: most effective inhibitors of bone resorption

• MOA: pyrophosphate (PPi) analogs → bind to bone minerals, then taken up by + inhibit osteoclasts

Question 15

Non-nitrogen bisphosphonates MOA?

Nitrogen bisphosphonates MOA

Answer 15

• Non-nitrogen BPh: incorporate into ATP and have a cytotoxic effect
• Nitrogen BPh: inhibits farnesyl PPi synthase + thus the mevalonate pathway

Question 16

Main effect of bisphosphonates lead to? Nitrogen or non-nitrogen bisphosphonates are used more often?

Answer 16

• Lead to ↓ bone turnover, initial ↑ bone mineral density + later stabilized bone mineral homeostasis
• Nitrogen-containing drugs (ex: alendronate) used more now than earlier non-nitrogen Bphs (ex: etidronate, the first BPh)

Question 17

Indications of bisphosphonates

Answer 17

• Osteoporosis
• Hypercalcemia- via hyper-PTH or malignant lytic lesions

Question 18

Side effects of osteoporsis

Answer 18

• Side Effects:
  
  • Upper GI effects - reflux, esophagitis w/ ulcers (w/ oral admin; prevent w/ hydration + sit upright)
  • Mandibular Osteonecrosis - rare; mostly with IV admin
  • Hypocalcemia- via osteoclast inhibition; transient + more with IV admin

Question 19

• SERMs
  
  • Drug name?
  • MOA?
  • Indication?

Answer 19

• SERMs - Raloxifene
• MOA: estrogen agonist in bone; antagonist in breast, uterus
• Indication: use in osteoporosis patients not tolerant to BPhs

Question 20

Synthetic PTH

Answer 20

Teriparatide

Question 21

What is the antibody used in osteoporsis?

Answer 21

Denosumab

• MOA: anti-RANKL monoclonal antibody

Question 22

Calcimimet drug? MOA? Use?

Answer 22

• Cinacalcet
  
  • Activates calcium sensing receptor (CaSR)
  • In the parathryoid gland by activating CaSRs will inhibit PTH secretion
  • Clinical use: secondary hyperparathyroidism (in chronic kidney disease), parathryoid carcinoma
  • CaSR antagonist might be used to stimulate intermittent PTH secretion in osteoporosis

Question 23

Nonhormonal agents affecting bone mineral homeostasis (4)

Answer 23

1. Cinacalcet
2. Thiazide diuretics
3. Fluoride
4. Strontium ranelate

Question 24

Thiazide diuretics effect in bone homestsis

Answer 24

Thiazide diuretics - ↑ PTH-mediated Ca resorption; ↓ hypercalciuria / stones

Question 25

Fluoride diuretics effect in bone homestsis

Answer 25

**Fluoride** - stabilizes hydroxyapatite; promotes bone growth + improves Ca balance (but no ↓ in fractures!)

Question 26

Strontium Ranelate in bone homeostasis

Answer 26

**Strontium Ranelate** - ↓ bone resorption via osteoclast apoptosis → ↑ bone formation (EU, not US)

Question 27

Calcitonin MOA and Indication

Answer 27

**Calcitonin** * MOA: directly inhibits osteoclasts → ↓ resorption → ↓ serum Ca; also ↑ renal Ca excretion * Indication: * **Osteoporosis**- 2nd line to ↓ resorption * **Severe hypercalcemia** - as in malignant lytic bone lesions * **Paget’s disease** - * _Side Effects_: * Hypocalcemia

Question 28

Endogenous drug given in osteoporosis due to deficiency in most people?

Answer 28

Vitamin D

Question 29

Osteoporosis definition

Answer 29

* Definition: a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture

Question 30

Bone T score

Answer 30

* 1 SD: normal * -1 – 2.5 SD: osteopenia * Below -2.5 SD: osteoporosis * Below -2.5 SD + at least one vertebral fracture: severe osteoporosis

Question 31

Risk factors for osteoporosis

Answer 31

1. **Genetic factors** 2. **Environmental factors**: smoking, alcohol, physical inactivity, thin habitus, low body weight \< 58kg, low calcium intake and little exposure to sun light 3. **Menstrual status**: meonpause \< 45 year, previous amenorrhea 4. **Drug therapy**: glucocorticoids, antiepileptic drugs (phenytoin), excessive substitution therapy with thyroxine, hydrocortisone, anticoagulants, heparin, dicoumarin derivatives 5. **Endocrine (hyperparathyroidism, thyretoxicosis), GI (malabsorption), rheumatologic, hematologic disease**

Question 32

Treatment strategy of postmenopausal osteoporosis. Main point?

Answer 32

* The main direction of therapy is the inhibition of the increased osteoclast activity * A substance truly stimulating bone formation did not reach yet the clinical practice

Question 34

Treatment options for osteoporosis

Answer 34

1. Hormone substitution therapy (for women) 2. Selective estrogen receptor modulators (SERM) (for women) 3. Denosumab 4. Bisphosphonates 5. Parathyroid hormone (PTH 1-34=Teriparatide) 6. Vitamin D intake 7. Thiazide diuretics

Question 35

* Hormone substitution therapy * What does menopause do to the bones? * How does hormone substitution therapy work? * What risks are increased iwth treatment?

Answer 35

* Hormone substitution therapy * The menopause induces accelerated bone loss the first 4-5 years, which is followed by a linear decrease, above 75 years of age bone loss becomes accelerated again * Hormone replacement therapy (HRT) increases BMD, decreased bone turnover and the number of bone fractures * It is effective until administered * Estrogen (combined with progestin if the uterus is intact) increases risk of breast cancer, may enhance the risk of cardiovascular disease Prolonged HRT is not recommended anymore

Question 36

Selective estrogen receptor modulators (SERM) drugs

Answer 36

1. Raloxifen 2. Tamoxifen

Question 37

SERMs effect

Answer 37

* Act on the estrogen receptors * In some organs they act as agonists, while in others as antagonists * In the treatment of osteoporosis those SERMs have clinical importance which are * Agonists: in the bones * Antagonists: in the breast and uterus

Question 38

Do SERMs increase the cardiovascular risk?

Answer 38

* SERMs do not increase the overall cardiovascular risk but increase significantly the risk of thromboembolism

Question 39

Raloxifen * Efficacy? * Risks? * Protects against what kind of fractures?

Answer 39

* Efficacy on the bones is equal to that of estrogen * The thickness of endometrium, breast pain, vaginal bleeding, hot flushes, did not increase compared with placebo * Imposes the same increased risk for venous thromboembolism as estrogen * Protects against spine fractures but not hip fractures (unlike bisphosphonates, denosumab and teriparatide protect against both)

Question 40

Parathyroid hormone drug? MOA?

Answer 40

* Teriparatide is the first 34 amino acids of the PTH * PTH stimulates both bone resorption and bone formation

Question 41

Continuous and intermittent treatment difference and similarities?

Answer 41

* Continuous and intermittent treatment stimulates bone formation equally, however: * Continuous treatment leads to persistent increase of PTH level and relatively larger bone resoprtion * Daily small doses lead to minimal bone resoprtion and substantial bone formation

Question 42

* Vitamin D drugs

Answer 42

* Vitamin D intake * Vitamin D3 (cholecalciferol) * Vitamin D2 (ergocalciferol) * Active forms of vitamin D * a-hydroxyvitamin D3 (1a-hydroxycalciferol) 1,25-dihydroxyvitamin D3 (1,25 dihydroxycholecalciferol)