Drugs acting on bone metabolism

Question 1

Describe what happens in bone remodelling?

Answer 1

• Cycle commences with Osteoclast RECRUITMENT by CYTOKINES e.g.IL-6
• OC adhere to trabecular bone, dig cowslip lacunae by secreting Hydrogen ions and proteolytic enzymes
• > LIBERATION of factors embedded in bone e.g. insulin like growth factor
• ISGF -> activate OB which have been primed to develop into precursor cells by parathyroid hormone and 1,25 dihydroxycholecalciferol
• OB invade pits , synethise and secrete OSTEOID, the organic matrix of bone
• the OSTEOID is then mineralised i.e. complex calcium phosphate crystals (hydroxyapatite) are deposited.
• OB and precursors secrete IGF-1 and IL-6 which become embedded in the bone and recruit OC.

Question 2

What type of drug are BISPHOSONATES?

Answer 2

• A class of drug characterised by a P-C-P BACKBONE RESISTANCE TO PHOSPHATASES

Question 3

Can you draw the chemical formulae for bisphosphonates?

Answer 3

OH R₁ OH

  I                 I                 I

O= P————-C————–P ===O

   |                  |                |

 OH             R<sub>2 </sub>             OH

Question 4

What secures the longevity of the bisphosphonates when given?

Answer 4

• The fact that nothing can metabolise the P-C-P backbone

Question 5

How do bisphosphonates act?

Answer 5

• By DIRECTLY STABILIZING THE HYDROXYAPATITE CRYSTAL -> making it MORE RESISTANT TO RESORPTION

Question 6

What is important about AMINOBISPHOSPHONATES?

Can you name some?

Answer 6

• They have MORE SPECIFIC OSTEOCLASTIC ACTIVITY than early bisphosphonates such as etidronate.
• examples include- PAMIDRONATE, ALENDRONATE

Question 7

How do AMINOBISPHOSPHONATES act? What does this do?

Answer 7

• By DIRECTLY INHIBITING THE ACTION OF OSTEOCLASTS via the Mevalonate pathway inhibiting FARNESYL PYROPHOSPHATE SYNTHASE. -> PREVENTS PRENYLATION ( formation of the brush border) and FUNCTIONING of SIGNALLING PROTEINS required for OC formation

Question 8

How are bisphosphonates given?

Answer 8

• Orally ( poorly absorbed) or parentally
• 50% of dose accumulates at sites of bone mineralisation, where it remains until bone is absorbed

Question 9

What is the use of bisphosphonates?

Answer 9

• tx POSTMENOPAUSE and GLUCORTICOID induced OSTEOPOROSIS
• PAGET’S DISEASE
• MALIGNANT HYPERCALCAEMIA
• OSTEOGENESIS IMPERFECTA
• FIBROUS DYSPLASIA

Question 10

What are the adverse effects of bisphosphonates?

Answer 10

• 1)ORAL intake must be on an EMPTY STOMACH-> GASTRIC PAIN and OESPHAGITIS
• 2) TRANSIENT LEUCOPENIA
• 3) SCLERITIS

Question 11

What are vitamin D analogue used for?

Answer 11

• metabolic bone disease

Question 12

Name some vitamin D derivatives ?

Answer 12

• Vitamin D3 - CHOLECALCIFEROL
  
  • formed in skin from dehydrocholesterol by UV light
• Vitamin D2- Ergocalciferol( calciferol)
  
  • formed in plants by UV radiation.
  • used to tx rickets, osteomalacia, and vit d deficiency
• 25 -OH- vitamin D3- aka calciferol
  
  • main storage form of vitamin D
• 1,25-OH- vitamin D3- aka calcitrol
  
  • most potent metabolite in regulating plasma calcium. used to tx renal osteodystrophy
• 1alpha -OH- cholecalciferol- aka alfocalcidol-
  
  • synthetic derivative of vitamin D3
  • undergoes hepatic25- hydroxylation to calciferol.
  • used to tx renal osteodystrophy ( increased calcitriol)

Question 13

what are the side effects of vitamin D Dervivatives?

Answer 13

• Xs intake -> HYPERCALCAEMIA
• Increased requirements for vitamin D if on anti convulsive medication - e.g. Phenytoin

Question 14

What is Calcitonin?

Answer 14

• calcitonin is a 32 amino acid peptide
• secreted by the PARAFOLLICULAR C CELLS of the thyroid gland

Question 15

When is calcitonin secreted ? When is it inhibited?

Answer 15

• In response to ELEVATED SERUM CALCIUM
• Inhibited by DECREASED SERUM CALCIUM

Question 16

What is Calcitonin’s function?

Answer 16

• Directs INHIBITS OSTEOCLASTS -> DECREASE in CALCIUM

Question 17

What preparations can the calcitonin derivates come in ?

Answer 17

• natural - porcine = calcitonin
• synthetic- salmon-= salcalcitonin

Question 18

How is calcitonin given?

Answer 18

• subcutanously
• im injection
• intranasally

Question 19

What are calcitonin’s clinical use?

Answer 19

• First line for PAGET’S disease to reduce pain and reduce neurologically complications
• MALIGNANT HYPERCALCAEMIA
• **POST MENOPAUSE **
• GLUCOCORTICAL INDUCED OSTEOPOROSIS

Question 20

What are calcitonin’s side effects?

Answer 20

• Nausea and Vomiting
• Facial flushing
• Tingling sensation in the hands
• Unpleasant taste in the mouth
• Increased risk of stress fractures

Question 21

What is PARATHYROID HORMONE? example ?

Answer 21

• Is an ANABOLIC agent used in the treatment of OSTEOPOROSIS Tetriparatide ( PTH)

Question 22

How can PTH be given?

Answer 22

• the 1-34 portion of the 84 amino-acid- peptide can be given by subcutaneous injection

Question 23

What is the anabolic effect of PTH?

Answer 23

• INCREASED BONE FORMATION
• IMPROVED MICROARCHITECTURE of bone

Question 24

What does Tetriparatide work on?

Answer 24

• the periosteal surface of bone, but it also causes endosteal resorption,
• INCREASING the diameter of bone and it BENDING & TORSIONAL STRENGTH BY INCREASING THEIR 2nd and POLAR MOMENTS OF INERTIA

Question 25

What also does PTH activate?

Answer 25

• Bone lining cells and osteoblasts partially if intermittent stimulation is used
• Osteoclasts are stimulated with continuous stimulation by teriparatide

Question 26

What are the concerns with Tetriparatide?

Answer 26

• increased osteosarcoma in rats
• subtrochanteric femoral fractures
• leg cramps
• dizziness

Question 27

What is Strontium?

Answer 27

• group 2 , period 5 element, with atomic no 38
• similar to calcium

Question 28

Where does it have a clinical role?

Answer 28

• In early tx of osteoporosis. given orally

Question 29

What are its effects ?

Answer 29

• INCREASE BONE FORMATION- anabolic effect
• DECREASE BONE RESORPTION- anticatabolic effect