1. Bisphosphonates (BP) http://en.wikipedia.org/wiki/Bisphosphonate

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3. Outline BP Structure BP History Bone Remodeling BP and Bone Remodeling
Use and Indications
BP Drugs
General Considerations

4. Bisphosphonates (BP) A B C Ionization

5. Bisphosphonates (BP) History 1897 Von Baeyer and Hoffman
1960 Blazer and Worms- Ca2+ and Mg2+ complexation
late 1960s Fleisch- reduced bone resorption in rats (2 x Science) and first clinical trials
1970s and 1980s- clinical development of Bisphosphonates (Procter and Gamble)
2009- Procter and Gamble prescription drug business sold to Warner Chilcott (formerly Galen)
etidronate
2 seminal papers in science
Ca2+
BP complexed with Ca2+

6. Bone Remodeling Breakdown Formation

7. Bisphosphonates and Bone Remodeling
Promote Osteoclast Apoptosis
Stabilize Bone Matrix

8. Bisphosphonates and Bone Remodeling
FPP
farnesyl pyrophosphate
2 x
3-isopentenyl pyrophosphate
dimethylallyl pyrophosphate B
mevalonate pathway A
Bone Breakdown C
Bisphosponates
– statins reduce bone resorption in vitro, but not in vivo
Osteoclast Formation
side effects ?
FPP = Farnesyl Pyrophosphate Synthase; HMG-CoA = 3-hydroxy-3-methyl-CoA

9. Bisphosphonates and Bone Remodeling
localize at sites of bone resorption.
2 phosphonates chelate exposed Ca2+ in the bone matrix
hydroxyapatite (i.e. bone)

10. Bisphosphonates and Bone Remodeling
Normal bone is formed on top of the compounds by osteoblasts
Incorporated into the matrix, but no pharmacological action
Continuously administered to maintain positive bone formation balance

11. Bisphosphonates use and indications
Osteoporosis
Glucocorticoid-induced osteoporosis
Paget’s disease
Cancer
Hypercalcemia
Osteolytic bone metastases

12. Bisphosphonates

13. Etidronate (Didronel®)
The first bisphosphonate
synthesized 1897
approved September 1977
Not very potent. Relative potency = 1
Poor oral bioavailability (only 3% absorbed)
Used IV most commonly

14. Etidronate (Didronel®)
Uses
Paget’s disease
Heterotopic ossification
Hypercalcemia from malignancy
Postmenopausal osteoporosis (OP)
Metabolism: Not metabolized
ADR: Bone pain and tenderness
– bone tissue forms outside of the skeleton

15. Clodronate (Bonefos®)
Marketed in Canada, Australia, UK, Italy (not U.S.)
Use: Postmenopausal OP, hyperparathyroidism, hypercalcemia in cancer
Analgesic (Italian Study)
deplete macrophages
Weak FPP synthase inhibition
Potency still weak, but 10-fold higher potency than etidronate

16. Clodronate (Bonefos®)
Absorption: 1-3%
Protein Binding: 2-36%
Metabolism: Not Metabolized
Half-life: 13 hours
Excretion: Fecal 97-99%

17. Tiludronate (Skelid®)
risedronate
alendronate
No amine
Oral Activity: Poor versus alendronate and risedronate
Use: Paget’s disease (400 mg/day)
Protein: 90% bound to serum albumin
Excretion: Kidneys
Metabolism: Not metabolized
Potency is weak similar to clodronate
Relative Potency = 10

18. Pamidronate (Aredia®)
Note: ethylamine chain
100-fold more potent than etidronate
Used IV only
etidronate

19. Pamidronate (Aredia®)
Uses
Moderate to severe hypercalcemia from malignancy w/wo bone metastases
Paget’s Disease
Osteolytic bone lesions from multiple myeloma
Metabolism: Not metabolized
ADR: Fever, Severe Joint, Bone Muscle Pain

20. Pamidronate (Aredia®)
Unlabeled Uses
Postmenopausal osteoporosis (OP)
Bone metastases in breast cancer
Hyperparathyroidism (hypercalcemia)
Glucocorticoid-induced osteoporosis (OP)
Immobilization-related hypercalcemia
leads to hypercalcaemia

21. Alendronate (Fosamax®)
Orally active
One carbon difference with pamidronate
5-fold higher potency
Esophageal erosions if taken incorrectly
i.e. Morning no lying down
weekly better, reduce incidence of erosions
BINOSTO® - effervescent tablet
citrate buffer solution
weekly

22. Alendronate (Fosamax®)
Uses
Osteoporosis in men and postmenopausal women
Paget’s disease
Glucocorticoid-induced osteoporosis
Metabolism: Not metabolized.
Elimination Half-Life: 126 months (> 10 years)
Excretion: Kidneys
ADR: Chest Pain, Osteonecrosis of the Jaw, Esophageal Ulceration

23. Ibandronate (Boniva®)
Orally active
3° amine, fairly lipophilic
2.5 mg daily and 150 mg once a month
Indicated for treatment and prevention of post-menopausal osteoporosis
2-fold higher potency than Alendronate
Relative potency = 1000

24. Ibandronate (Boniva®)
Bioavailability: 0.6%
Protein Binding: >90%
Metabolism: Not Metabolized
Excretion: Renal
ADR: Bone, Joint and Muscle Pain

25. Risedronate (Actonel®)
Orally active
May have less incidence of gastric problems than alendronate and 4-fold higher potency (relative potency=2000)
Use:
Osteoporosis
Glucocorticoid-induced osteoporosis
Paget’s disease
alendronate

26. Risedronate (Actonel®)
Bioavailability: 0.63%
Protein Binding: 24%
Metabolism: Not metabolized
Half-life: 1.5 h
Excretion: Renal and Fecal

27. Zoledronate (Zometa®)
OP = osteroperosis
Zoledronic acid does not inhibit human P450 enzymes in vitro (probably too water soluble)
IV only (over 15 minutes to reduce renal toxicity)
Use: Hypercalcemia from malignancy, OP, Paget’s disease
5-fold more potent than risedronate
Relative potency = 10,000
Reclast® once a year IV for OP

28. Zoledronate (Zometa®)
OP = osteroperosis
Protein Binding: 22%
Metabolism: Not Metabolized
Half-life: 146 hours
ADR: many, severe joint, bone and muscle pain

29. Bisphosphonates

30. Pharmacophore N
~4 Å ..
Angle of the nitrogen should be around ~15o from the center line

31. Bisphosphonates: General Considerations
Care needed
Side effects, Possible long half-life
Strong acids (pKa < 1)
will not chelate. Lose effectiveness.
Fairly high affinity for calcium and other di- and trivalent minerals ( Mg, Fe, Al, etc. )
Plain water
avoid water containing minerals (e.g. mineral, spring, tap and well water) because of chelation
Food affects absorption
empty stomach
(very good article)

32. Outline BP Structure BP History Bone Remodeling BP and Bone Remodeling
Use and Indications
BP Drugs
General Considerations