Bisphosphonates (BP)
Outline
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BP Structure
BP History
Bone Remodeling
BP and Bone Remodeling
Use and Indications
BP Drugs
General Considerations
Bisphosphonates (BP)
A
C
B
Ionization
Bisphosphonates (BP)
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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)
Ca2+
BP complexed with Ca2+
Bone Remodeling
Breakdown
Formation
Bisphosphonates and Bone
Remodeling
 Promote Osteoclast Apoptosis
 Stabilize Bone Matrix
Bisphosphonates and Bone
Remodeling
2x
mevalonate pathway
B
A
Bone Breakdown
dimethylallyl
pyrophosphate
C
Osteoclast Formation
Bisphosponates
side effects ?
FPP = Farnesyl Pyrophosphate Synthase; HMG-CoA = 3-hydroxy-3-methyl-CoA
3-isopentenyl
pyrophosphate
FPP
2x
farnesyl pyrophosphate
Bisphosphonates and Bone
Remodeling
 localize at sites of bone resorption.
 2 phosphonates chelate exposed Ca2+ in the bone matrix
hydroxyapatite (i.e. bone)
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
Bisphosphonates
use and indications
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Osteoporosis
Glucocorticoid-induced osteoporosis
Paget’s disease
Cancer
 Hypercalcemia
 Osteolytic bone metastases
Bisphosphonates
Etidronate (Didronel®)
O
HO
OH
O
P
P
O
CH3 O
OH
 The first bisphosphonate
 synthesized 1897
 approved September 1977
 Not very potent. Relative potency = 1
 Poor oral bioavailability (only 3% absorbed)
 Used IV most commonly
Etidronate (Didronel®)
O
HO
OH
O
P
P
O
CH3 O
OH
 Uses
 Paget’s disease
 Heterotopic ossification
 Hypercalcemia from malignancy
 Postmenopausal osteoporosis (OP)
 Metabolism: Not metabolized
 ADR: Bone pain and tenderness
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
Clodronate (Bonefos®)
•
•
•
•
•
Absorption: 1-3%
Protein Binding: 2-36%
Metabolism: Not Metabolized
Half-life: 13 hours
Excretion: Fecal 97-99%
Tiludronate (Skelid®)
O
HO
H
P
O
P
S
O
O
OH
HO
OH
risedronate
O
P
P
O
CH2 O
OH
O
N
No amine
O
HO
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Cl
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
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Relative Potency = 10
OH
alendronate
O
P
P
O
O
OH
CH2CH2CH2NH 2
Pamidronate (Aredia®)
O
HO
OH
O
P
P
O
O
OH
CH2CH2NH2
 Note: ethylamine chain
 100-fold more potent than etidronate
 Used IV only
HO
etidronate
O
OH
O
P
P
O
CH3 O
OH
Pamidronate (Aredia®)
O
HO
OH
O
P
P
O
O
OH
CH2CH2NH2
 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
Pamidronate (Aredia®)
O
HO
OH
O
P
P
O
O
OH
CH2CH2NH2
 Unlabeled Uses
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Postmenopausal osteoporosis (OP)
Bone metastases in breast cancer
Hyperparathyroidism (hypercalcemia)
Glucocorticoid-induced osteoporosis (OP)
Immobilization-related hypercalcemia
Alendronate (Fosamax®)
O
HO
OH
O
P
P
O
O
OH
CH2CH2CH2NH 2
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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
Alendronate (Fosamax®)
O
HO
OH
O
P
P
O
O
OH
CH2CH2CH2NH 2
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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
Ibandronate (Boniva®)
O
HO
OH
O
P
P
O
CH2 O
OH
CH2
CH3
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N
CH 2CH 2CH 2CH 2CH 3
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
Ibandronate (Boniva®)
O
HO
OH
O
P
P
O
CH2 O
OH
CH2
CH3
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N
CH 2CH 2CH 2CH 2CH 3
Bioavailability: 0.6%
Protein Binding: >90%
Metabolism: Not Metabolized
Excretion: Renal
ADR: Bone, Joint and Muscle Pain
Risedronate (Actonel®)
O
HO
OH
O
P
P
O
CH2 O
OH
N
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Orally active
May have less incidence of gastric problems than alendronate and 4-fold
higher potency (relative potency=2000)
O
OH O
Use:
HO P
P OH
 Osteoporosis
O
O
 Glucocorticoid-induced osteoporosis
CH2CH2CH2NH 2
 Paget’s disease
alendronate
Risedronate (Actonel®)
O
HO
OH
P
P
O
CH2 O
N
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O
Bioavailability: 0.63%
Protein Binding: 24%
Metabolism: Not metabolized
Half-life: 1.5 h
Excretion: Renal and Fecal
OH
Zoledronate (Zometa®)
O
HO
OH
O
P
P
O
O
OH
N
N
Zoledronate (zoledronic acid)
 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
Zoledronate (Zometa®)
O
HO
OH
O
P
P
O
O
OH
N
N
Zoledronate (zoledronic acid)
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Protein Binding: 22%
Metabolism: Not Metabolized
Half-life: 146 hours
ADR: many, severe joint, bone and muscle pain
Bisphosphonates
Pharmacophore
O
HO
OH
O
P
P
O
O
~4 Å
OH
CH2CH2NH2
..N
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
Outline







BP Structure
BP History
Bone Remodeling
BP and Bone Remodeling
Use and Indications
BP Drugs
General Considerations