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Bisphosphonates (BP)
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Outline
BP Structure BP History Bone Remodeling BP and Bone Remodeling Use and Indications BP Drugs General Considerations
Bisphosphonates (BP)
Ionization
A B
C
Bisphosphonates (BP)
Ca2+
BP complexed with Ca2+
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
Bone Remodeling
Breakdown
Formation
Bisphosphonates and Bone Remodeling
Promote Osteoclast Apoptosis Stabilize Bone Matrix
Bisphosphonates and Bone Remodeling
Bisphosponates
FPP = Farnesyl Pyrophosphate Synthase; HMG-CoA = 3-hydroxy-3-methyl-CoA
side effects ?
FPP
farnesyl pyrophosphate
2 x
2 x
3-isopentenyl pyrophosphatedimethylallyl pyrophosphate
AB
C
Ost
eocl
ast F
orm
atio
nB
one
Bre
akdo
wn
mevalonate pathway
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
Bisphosphonatesuse and indications
Osteoporosis Glucocorticoid-induced osteoporosis Paget’s disease Cancer
Hypercalcemia Osteolytic bone metastases
Bisphosphonates
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
Etidronate (Didronel®)
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®)
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
risedronate
No aminealendronate
Pamidronate (Aredia®)
Note: ethylamine chain 100-fold more potent than etidronate Used IV only
etidronate
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
Pamidronate (Aredia®)
Unlabeled Uses Postmenopausal osteoporosis (OP) Bone metastases in breast cancer Hyperparathyroidism (hypercalcemia) Glucocorticoid-induced osteoporosis (OP) Immobilization-related hypercalcemia
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
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
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
Ibandronate (Boniva®)
Bioavailability: 0.6% Protein Binding: >90% Metabolism: Not Metabolized Excretion: Renal ADR: Bone, Joint and Muscle Pain
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
Risedronate (Actonel®)
Bioavailability: 0.63% Protein Binding: 24% Metabolism: Not metabolized Half-life: 1.5 h Excretion: Renal and Fecal
Zoledronate (Zometa®)
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®)
Protein Binding: 22% Metabolism: Not Metabolized Half-life: 146 hours ADR: many, severe joint, bone and muscle pain
Bisphosphonates
Pharmacophore
N
~4 Å
..
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