Bisphosphonates (BP)

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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