Bisphosphonates (BP) http://en.wikipedia.org/wiki/Bisphosphonate http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667901/ http://www.duc.auburn.edu/~deruija/endo_bisphos.pdf

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

Bisphosphonates (BP) A B C Ionization http://en.wikipedia.org/wiki/Bisphosphonate http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667901/ http://www.duc.auburn.edu/~deruija/endo_bisphos.pdf

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 http://www.ismni.org/jmni/pdf/27/03FRANCIS.pdf 2 seminal papers in science http://en.wikipedia.org/wiki/Procter_%26_Gamble Ca2+ BP complexed with Ca2+

Bone Remodeling Breakdown Formation http://en.wikipedia.org/wiki/Osteocyte http://en.wikipedia.org/wiki/Osteoid http://en.wikipedia.org/wiki/Osteoblast http://en.wikipedia.org/wiki/Mesenchymal_stem_cells http://en.wikipedia.org/wiki/Osteoclast http://en.wikipedia.org/wiki/Macrophages http://en.wikipedia.org/wiki/Monocytes

Bisphosphonates and Bone Remodeling Promote Osteoclast Apoptosis Stabilize Bone Matrix

Bisphosphonates and Bone Remodeling FPP farnesyl pyrophosphate 2 x 3-isopentenyl pyrophosphate dimethylallyl pyrophosphate B mevalonate pathway A Bone Breakdown C Bisphosponates http://theoncologist.alphamedpress.org/content/9/suppl_4/3.full.pdf+html http://en.wikipedia.org/wiki/Zoledronic_acid http://en.wikipedia.org/wiki/Statins http://www.ncbi.nlm.nih.gov/pubmed/10934645 http://www.ncbi.nlm.nih.gov/pubmed/12510809 – statins reduce bone resorption in vitro, but not in vivo http://www.ncbi.nlm.nih.gov/pubmed/16278780 http://en.wikipedia.org/wiki/Clodronic_acid Osteoclast Formation side effects ? FPP = Farnesyl Pyrophosphate Synthase; HMG-CoA = 3-hydroxy-3-methyl-CoA

Bisphosphonates and Bone Remodeling localize at sites of bone resorption. 2 phosphonates chelate exposed Ca2+ in the bone matrix http://en.wikipedia.org/wiki/Osteoclast http://www.ismni.org/jmni/pdf/27/03FRANCIS.pdf http://en.wikipedia.org/wiki/Hydroxyapetite 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 Osteoporosis Glucocorticoid-induced osteoporosis Paget’s disease Cancer Hypercalcemia Osteolytic bone metastases http://en.wikipedia.org/wiki/Paget%27s_disease_of_bone http://en.wikipedia.org/wiki/Osteoporosis http://www.viking.ucla.edu/Scientific_American/Egils_Bones.htm http://www.natap.org/2009/HIV/042009_14.htm http://en.wikipedia.org/wiki/Hypercalcaemia http://www.ncbi.nlm.nih.gov/pubmed/14691012 http://joe.endocrinology-journals.org/content/175/1/155.full.pdf

Bisphosphonates http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667901/

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 http://www.rxlist.com/didronel-drug.htm http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=9544 http://www.medicinenet.com/etidronate/article.htm

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

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 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667901/ http://en.wikipedia.org/wiki/Clodronic_acid http://www.drugs.com/mmx/disodium-clodronate.html

Clodronate (Bonefos®) Absorption: 1-3% Protein Binding: 2-36% Metabolism: Not Metabolized Half-life: 13 hours Excretion: Fecal 97-99% http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667901/ http://en.wikipedia.org/wiki/Clodronic_acid http://www.drugs.com/mmx/disodium-clodronate.html

Tiludronate (Skelid®) risedronate alendronate No amine http://www.drugbank.ca/drugs/DB01133 http://www.ncbi.nlm.nih.gov/pubmed/8573422 http://www.rxlist.com/skelid-drug/clinical-pharmacology.htm 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

Pamidronate (Aredia®) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667901/ 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 http://www.rxlist.com/aredia-drug.htm

Pamidronate (Aredia®) Unlabeled Uses Postmenopausal osteoporosis (OP) Bone metastases in breast cancer Hyperparathyroidism (hypercalcemia) Glucocorticoid-induced osteoporosis (OP) Immobilization-related hypercalcemia http://en.wikipedia.org/wiki/Hyperparathyroidism leads to hypercalcaemia

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 http://www.rxlist.com/fosamax-drug.htm

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 http://en.wikipedia.org/wiki/Alendronic_acid http://www.ncbi.nlm.nih.gov/pubmed/8298197

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 http://www.rxlist.com/boniva-drug.htm http://en.wikipedia.org/wiki/Ibandronic_acid

Ibandronate (Boniva®) Bioavailability: 0.6% Protein Binding: >90% Metabolism: Not Metabolized Excretion: Renal ADR: Bone, Joint and Muscle Pain http://www.rxlist.com/boniva-drug.htm http://en.wikipedia.org/wiki/Ibandronic_acid

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®) OP = osteroperosis http://en.wikipedia.org/wiki/Zoledronic_acid http://link.springer.com/article/10.2165/00003495-200161060-00010 http://www.rxlist.com/zometa-drug/clinical-pharmacology.htm 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

Zoledronate (Zometa®) OP = osteroperosis http://en.wikipedia.org/wiki/Zoledronic_acid http://www.rxlist.com/zometa-side-effects-drug-center.htm Protein Binding: 22% Metabolism: Not Metabolized Half-life: 146 hours ADR: many, severe joint, bone and muscle pain

Bisphosphonates http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667901/

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

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 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667901/ (very good article)

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