Alendronate Fosamax

Structural Formula Ball-and-Stick Model Space-filling Model po3h2

A = Carbon

= Hydrogen

= Oxygen

= Nilrogen

■ Phosphorous

Year of discovery: 1977; Year of introduction: 1995 (Merck); Drug category: Inhibitor of bone resorption/farnesyl pyrophosphate synthase inhibitor; Main uses: Prevention and treatment of osteoporosis and Paget's disease; Other brand names: Fosavance (with vitamin D); Related drugs: Etidronate (Didronel), Risedronate (Actonel), Ibandronate (Boniva), Zoledronic acid (Zometa).

Alendronate, a simple bisphosphonate structure, in which two phosphate fragments are linked by carbon, is widely used for the treatment and prevention of osteoporosis. Osteoporosis can be caused by aging, physical immobility, inflammation, lowered estrogen levels in postmenopausal women or extended use of glucocorticoids (e.g., prednisone). Alendronate has also been applied to the treatment of Paget's disease, a chronic condition, in which defective bone remodeling leads to soft, brittle and deformed bones.

Bisphosphonates are ionized, water-soluble compounds that mimic the pyrophosphate ion, (H0P02-0-P020H)2", which is produced biochemically in the body by several different processes (e.g., the conversion of ATP to AMP). In contrast to pyrophosphate, which is prone to cleavage in water with formation of phosphate ions, the bisphosphonates are resistant to hydrolysis. As with pyrophosphate, the bisphosphonates have an affinity for calcium ions, which is a major constituent of bone along with phosphate and collagen type proteins. Because of this affinity, bisphosphonates were investigated in the 1960s for the amelioration of atherosclerosis, which involves the deposition of calcium as a part of atherosclerotic plaque. However, bisphosphonates were found not to inhibit plaque formation. They were also studied unsuccessfully as inhibitors of dental plaque deposition.

Somewhat surprisingly, it was discovered that bisphosphonates are not only taken up by bone, but also inhibit bone resorption. Because bone is a dynamic structure in living organisms, constantly being dissolved (by cells called osteoclasts) and replaced (by cells called osteoblasts), this discovery led to the application of bisphosphonates to the treat ment and prevention of osteoporosis, and even for palliative treatment of metastatic bone cancer.

The antiresorptive potency of the first generation bisphosphonates such as etidronate (Didronel) was improved by adding a nitrogen-containing side chain to the bisphosphonate unit. This led to the development of alendronate (Fosamax), which achieved annual sales over $3 billion.1 Even more potent antiresorptive agents are now available including ibandronate (Boniva) and zoledronic acid (Zometa). Once-a-week dosing with alendronate or once a month dosing with ibandronate or a single annual infusion of zoledronic acid (5 mg over 15 min) are just as effective as once daily alendronate.

Zoledronic acid (Zometa™)

P03HNa HO-C-CHj Na HO3P Etidronate

>|TM, bisphosphonates

After administration, accumulate at the site of bone resorption, where they are taken up by osteoclasts. There is evidence that alendronate inhibits farnesyl pyrophosphate synthase (see below), 2 which inhibits signaling proteins that activate osteoclasts

1. Ann. N. Y. Acad. Sei. 2006, 1068, 367-401; 2. ChemMed-Chem 2006. 1, 267-273 (2F92); 3. Endocr. Rev. 1998, 19, 80-100; Refs. p. 106
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