Fosamax

Mild-mannered industrial chemicals turn super-pharmaceuticals in 30-year "overnight" success story. That, in a nutshell, is the tale of bisphosphonates, which began life in the mid-1800s for various industrial applications, including as treatments to prevent buildup of calcium carbonate scale in water canals and containers.

In the 1960s, however, research into the world of phosphates opened the way to bisphosphonates being developed for human health applications.

Work by Herbert Fleisch, at the University of Berne, Switzerland, found that blood and urine contained substances that prevented formation of calcium phosphate crystal formation and dissolution. He identified these substances as pyrophosphates, well-known for their inhibitory effect on calcium carbonate deposition and for their use as a water softener.

And although it took roughly 30 years from Fleisch's findings on pyrophosphates to be translated into commercial success for the related family of bisphosphonates, the result has been remarkable. The bisphosphonates were the first oral pharmaceuticals able to prevent bone destruction by inhibiting the ability of osteoclasts to break down bone. That action decreases the devastating effects of osteoporosis and other bone diseases.

Fleisch suggested that pyrophosphates were an important regulator of bone mineralization and demineralization, and he hypothesized that they could be used as a drug to prevent abnormal calcification and excessive bone destruction. But there was a major problem: The compounds were quickly broken down in the body by enzymes and did not work adequately.

SO HE LOOKED for pyrophosphate analogs that would be similar in structure and not be broken down so easily. A collaboration between Fleisch and researchers in the dental group of Procter & Gamble proved the hypothesis: The bisphosphonates blocked calcification as well as bone destruction.

Fleisch's first oral presentation on the activity of bisphosphonates was in 1968, with publication in Science the following year.

The next several decades, he recalls, he spent "trying to convince clinicians that these compounds could be useful." At some point, he suggested to researchers at Merck that they study Fosamax, a compound he had helped to develop at a small Italian pharmaceutical company, Gentili.

"That was the start of Fosamax at Merck," he observes. "Then, the moment people knew Merck was working on it, everyone else jumped on the bisphosphonate bandwagon." Some work focused on use of the product as an injectable treatment against bone tumors--the route explored by Novartis, for example.

Merck's Fosamax gained market clearance in 1996 as a tablet taken once a day. Subsequent formulations of Fosamax, and competing bisphosphonate molecules from a host of pharmaceutical giants around the world, have brought dosage time down to once a week.

That's an important benefit, as the compounds can have unpleasant gastrointensinal side effects. To help minimize side effects while maximizing absorption, patients are directed to take the medication first thing in the morning, on an empty stomach, with eight ounces of water. Patients must remain upright for another 30 minutes to minimize the chance of the pill lodging in the esophagus, causing gastric irritation, before having anything to eat or drink.

In a further step toward convenience, a once-a-month version of ibandronate, developed by Roche, was given approval by the Food & Drug Administration in March. It will be copromoted, as Boniva, by GlaxoSmithKline.

First synthesized in December 1988 by Fleisch in collaboration with the German drug company Boehringer Mannheim, ibandronate became a Roche compound when the Swiss giant acquired the German firm in 1997. At that time, oncology and bone metabolism were already two strategic areas for R&D at Roche, company researchers point out.

Bone is constantly being rebuilt, going through a balanced process of bone breakdown and new bone formation, Roche chemists note. After years of bone loss, bones become brittle and more likely to break.

It is a particular problem for women: After menopause, the balance is disrupted and women lose bone faster than it is rebuilt. But it is not solely a women's problem. In fact, according to the National Osteoporosis Foundation, one in two women and one in four men over the age of 50 will have an osteoporosis-related fracture sometime in the course of their remaining lifetime.

According to the National Osteoporosis Foundation, 44 million Americans over the age of 50 are affected by or at risk for osteoporosis--55% of that age group. In 2002, the condition cost the U.S. more than $18 billion, and the figure rises each year. And the International Osteoporosis Foundation estimates that the disease costs national treasuries in the European Union nearly $10 billion each year in hospital health care alone.

The goal of osteoporosis treatment is to restore the bone balance, increasing bone density and consequently decreasing the risk of osteoporotic fractures--a job now being handled elegantly by a family of humble industrial chemicals.