Q I would be very interested to learn more about the drug Fosamax, which my doctor has prescribed for my osteoporosis. I'm worried about the possible side-effects, but I've read that it's an innovative drug which seems to have been adopted quite widely. - PJ, London
A Yes, Fosamax appears to be one of those 'magic bullet' discoveries that drug companies pray for, particularly if they can be prescribed for a chronic long-term disease. Osteoporosis is an ideal condition to find a drug for, as it will affect one in three women from the time of the menopause until death - which could be as long as 40 or 50 years.
However, doctors, who are more wary of drug-based solutions, tend to regard osteoporosis not as a disease, but as a condition that can be prevented - largely by taking regular weight-bearing exercise. Even if osteoporosis strikes, it can be kept at bay by moderate calcium supplementation. The latest evidence suggests that 800 mg/day can increase bone mineral density (BMD), making the bone stronger, and reduce the risk of fractures by about 70 per cent (J Int Med Res, 1999; 27: 1-14).
Since its introduction by the US drug company Merck in 1995, Fosamax, a bisphosphonate drug, has become an international best-seller, with over half a million people taking it worldwide. The majority of takers are postmenopausal women, the group that suffers most from osteoporosis. But men can suffer from it too, particularly as a side-effect of prescribed drugs.
Fosamax is turning out to be a successful moneyspinner, producing sales in 2002 of over $2 billion. Merck expects even more profits after the recent dramatic fall from grace of HRT, which was once the doctors' treatment of choice for osteoporosis.
Fosamax is the trade name for alendronate sodium, a chemical that is claimed to mimic the bone-building compounds that are naturally found in the body. However, unlike the natural compound, Fosamax does not permanently incorporate itself into the bone, which is why patients have to take a daily dose. For postmenopausal women, Merck recommends 5-10 mg/day, week in and week out, in perpetuity.
When the first clinical trials were carried out in order to obtain a marketing licence, Fosamax looked impressive, with an up to 70 per cent reduction in the chemical markers that indicate bone loss. However, the actual benefit to patients wasn't quite so dramatic.
In fact, after three years of treatment, the BMD - a key measure of osteoporosis - was improved by no more than 10 per cent.
The effect of Fosamax on bone fractures was likewise nothing to crow about. In one controlled trial with over 2000 postmenopausal women, 13.8 per cent of the women taking the drug had one or more fractures, compared with 18.1 per cent of those taking placebo tablets - not a vast difference and certainly no better than calcium supplementation.
Furthermore, Fosamax does not arrest the bone shrinkage normally associated with osteoporosis in the elderly - older people taking Fosamax can still expect to lose 1 mm a year in height compared with 1.5 mm with a placebo.
Fosamax is also marketed as a so-called 'chaser drug'. These are drugs that are given in tandem to alleviate the side-effects of other medications. Osteoporosis is a well-known side-effect of corticosteroid drugs, which are often prescribed for inflammatory conditions such as rheumatoid arthritis and asthma. So another key market for this drug is the thousands of people taking corticosteroid drugs such as prednisone.
What of Fosamax's own side-effects? During its initial clinical trials, the drug looked promising, with only relatively minor side-effects being reported. However, once the drug entered into more widespread use, the picture began to look decidedly less rosy. Patients started to complain of stomach pain, heartburn, nausea and, in particular, irritation of the oesophagus (gullet). In some patients, the irritation was so severe that the oesophagus became perforated, resulting in death (Am J Gastroenterol, 2001; 96: 3212-3). So far, 31 people have been hospitalised because of this adverse effect.
Recently, there was a worldwide alert concerning the effects of Fosamax on the gullet. Patients were told to take the drug with a large glass of water while standing up - and to remain standing upright for at least half an hour to reduce the time that the drug is in contact with the lining of the oesophagus. Anyone with a history of swallowing problems was also warned to steer clear of the drug.
However, worse was to come. Gastroenterologists soon discovered that, in addition to damage to the oesophagus, Fosamax also causes stomach ulcers (Dig Dis Sci, 2002; 47: 1665- 78). In some cases, the stomach ulcers persisted even after Fosamax was withdrawn (MedGenMed, 2002; 4: 3).
Problems with the drug multiplied as more and more doctors reported new side-effects, including acute hepatitis described as 'severe' (Gastroenterol Clin Biol, 2002; 26: 179-80), skin 'poisoning' (Aten Prim, 2002; 29: 61-2) and a painful inflammation of the eye called anterior uveitis (Invest Clin, 2002; 43: 49-52).
Yet, despite these serious drug 'complications', Merck has recently been given permission to market Fosamax not only to treat osteoporosis, but also to prevent it. This additional indication was based on the results of a Merck study of women who had just passed the menopause that Fosamax at 5 mg/day for two years increased BMD by about 2 per cent vs a slight decrease with placebo.
Doctors are now suggesting that women take Fosamax for at least 10 years after the menopause (Dan Med Bull, 2002; 49: 1-18). However, researchers have uncovered a nagging problem with long-term Fosamax. Close analysis of the data shows that women taking the drug for seven years had three times more vertebral (spinal) fractures in the last two years than during the first three years, despite increased bone density. This paradoxical effect has been put down to a long-term action of the drug in which 'the profound suppression of the bone formation rate may begin to have a negative effect' (J Clin Endocrinol Metab, 2001; 86: 1835).
Children are another potential market for Fosamax, says Merck. Doctors at the University of Milan have been testing the drug on children with rare diseases that cause osteoporosis, such as lupus and juvenile arthritis. Fosamax apparently increases bone mineral density in these children, but not without the gastrointestinal side-effects found in adults. Furthermore, as the researchers note, '. . . results on long-term toxicity remain to be determined and are still a serious concern'.
There is yet another cloud on Merck's horizon. On 20 January, the British High Court ruled that Merck's two patents for Fosamax are invalid in the UK, opening the way for a generic version of the drug. So, although alendronate will be available here, it won't be called Fosamax.