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Bisphosphonates

by Dr Cedric Nazareth

 

Osteoporosis is characterised by a reduction in bone mass and an alteration in bone microarchitecture resulting in increased susceptibility to fractures. Postmenopausal women, in whom osteoporosis is common, are particularly at risk for developing fractures. The cumulative lifetime risk of symptomatic fracture for a 50-year-old woman is estimated about 35-40%, whereas the corresponding figure for a 50-year-old man is only 5%. With improvement in life expectancy and a larger aging population, the occurrence of osteoporotic fractures is increasing. Fractures are also associated with increased disability and mortality. Worldwide, there are nearly 200 million post menopausal women atrisk of developing osteoporosis. In India, osteoporosis is the second commonest metabolic bone disease.

Throughout life, bones in the body undergo remodelling, with ongoing formation and resorption. In osteoporosis, the rate of bone resorption exceeds the rate of formation. In both sexes, bone mass is reduced with aging, but in women, the process is accelerated with menopause. A fracture, occurring with minimal trauma, is often the first clinical feature of the condition. It is estimated that less than 15% of post menopausal women take any medication at all for osteoporosis. The standard treatment for this condition has involved oestrogen with or without anabolic steroids, combined with calcium and vitamin D.

The bisphosphonates are a relatively new drug category, effective in the prevention and treatment of osteoporosis. These agents are structurally similar to pyrophosphate, a normal by-product of metabolism having potent inhibitory effects on bone resorption. Thus the bisphosphonates inhibit the resorption of bone by osteoclasts (which remove bone) and may also act on the osteoblasts (which contribute to bone formation). These properties make the bisphosphonates useful in the treatment of conditions associated with increased bone resorption, such as osteoporosis, hypercalcaemia of cancer, bony metastasis, multiple myeloma and Pagetís disease.

Bisphosphonates that have already been approved for use in one or more countries include etidronate, clodronate, pamidronate, alendronate, risedronate, tiludronate and ibandronate.Others in the pipeline are zoledronate, incadronate, olpadronate and neridronate. The early bisphosphonates were etidronate and clodronate, but with pamidronate and alendronate, the antiresorptive potency was increased by up to one hundred times. Later modifications in the chemical structure produced ibandronate and olpadronate, with further increase in potency. The most potent agents today, risedronate and zoledronate, are up to 10,000 times more potent than epidronate in some experimental systems. Pamidronate is the only intravenous bisphosphonate currently available, and may be useful in patients who cannot tolerate oral therapy.

Age and menopausal status, in addition to the severity of osteoporosis, would govern the selection of women for bisphosphonate therapy. Their efficacy in premenopausal women with osteoporosis has not been demonstrated. In perimenopausal women or in early postmenopause, oestrogen replacement therapy may be preferred, but women above 75 years of age are less likely to accept hormonal therapy. However, the bisphosphonates may be combined with oestrogen therapy and are equally effective in younger and older postmenopausal women.

The world market for osteoporosis is currently estimated to be over $10 billion in sales and is expected to grow. Future prospects can be gauged by the fact that sales from just one of the bisphosphonates, risedronate, is expected to be above $1 billion within 10 years.

Apart from postmenopausal osteoporosis, the other possible uses for the bisphosphonates include the treatment of osteoporosis in men and the prevention of glucocorticoid-induced osteoporosis. Since the bisphosphonates affect metabolic pathways throughout the body and not just in bone cells, it is possible that additional indications for these drugs will emerge in the future.

 

6 January 2001.
Pharma Marketing Page. http://pharmapage.tripod.com/1.html
This article appeared in Pharma Business, January 26, 2001.
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