Bone builders: preventing and treating osteoporosis^†

Osteoporosis is a bone-thinning disease that makes bones fragile and prone to fractures. It afflicts about half of all women over age 65 and as many as 2 out of 10 men over age 70. It frequently causes the bones in the spine to collapse, resulting in a curvature often referred to as a ‘dowager's hump’. Hip fractures due to osteoporosis are disabling and can be fatal. According to the National Osteoporosis Foundation, the annual costs of osteoporosis exceed $14 billion in this country.

The image of old women bent with age is ingrained in classical works of literature and art; but this posture can now be prevented with recent improvements in the diagnosis and treatment of osteoporosis and new insight into the mechanism of bone growth. Many of these improvements stem not from targeted research on osteoporosis, but from basic research aimed at answering fundamental questions, e.g., why do female pigeons have more massive bones than males? Why do cows fail to thrive under certain diets?

John Hunter, an English medical pioneer of the eighteenth century, discovered through his experiments with animals and his observations of human jaws that as new bone is laid down in the body, old bone is destroyed or reabsorbed. Today, after another 200 years of observations and experiments by basic scientists, we know that bones consist of a matrix of the protein collagen, hardened by calcium and other minerals. Within living bones are cells called osteoclasts, which break down bones, and osteoblasts, which build them up. In this way, the human skeleton is constantly being replaced. Osteoporosis weakens the skeleton by eating away at cortical bone, which forms the outer portion of bones, and trabecular bone, which forms the honeycomb network of intersecting plates within bones, making it prone to breaking.

Fuller Albright, a clinical researcher in the 1930s, observed that most of his patients with osteoporosis were postmenopausal women. Around the same time, anatomists noticed that bones of ovulating female pigeons were more massive than those of male pigeons. Researchers found that by injecting estrogen, a hormone made primarily by the ovaries, the bone mass of male pigeons increased dramatically. Given this, Albright proposed that estrogen triggers the buildup of calcium reserves in bone. After menopause, the reduction in estrogen leads to bone loss. Estrogen replacement therapy has proven to be effective at staving off osteoporosis in both women and men. This hormone can boost some women's risk of developing breast cancer, but the new drug, Raloxifene (Evista), a selective estrogen receptor modulator drug, has estrogenlike effects in the bone but not the breast. Women who take this drug actually have a lowered risk of developing

Other new drugs for osteoporosis resulted from basic research on calcium and parathyroid glands. This research led to the link between parathyroid hormones and the amount of calcium lodged in the skeleton. James B. Collip, a Canadian biochemist, showed that parathyroid hormone boosted the level of calcium in the blood. When calcium level is low, parathyroid hormone stimulates bones to release calcium into the bloodstream. The hormone also enhances the absorption of calcium from the intestines and decreases the amount that is lost through urine. Although large doses of parathyroid hormone foster bone resorption, regular small doses of the hormone lead to bone formation in rats. Thus, parathyroid hormone treatment holds promise for regenerating lost bone mass in women suffering from postmenopausal osteoporosis.

Basic research on calcium also led researchers to discover pyrophosphate-mimicking drugs, another group of new drugs that effectively treat osteoporosis. Some of these drugs appear to suppress bone resorption by inhibiting the capacity of osteoclasts. The first of these drugs was discovered by Herbert Fleisch, a Swiss physiologist interested in what causes calcium to be deposited in, or removed, from bone. Elmer McCol-lum, a biochemist who was searching for answers to why cows suffered malnutrition under certain diets, discovered that vitamin D also helps prevent osteoporosis. This vitamin boosts the body's calcium levels by fostering the ability of intestines to absorb calcium from the diet.

Thanks to the work of scientists and researchers from many disciplines, many women today no longer need to suffer from pain and disability because they have osteoporosis. These investigators were catalysts in the development of six effective drugs for the disease. Early detection of bone loss, made possible by devices such as the densitometer, and blood or urine tests that access the rate of bone loss, allow osteoporosis to be treated before it seriously damages the body. All of today's drugs used to treat osteoporosis work by stemming bone resorption; however, new discoveries of compounds that stimulate the production and activity of bone-forming osteoblasts may eventually offer drugs that restore, and not merely prevent bone loss.