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MEDICINE New Therapy Strengthens Fight Against OsteoporosisHormone Reduces Fractures by Building Bone A substance secreted by four tiny glands at the crook of the neck could provide the most powerful fracture prevention treatment to date for osteoporosis. Massachusetts General Hospital researchers, working with scientists at Eli Lilly and elsewhere, report that postmenopausal women with osteoporosis who took daily doses of human parathyroid hormone cut their risk of developing a new spinal fracture by 65 percent or more compared to women who did not take the substance.
Robert Neer and his colleagues detected many fewer spinal fractures in women who took daily doses of parathyroid hormone. Photo by Steve Gilbert "Parathyroid hormone reduces the fraction of women who develop a new vertebral fracture by 65 to 69 percent," said Robert Neer, HMS associate professor of medicine and director of the Osteoporosis Center at MGH. "No other drug has reduced it more than 40 to 50 percent." In their study of 1,326 women, which appears in the May 10 New England Journal of Medicine, Neer and his colleagues found that parathyroid hormone lowered a woman's risk of developing multiple hairline spinal fractures even more strikingly—by 77 to 80 percent. "Severe fractures it reduces by 78 to 90 percent," said Neer. What distinguishes the drug from the current pack of osteo-porosis therapies—and is the key to its enhanced fracture-thwarting powers—is its novel principle of action. Most osteoporosis treatments on the market, such as Fosamax, estrogen, and Evista slow bone resorption. But parathyroid hormone promotes the formation of new bone. "Parathyroid hormone stimulates bone formation dramatically—it doubles it," Neer said. Of the women he and his colleagues analyzed, those taking the hormone had 12.6 percent more bone mass in their spine than those taking placebo after only 21 months. The average increase in bone mass for women taking marketed drugs is 9 percent or less after two or three years. "It increases bone mass more, and it reduces fractures more than any currently marketed therapy," said Neer. The need for an effective fracture-reducing drug has never been greater. Fourteen million Americans are currently affected by osteoporosis. Between 9 and 10 billion dollars are spent annually on the care of their fractures. And the numbers will go up as the population ages, said Neer. "Osteoporosis and osteoporosis-related fractures are becoming more and more prevalent every year," he said. The current NEJM study is a continuation of more than 70 years of parathyroid research at MGH and elsewhere. In the 1920s, researchers at the hospital discovered that parathyroid hormone, in addition to regulating calcium levels in the blood, could cause animals to gain bone mass. Human parathyroid hormone was synthesized for the first time by MGH researchers in the 1970s. In a series of clinical studies reported in the 1980s, Neer and his colleagues showed that daily doses of the hormone significantly increased bone mass in women and men. Patient TrialsTo see whether it could also reduce fractures, Neer and his colleagues persuaded scientists at Eli Lilly to undertake a clinical trial. Working with 99 investigators in 17 countries, the team enrolled 1,637 postmenopausal women with osteoporosis.Each of the women, none of whom was taking other prescription drugs for osteoporosis, was placed on one of three regimens: placebo, 20 micrograms of parathyroid hormone injected subcutaneously each day, or 40 micrograms of parathyroid hormone per day. Originally, the plan was to rotate the women through the treatments so each would receive the hormone for two years. "Everybody would get parathyroid hormone but some would get it first, others would get it last," Neer said. "We hypothesized that by study's end, everybody would be better off than if they had taken the best current osteoporosis therapy." At the end of the study, women who could be analyzed for spine fractures had more bone mass and fewer vertebral fractures than if they had taken any currently marketed treatment for four years. In addition to having a much lower risk of developing new spinal fractures, women taking 20 and 40 micrograms of hormone were, respectively, 35 and 40 percent less likely to develop one or more new fractures elsewhere in their skeleton. A Warning SignBut some participants never received parathyroid hormone because the clinical trial ended early when a parallel Eli Lilly study revealed that laboratory rats given high doses of parathyroid hormone for two years—essentially the rats' lifetime—developed massive bone overgrowths and bone tumors. The investigators subsequently undertook extensive reviews and wide consultations, Neer said, and have concluded that high dose toxicology studies in rats do not predict the effects of parathyroid hormone in humans. In addition, humans who have overactive parathyroid glands and, as a result, chronically produce high amounts of parathyroid hormone have not been found to have an increased risk of bone tumors or bone cancer.Eli Lilly has recommenced research on the hormone and has recently filed a claim to market it as a treatment for osteoporosis. That treatment may eventually extend to all people with osteoporosis. "Because parathyroid hormone acts at a very fundamental level to stimulate new bone production, it has worked on all forms of osteoporosis tested to date, including osteoporosis in men and osteoporosis induced by cortisonelike drugs," Neer said. "And it prevents estrogen-deficient bone loss in women with normal bones." While parathyroid hormone could help stem the looming tide of osteoporosis-related fractures in people with osteoporosis, it will not, by itself, provide a cure, said Neer. "To cure osteoporosis, the most logical approach would be to increase bone formation and simultaneously suppress bone destruction. And that will require administering two drugs," he said. He and others are currently investigating this cocktail approach with funding from the National Institutes of Health. —Misia Landau |
