May 10, 2001 A substance secreted by four tiny glands in the neck could provide the most powerful treatment to date for osteoporosis, the bone-eroding disease that currently affects millions of Americans. In this week’s New England Journal of Medicine, a Massachusetts General Hospital (MGH) researcher working with scientists elsewhere reports that postmenopausal women with osteoporosis who took daily doses of human parathyroid hormone had significantly fewer spine and nonspine fractures. By promoting bone formation, the hormone also significantly increased bone density in their spine, hip, and total body.
"The key to parathyroid hormone’s fracture-thwarting powers is that it stimulates bone formation dramatically—it doubles the normal rate," says Robert Neer, MD, director of the Osteoporosis Center at MGH. Currently available osteoporosis treatments slow bone resorption and bone loss. In contrast to these anti-resorption drugs, parathyroid hormone promotes bone formation. The study showed that after 21 months, the women taking parathyroid hormone had up to 13 percent more bone in their spine than those taking placebo. The average increase in bone for women taking currently available drugs is 9 percent or less, after two to three years of treatment.
The effect can be illustrated by a half-filled glass of water with a hole in the bottom. Current drugs concentrate on slowing the leak, but parathyroid hormone acts by replenishing the water at a greater rate than is lost through the leak.
Neer was principal investigator in the international clinical trial sponsored by Eli Lilly and Company. Working with 99 investigators in 17 countries, the team enrolled 1,637 postmenopausal women with osteoporosis. None of the women were taking other prescription drugs for osteoporosis, and each was placed on one of three regimens: placebo, 20 or 40 micrograms of parathyroid hormone injected subcutaneously each day.
"Parathyroid hormone reduces the percentage of women with osteoporosis who develop a new vertebral fracture by 65 and 69 percent. No other drug has reduced it more than 40 to 50 percent," says Neer. The hormone lowered a woman's risk of developing multiple spinal fractures even more strikingly-by 77 and 86 percent, and it also reduced the risk of nonspine fractures by 35 and 40 percent.
Volunteers were treated for a mean of 18 months. The trial was terminated when a Lilly study in rats revealed that high-doses of parathyroid hormone given for two years caused massive bone overgrowth and bone cancer in the animals. The investigators subsequently undertook extensive reviews and wide consultations, Neer says, and concluded that these high dose toxicology studies do not predict the effects of parathyroid hormone in humans. 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 cancer. None of the women in this study or previous studies with parathyroid hormone developed bone cancer. Lilly has resumed studies on the hormone and has requested U.S. Food and Drug Administration (FDA) approval to market it as a treatment for osteoporosis.
Treatment may eventually extend to other people with osteoporosis. "Because parathyroid hormone acts at a very fundamental level to stimulate new bone formation, it has worked on all forms of osteoporosis tested to date, including osteoporosis in men and osteoporosis induced by cortisone-like drugs," Neer says. "And it prevents estrogen-deficiency bone loss in women with normal bones."
While parathyroid hormone reduces osteoporosis-related fractures, it will not, by itself, provide a cure for most patients, says 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," Neer says. With the half-filled glass analogy, that would mean replenishing the water in addition to plugging the leak. Neer and others are currently investigating this type of approach with funding from the National Institutes of Health.
The need for an effective fracture-reducing drug has never been greater. In the United States today, 10 million individuals already have osteoporosis. Between $9 billion and $10 billion are spent annually to treat osteoporosis-related fractures. And the numbers will go up as the population ages, says Neer.
The current NEJM study is a continuation of more than 70 years of parathyroid research at MGH and elsewhere. In the 1920s, MGH researchers discovered that parathyroid hormone not only regulated calcium levels in the blood, but also increased bone density in animals. By the 1970’s, MGH researchers were the first to determine the chemical structure of human parathyroid hormone, which then enabled them to synthesize it for the first time. In a series of clinical studies reported in the 1980’s, Neer and his colleagues first showed that daily doses of the hormone significantly increased bone density in women and men.
The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photo-medicine. In 1994, the MGH joined with Brigham and Women’s Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.
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