FULL BONE MASS RESTORED TO MOST POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS IN TWO-YEAR TRIAL OF NEW TREA

By Wallace Ravven on June 15, 1999

SAN DIEGO—The first fully controlled two-year study of a new treatment for osteoporosis in postmenopausal women restored bone mass to its original level in nearly two thirds of the women participating in the trial, UC San Francisco scientists reported today.

The new drug treatment—a synthetic version of part of a natural human protein called parathyroid hormone (hPTH 1-34)—was three times more effective at reversing bone loss than the best drugs currently available, the UC San Francisco scientists reported.

The results suggest a way to cure the debilitating disease for the first time, said Claude Arnaud, MD, professor emeritus of medicine and physiology at UCSF and director of the osteoporosis study funded by the National Institute of Aging. Arnaud is senior author of the report presented today at the annual meeting of the Endocrine Society in San Diego. First author Bruce Roe, assistant clinical professor of medicine at UCSF, presented the paper.

About 25 million older women in the U.S. suffer bone loss due to the osteoporosis, which results in 1.5 million fractures a year. About half of those fractures (700,000) occur in the spine and more than 280,000 are hip fractures, which hasten patients’ move to wheelchairs, nursing homes and irreversible debility, Arnaud said.

The annual cost of osteoporosis in the U.S. is about $14 billion, a figure expected to increase to some $240 billion over the next 50 years as the population ages, Arnaud said.

“This is comparable to our current defense budget, and is an amount that our country probably cannot afford,” he said. “If bone loss can be restored, we can avoid much suffering and spare society this enormous cost.”

The results of the study suggesting a potential cure for osteoporosis must overcome a concern from a related finding, however. A recent parathyroid hormone study by the pharmaceutical company Eli Lilly, using laboratory rats, found that a small percentage of the rats developed a kind of malignant bone tumor known as osteogenic sarcoma when the animals were given doses of parathyroid hormone considerably higher than the human dose used in the UCSF study. The rats were also given the hormone throughout their entire lives.

These tumors occur only rarely in people, and primarily in those under 25 years old. The Food and Drug Administration advised the medical community not to administer parathyroid hormone to young people, but the FDA recommendation did not apply to the two-year osteoporosis study reported today, since those taking the drug were all postmenopausal women and thus very unlikely to develop cancer from the hormone. No bone tumors were detected during the study according to Arnaud.

In addition, malignant bone tumors have been rarely if ever reported among the thousands of adults with excessive amounts of parathyroid hormone in their blood due to diseases of their parathyroid glands, Arnaud added. 

There are two major types of bone cells: those known as osteoclasts which normally dissolve and remove old, fatigued bone, and cells known as osteoblasts, which rebuild and replace bone that has been removed. Throughout the premenopausal lifetime of a woman, the hormone estrogen acts to restrain the activity of the osteoclasts. But loss of estrogen at menopause releases these restraints and can cause a buildup of the osteoclasts’ destructive army. Bone removal then begins to exceed bone replacement, resulting in a net bone loss.

Most osteoporosis drug development has focused on agents that suppress bone removal. Estrogen; selective estrogen receptor modulators (SERMS), such as raloxifene; biophosphonates (alendronate); and calcitonin are the primary drugs in use.

Parathyroid hormone has an opposite mode of action. It stimulates bone formation by increasing the number of osteoblasts, or bone rebuilding cells.

Women in the study reported by Roe, Arnaud and colleagues had already been taking estrogen for osteoporosis for at least one year prior to the parathyroid hormone treatment. Subjects in the study continued on estrogen and added parathyroid, so they were taking both throughout the two-year trial, estrogen daily in pill form and parathyroid hormone by daily self-injection.

Estrogen treatment commonly increases bone mass in the spine by about six percent in the first year and then adds little more bone mass.  The control group in the UCSF-based study—those continuing with their estrogen but not taking parathyroid—showed a 1.5 percent increase in bone mass over the two-year course of the trial, Arnaud said.

By contrast, women who took both estrogen and parathyroid hormone
experienced a striking 30 percent increased density of their vertebrae, and about an 11 percent increase in the density of their hip bones, the researchers found— far in excess of increases achieved using current treatments.  Sixty four percent of these women experienced bone mass restored to its pre-osteoporosis levels.

There were 26 women in the group that received both parathryroid hormone and estrogen, and 32 in the placebo group, which received only estrogen.

This is the first randomized, placebo-controlled, double-blinded study of the hormone’s ability to increase bone mass in postmenopausal women with osteoporosis. A previous randomized, but not placebo-controlled study by UCSF’s Nancy Lane, MD, associate clinical professor of medicine, and Arnaud showed similar bone mass effects from an estrogen and parathyroid hormone regimen in subjects with corticosteroid-induced osteoporosis. 

The Eli Lilly finding in rats, Arnaud says, “should serve to alert us to be cautious as we proceed toward further development of parathyroid hormone as a powerful treatment for established osteoporosis in older adults.”

One of the first goals, he said, is to confirm that the large increase in bone mass induced by the hormone translates into a marked decrease in fracture risk.

Colleagues in the UCSF research and co-authors on the report are:
Sarah D. Sanchez, MS, administrative analyst; Gustavo A del Puerto, MS, research coordinator; Elena Pierini, RN, BSN, research nurse; Peter Bachetti, PhD, associate professor of epidemiology and biostatistics; Chris Cann, PhD, professor of radiology.

  The clinical study was supported by the National Institute of Aging grant, “Building Bone with PTH and Estrogen.”