Gina Kolata, Bloomberg
The Food and Drug Administration on Tuesday approved an osteoporosis drug that represents the first new treatment approach in nearly two decades — a strategy based on a rare gene mutation in people with bones so dense that they never break.
About 10 million people in the United States have osteoporosis. Worldwide, about 200 million people have brittle bones; one in three women, and one in five men, will suffer a fracture because of osteoporosis, often of the hip or spine. For many, the break leads to a downward spiral of disability.
Standard treatments, drugs called bisphosphonates, stop the loss of bone but do not build it. The alternatives, parathyroid hormone and a derivative, build bone but also break it down, limiting the therapeutic effect.
The new drug, romosozumab (brand name Evenity), developed by Amgen in collaboration with the Belgian drug company UCB, restores bone without breaking it down, according to the findings of two large clinical trials.
It was approved only for postmenopausal women with a high risk of fracture, and will carry a warning on its label that it may increase the risk of heart attack or stroke, the F.D.A. said.
“This is an extraordinarily important drug,” said Dr. Richard Bockman, chief of the endocrine service at the Hospital for Special Surgery in New York. “It’s a true bone-building drug that takes advantage of the underlying biology of bone.”
In large clinical trials, patients taking the drug saw increases in bone density in their spines on the order of 15 percent — a huge figure, similar to the amount of bone made in early adolescence, said Dr. Clifford J. Rosen, an osteoporosis expert at Maine Medical Center Research Institute and member of an F.D.A. panel that evaluated the data.
Merely a 6 percent increase in bone density can translate into a doubling of bone strength, Dr. Bockman said. In the trials, patients taking the drugs saw a reduction in breaks, both in the spine and “clinical” fractures — broken bones that a patient notices, rather than, say, a collapsed vertebra discovered only in X-rays.
In one study, spinal fractures occurred in 127 of 2,046 patients taking the new drug, compared with 243 of 2,047 taking aldendronate, an older drug.
“It’s a tremendous advance,” said Dr. Dolores Shoback, a professor of medicine and an osteoporosis expert at the University of California, San Francisco.
But there also was a small, unexpected increase in heart attacks, strokes and sudden deaths in that study — 50 of 2,040 patients, or 2.5 percent, taking Evenity, compared with 38 of 2,014, or 1.9 percent, taking aldendronate.
The effect was seen in one of the two large clinical trials, but not the other.
The F.D.A. said it was requiring the boxed warning on the drug’s label saying the drug should not be used by people who had a heart attack or stroke in the past year. Doctors should also consider whether to prescribe the drug to patients at high risk for heart attacks and strokes. Patients who have a heart attack or stroke while taking Evenity should stop taking the drug.
Side effects can include joint pain and headaches and irritation at the injection site.
The agency is requiring the company to conduct a post-marketing study of cardiovascular risks.
It is hard to know what to make of the possible risk, said Dr. Bart Clarke, a professor of medicine at the Mayo Clinic and president of the American Society for Bone and Mineral Research.
“Maybe there is something unique about those patients,” he said.
Amgen would not disclose the price at the time of approval, saying it would be disclosed next week.
Evenity will be given as a monthly injection. Parathyroid hormone is given as a daily injection, while the drugs in the other major treatment class, the bisphosphonates, are taken as pills.
The new drug has a striking back story.
In 1964, researchers began studying an unusual group of Afrikaner patients in South Africa. They were tall and heavy, but not fat. Instead, their bones were large and dense.
Their bones grew so profusely that their heads became distorted: Their jaws were large, and an overgrowth of bone in their skulls impinged upon nerves, often causing deafness or facial palsy. Many had terrible headaches. In some, the index and middle fingers fused together.
In 2001, scientists reported that all these effects resulted from a single gene mutation. The finding led researchers to understand how the body controls the building of bone.
Bones are in a state of constant flux, built up and broken down by the body. In osteoporosis, the balance is disrupted — more bone is broken down than is made.
Bone cells make a protein called sclerostin that halts the production of bone and increases its breakdown. The gene mutation in the Afrikaner patients stops the production of sclerostin, so their bodies keep building bone without brakes.
Scientists reasoned that if they could mimic the mutation by blocking sclerostin with an antibody, people with osteoporosis should build more bone.
Once bone density increased, patients could stop taking the sclerostin-blocking drug and switch to an older drug to maintain the new bone. Animal studies were successful, as were clinical trials, culminating in two large studies involving more than 10,000 postmenopausal women.
In one trial, Evenity was compared to a placebo; in the other, it was compared to a bisphosphonate. In both studies, women taking Evenity ended up with more bone and fewer fractures.
In January, Evenity was reviewed by an advisory committee to the F.D.A., which voted 18 to 1 for approval — but called for Amgen to do more research to understand the possible cardiovascular side effects.
“There is a tremendous need for this medication, and there is an amazing amount of morbidity and mortality with this disease,” said Dr. Frederick G. Kushner, a cardiologist at the Heart Clinic of Louisiana and a panel member, who voted to approve the drug.
The next step, Dr. Bockman said, is for companies to develop pills to block sclerostin so patients do not have to have monthly injections.
It may not be easy to convince patients to take the new drug.
Experts anticipate that it will be offered to patients at highest risk: those who have had a serious fracture, or who have taken bisphosphonates and parathyroid hormone, and did not respond or experienced serious side effects.
All too often, however, high-risk patients are afraid to take drugs to prevent fractures. They remember stories of the rare patients who took bisphosphonates and had an unusual fractures or deterioration of the bones in their jaws.
“They don’t remember the good — that fractures are being prevented,” Dr. Shoback said. “They remember some pivotal terrible thing that someone told them.”
Dr. Bockman has seen these patients, too, but hopes they can be convinced at least to try Evenity.
“This is a very important, great new drug,” he said. “And it is something we really need.”
Gina Kolata writes about science and medicine. She has twice been a Pulitzer Prize finalist and is the author of six books, including “Mercies in Disguise: A Story of Hope, a Family’s Genetic Destiny, and The Science That Saved Them.”