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New osteoporosis drug restores bone without breaking it down

Romosozumab approved only for post-menopausal women with high fracture risk

New York

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.

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The new drug, romosozumab (brand name Evenity), developed by Amgen in collaboration with Belgian drug company UCB, restores bone without breaking it down, according to the findings of two large clinical trials. It was approved only for post-menopausal 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 FDA 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 in the order of 15 per cent - 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 FDA panel that evaluated the data.

Merely a 6 per cent 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 per cent, taking Evenity, compared with 38 of 2,014, or 1.9 per cent, taking aldendronate.

The effect was seen in one of the two large clinical trials, but not the other.

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 backstory. 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 FDA, which voted 18-1 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 so patients do not have to have monthly injections. NYTIMES