New antiosteoporosis agents show promise

The latest science on the diagnosis and treatment of osteoporosis was the focus of many reports from the annual meeting of the American Society for Bone & Mineral Research (ASBMR), held in Nashville late last month. Here are some of the highlights:

A new drug in the Novartis pipeline, AAE581, prevented the loss of bone mass and strength in a study of osteoporotic monkeys. The compound inhibits cathepsin K, an enzyme stimulating the gradual destruction of bone matrix in nature's cycle of bone breakdown and buildup. Osteoporosis ultimately develops when bone destruction (resorption) exceeds bone formation.

The study was designed to fulfill Food & Drug Administration requirements for antiosteoporosis agents, explained lead investigator Christopher P. Jerome, Ph.D. "AAE581 given orally once a day should inhibit the process of bone breakdown, reduce bone loss, and thus prevent osteoporosis." He and colleagues at SkeleTech Inc., in Bothell, Wash., along with Novartis researchers in Basel, Switzerland, examined 18-month data on 100 female monkeys treated with various oral dosages of AAE581 or placebo. Earlier, 80 of the monkeys had their ovaries removed, "inducing bone fragility like that seen in many women after menopause," he noted. The other 20 monkeys (controls) had sham surgery and received placebo.

"Unexpectedly, however, we also found strong new bone formation on the outer surfaces of the bones," said Jerome. "All this suggests that AAE581 may prevent bone loss, increase bone strength, and, apparently, add new bone that could improve resistance to fracture." By contrast, he noted, while bisphosphonates such as alendronate (Fosamax, Merck) inhibit bone breakdown, they slow bone formation as well.

At last year's ASBMR meeting, Amgen Inc. reported that its investigational drug for bone loss, AMG 162, greatly increased bone mineral density with only two injections a year. That study, designed to compare the safety and efficacy of AMG 162, placebo, or alendronate in postmenopausal women with osteoporosis, showed that AMG 162 injected subcutaneously at six and 12 months outperformed the comparators given once weekly over a year.

The compound, now called denosumab, is a fully human monoclonal antibody that inhibits the activity of human RANKL (receptor activator of nuclear factor kappa B ligand), a key factor in bone resorption.

This year, Amgen scientists presented six updated trials of denosumab; their results confirm that twice-yearly injections (at 60 mg) reduce bone resorption and improve bone density, especially of the lower spine. These early trials also show the drug is safe.

A poster study of the pharmacokinetics of denosumab, evaluating multiple subcutaneous dosing regimens twice annually in older women with low bone mass, indicated the drug did not accumulate in the body at any dose, nor did any dose alter the basic pharmacokinetics.

In a related poster study, researchers treated male monkeys with denosumab at six and 12 months, followed by a three-month recovery period. They used pQCT imaging for bone mineral content and geometry, and analyzed lumbar vertebrae by dual X-ray (DXA) for mineral content and density. As before, they found that two annual shots of denosumab increased bone mass and strength at key sites.

Another pioneering finding from the lab of Pierre D. Delmas, M.D., from the Claude Bernard University, in Lyon, France, provides cellular evidence that strontium ranelate (Protelos, Servier), a new osteoporosis treatment marketed only in Europe, decreases bone breakdown while increasing bone formation. "It is the first available agent to demonstrate this dual mode of beneficial action," he said. Bisphosphonates and most other standard osteoporosis drugs reduce bone resorption-but also inhibit bone formation.

The French researchers compared hip bone specimens from 49 older osteoporotic women treated with strontium ranelate and 87 given placebo. They took biopsies either early in the study or after one to five years of therapy. In the active drug-treated group, they found significant bone-building cell activity and reduced bone-breakdown cell activity. The drug is the first in a new class of osteoporosis treatments.

The Author is a writer based in Brooklyn, N.Y