Bone-preserving drug passes tests in men, women

Results may set stage for regulatory approval

A new drug increases bone density and reduces the number of fractures in men fighting prostate cancer and in elderly women with bone loss, researchers report in two studies appearing August 11 in the New England Journal of Medicine.

The results of these clinical trials might clear the way for approval of the drug, called denosumab, by the Food and Drug Administration, which has scheduled an advisory panel to assess these and other data on August 13. “This certainly goes a long way toward fulfilling the criteria the FDA uses,” says Sundeep Khosla, an endocrinologist at the Mayo Clinic in Rochester, Minn., who didn’t participate in these trials.

Denosumab prevents old bone from being dissolved faster than it can be replaced by new bone. While bone mineral removal and replacement is a natural balancing act, the loss of hormones can put it out of sync. In post-menopausal women lacking estrogen, and in men with prostate cancer who are being treated with androgen-deprivation therapy, bone loss results when bone-dissolving cells called osteoclasts outpace their bone-building counterparts.

In one of the new studies, researchers identified nearly 8,000 women in North America, South America, Europe and Australia, average age 72, who had low bone-density scores. Half received denosumab shots every six months for three years, while the others got placebo injections.

The bone density of vertebrae rose, on average, by 9.2 percent and hip bone density by 6 percent in women getting denosumab, whereas women in the placebo group showed no gains.  Also, 2.3 percent of women getting denosumab had a vertebral fracture during the three years of the study, compared with 7.2 percent of women getting the inert shots.

For the other study, scientists enrolled 1,468 prostate cancer patients, average age 75 years, who were undergoing androgen-deprivation treatment, which reduces male hormone levels. There are about 2 million prostate cancer survivors in the United States and roughly one-third of them are getting such therapy, says study coauthor Matthew Smith, a medical oncologist at Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston.

As in the other trial, half the volunteers received a denosumab injection every six months for three years while the others got placebo shots. Those getting the drug showed on average a 5.6 percent increase in vertebral density in the lower spine after two years, compared with a 1 percent loss in the placebo group ― a divergence that continued during the third year. Also, only 1.5 percent of the men receiving denosumab experienced a vertebral fracture by the end of the third year compared with 3.9 percent of the placebo recipients.

“This demonstrates clinically meaningful improvements in bone density” and is the first large-scale study to do so in men undergoing this cancer treatment, Smith says.

Amgen, the company that makes denosumab, provided support for both studies.

Denosumab and another class of drugs already on the market called bisphosphonates interfere with osteoclasts’ function of dissolving bone. But denosumab also stops the actual formation of new osteoclasts. As such, denosumab may represent the maximum available therapy against bone resorption, says Steven Cummings, an internist at the University of California, San Francisco, who coauthored the trial in women. Future treatments for bone loss will take the form of experimental drugs to boost bone rebuilding, he predicts. But such agents would not be suitable for cancer patients, Smith notes. That’s because growth agents risk contributing to cancer pathology.

Meanwhile, bisphosphonates are available in pill or injection form, but roughly half of patients prescribed the pills stop taking them within a year, often due to stomach upset or heartburn, says Khosla. Denosumab is injected twice a year and a bisphosphonate called zoledronic acid is injected annually, both of which lead to better compliance, he says.

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