The only reliable detection method for osteoporosis before a fracture is a bone density scan. Such tests have shown that a full 44 million Americans have low bone mass and 10 million, most of them women, have osteoporosis. In men, the disease is linked to low testosterone levels, smoking and alcohol use, and lack of physical activity. In women, it is linked closely to menopause, when estrogen levels in the body drop. In the 1980s and 1990s, doctors recommended that postmenopausal women prevent osteoporosis and fractures by taking estrogen supplements, which jam two cellular pathways used for bone resorption—one pathway involves compounds called cytokines and a second is called the Rank ligand pathway. But in 2002, researchers running a long-term trial called the Women’s Health Initiative reported that estrogen plus progestin supplements raised the risk for breast cancer and stroke; two years later, estrogen alone was found to also increase the risk for stroke. Estrogen use plummeted.

Fortunately, by then researchers had begun uncovering cellular signaling pathways that maintain bone’s thickness and strength. Three types of bone cells balance breakdown and repair: osteoclasts, which clear away patches of weak or defective bone; osteoblasts, which build it; and osteocytes, which are entombed in solid bone, sensing and directing the others. For all these cells, “the quest is to find out how signaling works and start designing therapies around that,” says bone biologist Alex Robling of Indiana University School of Medicine.

Today, several targeted therapies are available to prevent and treat osteoporosis by blocking bone breakdown. They include four members of a class of drugs called bisphosphonates—Fosamax, Actonel, Boniva, and Reclast—and Denosumab, which blocks the Rank ligand pathway. These bone-preserving drugs are also used to treat osteogenesis imperfecta, which causes children to produce weak, defective bone.

But while bisphosphonates and Denosumab are effective at preventing bone resorption, they also cripple the bone-degrading cells that are supposed to clean out weak or damaged bone. Over time this can make bones even more brittle, increasing the risk of fractures and, rarely, cause the jawbone to decay. Researchers are now investigating ways to get around this dangerous side effect, such as giving patients drug holidays after a few years.

Bone endocrinologist and geneticist Gerard Karsenty of Columbia University Medical Center likens osteoporosis to a house fire and antiresorptive drugs to water. “If you come with water you are going to stop the destruction, but you still need to rebuild,” he says. Just one drug exists to rebuild lost bone—Forteo (teriparatide), a synthetic form of human parathyroid hormone. Although the drug looks safe in humans so far, long-term treatment with high doses of it caused bone cancer in rats; as a result, doctors stop giving it to patients after two years. New drugs that build bone would be helpful. “That’s where the need is,” says endocrinologist and bone expert Sundeep Khosla of the Mayo Clinic in Rochester, Minnesota.

Learning from Overgrowth

Researchers have identified at least three ways to build bone. Two involve a cellular signaling pathway called Wnt. In 2001, an international consortium led by HHMI investigator Matthew Warman, a pediatrician and geneticist at Children’s Hospital in Boston, showed that a Wnt pathway gene called LRP5 is mutated in a disease called osteoporosis-pseudoglioma syndrome, which causes people to develop brittle bones.

A year later, HHMI investigator Richard Lifton of Yale University School of Medicine reported a different LRP5 mutation that makes the LRP5 protein overactive, leading patients to make too much bone. His team showed that the mutation causes high bone mass by preventing the natural antagonist Dkk and, by inference, the related protein sclerostin from inhibiting LRP5 function. Warman and Lifton later found other LRP5 mutations in patients with syndromes characterized by high bone density.

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