But in the past 20 years, drugs have appeared to treat osteoporosis. Most of the ones on the market inhibit bone breakdown, or resorption, one way or another. One class of drugs is the bisphosphonates, which trigger apoptosis in osteoclasts. “The bisphosphonate category is probably about 80 percent of the osteoporosis drug use in the United States right now,” notes Art Santora of Merck.
Another drug is a monoclonal antibody called denosumab, which is produced by Amgen. It is an inhibitor of RANK ligand, which was shown in the 1990s to be the key stimulator of osteoclast development through the Wnt/β-catenin pathway. By inhibiting RANK ligand, the drug prevents osteoclasts from maturing and chewing away the bone.
All these drugs are catabolic agents in that they stop the breakdown of bone. Given their numbers, Scott Simonet of Amgen says, “That area of the market is pretty saturated.”
The excitement lies in drugs that can help build bone. The only anabolic agent on the market is a recombinant version of parathyroid hormone called teriparatide, marketed as Forteo by Lilly. The drug stimulates osteoblasts to put down new bone. Parathyroid hormone’s classical role is to stimulate bone breakdown so that calcium is released to maintain serum calcium levels. But, for reasons not yet known, the hormone does the opposite and builds bone when injected once daily. The drug is effective for only 12 to 18 months.
Experts are excited about a drug that Amgen, in partnership with a company called UCB, has in phase III clinical trials. Simonet says that the drug is being developed for osteoporosis and fracture repair. The anabolic drug AMG 785 is a monoclonal antibody that targets a molecule called sclerostin.
The story of sclerostin best illustrates how molecular biology has been pivotal for bone therapeutics. In 1958, sclerosteosis was first described in two South African girls of Dutch-Afrikaner descent. Sclerosteosis patients have heavy, thick bones with large jaws and protruding foreheads; their thick facial bones pinch their facial nerves. Several research groups established that the gene involved was SOST and that sclerosteosis was a loss-of-function mutation of that gene.
“We didn’t know where sclerostin was coming from, but, after several years of soul-searching, it became clear that it was coming from the skeleton,” says Rosen. Coincidentally, at the same time, the Bonewald group’s osteocyte lines were coming out. Those cell lines helped researchers establish in the mid-2000s that osteocytes were secreting sclerostin to stop bone formation. Amgen’s AMG 785 shuts down sclerostin by blocking its inhibitory activity on osteoblasts.
Clemens and others take delight in pointing out that researchers had known about sclerostin’s existence for many years. But once its molecular biology was established, it took less than a decade to get a drug against it in the pipeline. “It’s really remarkable,” says Clemens.