SAN FRANCISCO – Three experimental therapies may improve bone mass more than do existing treatments for osteoporosis.
One of them, anti-sclerostin antibodies, "may be the most potent agent yet for formation of bone," Dr. Steven R. Cummings said at a meeting on osteoporosis sponsored by the University of California, San Francisco.
Anti-sclerostin monoclonal antibodies are in phase II clinical trials. "It will probably be 3-4 years before we see results in terms of risk of fracture," said Dr. Cummings, professor of medicine and epidemiology and biostatistics at the university.
A phase III trial that will assess impact on fracture risk is underway for a different drug, the cathepsin K inhibitor odanacatib, which appears to improve bone mineral density, compared with placebo, he said. Data on whether odanacatib reduces the risk of nonvertebral fractures more than current therapies should be available in approximately 2 years.
The third promising agent is a well-known drug used off label: nitroglycerin. A preliminary study suggests it increases bone mineral density and bone strength, but the fact that nitrates are generic and widely available makes it unlikely that a pharmaceutical company will sponsor clinical trials for this indication.
"We’d like to do a phase II study to compare several doses" of nitroglycerin in patients with low bone density, "but we can’t get the funding from the National Institutes of Health," Dr. Cummings said.
These promising agents might strengthen a weak spot in osteoporosis treatment by helping to reduce nonvertebral fractures, he said. Current treatments can produce a 10%-30% reduction in nonvertebral fractures, which account for approximately 90% of days of disability due to fractures.
"We need more effective treatments," he said.
Sclerostin is produced by mature osteocytes in response to decreased loading, and is found in no other cells. It inhibits the formation of osteoblasts.
An initial trial of various doses in 48 healthy postmenopausal women found a 5%-6% increase in spine bone mineral density and a 3%-4% increase in total hip bone mineral density in less than 3 months in the 6 women randomized to a single 10-mg/kg injection.
"These are breathtaking increases in bone mineral density, but this is very early, preliminary data," Dr. Cummings said.
Although osteoblasts usually form bone where it has been reabsorbed, anti-sclerostin antibodies induce formation of bone on "quiet" surfaces such as the periosteum, which increases the diameter and bending strength of long bones, he said.
Osteoclasts produce cathepsin K, which is released during bone resorption and degrades collagen. Blocking cathepsin K blocks the resorption of proteins and limits bone resorption to shallower pits than usual. This might decrease resorption a little yet allow full bone formation, theoretically.
Unpublished data from a 48-month trial suggest that a weekly 50-mg dose of the cathepsin K inhibitor odanacatib produced an 11% increase in lumbar spine bone mineral density, compared with less than a 1% increase on placebo, and a 9% increase in femoral neck bone mineral density on odanacatib, compared with nearly a 2% decrease on placebo.
"These increases over a 4-year span are impressive," said Dr. Cummings, who said he looks forward to results of the fracture end point trial.
Nitroglycerin prevented bone loss due to ovariectomy in rodent studies. A preliminary study in 243 postmenopausal women randomized them to apply ointment containing 15 mg nitroglycerin or placebo every night, and 93% completed a 2-year evaluation.
Femoral neck bone density increased by approximately 6% on nitroglycerin and decreased by approximately 1% on placebo. In general, bisphosphonates increase femoral neck bone density about 4%-5%, he said. Nitroglycerin increased lumbar spine density by nearly 8%, compared with approximately a 1% increase on placebo.
Measures of bone geometry suggested increases in bone size and strength on nitroglycerin. For the radius, cortical thickness increased 14%, periosteal circumference increased 7%, and the polar moment of inertial increased 7% in the nitroglycerin group, compared with placebo. For the tibia, cortical thickness increased 25%, periosteal circumference increased 3%, and the polar moment of inertia increased 10% in the nitroglycerin group, compared with placebo.
Measurements of markers of bone formation and resorption suggest that nitroglycerin "uncouples" bone formation and resorption, he added.
Headaches were common but decreased with time. In a run-in phase of the study, 25% of women stopped treatment due to headache. One year into the study, 6% on nitroglycerin and 2% on placebo had stopped treatment due to headache. After 1 year, only two women in the nitroglycerin group reported headache.
Dr. Cummings has been a consultant to Amgen, which is developing an anti-sclerostin antibody drug, as well as for Merck, which is developing odanacatib, and Eli Lilly.