DESTIN, FLA. — Investigational antiresorptive agents with novel methods of action and dosing regimens may improve patient compliance and persistence, but will not reduce the risk of fracture associated with osteoporosis beyond that seen with current agents.
“The objective of all these drugs is to normalize bone turnover, which we already do extraordinarily well and easily with bisphosphonates,” Dr. Michael McClung said at a rheumatology meeting sponsored by the Virginia Commonwealth University.
However, some of the investigational antiresorptives are just as good at increasing bone mineral density as are the bisphosphonates, and may be easier for patients to take, he added.
Denosumab, currently in phase III studies, has shown some promising effects. The agent inhibits the binding of the RANK protein to its ligand. The binding increases the population of osteoclasts and allows them to live longer, inhibiting the binding blocks that process, thus reducing bone turnover.
A phase II study compared different denosumab doses to placebo and to alendronate. It found that denosumab increased bone density as well or better than alendronate, especially at sites greater in cortical bone. Denosumab reduced serum C-telopeptide levels more than did alendronate. Within 3 days of initiating therapy, the levels dropped 80% with all doses of denosumab, compared with 25% with alendronate (N. Engl. J. Med. 2006;354:821–31).
The drug was well tolerated, said Dr. McClung, director of the Oregon Osteoporosis Center, Portland, and principal investigator of the study. There were no injection site reactions or adverse events that increased with dosage, and no observed immune response problems, he said at the meeting, also sponsored by the International Society for Clinical Densitometry and the Alabama Chapter of the Arthritis Foundation. The phase III study is looking at the effects of a 60-mg subcutaneous dose once every 6 months.
Intravenous bisphosphonates given every few months avoid the gastrointestinal side effects and could improve persistence in therapy. They will be especially convenient for nursing home residents, Dr. McClung said.
Ibandronate was recently approved for intravenous dosing of 3 mg every 3 months. A trial showed that bone mineral density and bone turnover marker responses to this dose were similar to those achieved with daily oral dosing of 2.5 mg. There are no fracture data available for the new dosing schedule, but a previous study showed that infusions of 0.5 or 1 mg of ibandronate every 3 months did not persistently suppress markers of bone turnover and did not significantly reduce fracture risk. (Bone 2004;34:890–9).
Intravenous zoledronic acid, already approved in 4-mg doses for the treatment of cancer-related bone diseases, is now being studied for an osteoporosis indication. A phase II study demonstrated that a single dose of 4 mg IV suppressed indices of bone turnover for at least 12 months. A phase III study is exploring yearly infusions of 5 mg IV zoledronic acid for the treatment of osteoporosis.
Cathepsin K inhibitors are also being investigated in phase II trials, he said. Cathepsin K is an enzyme required for hydrolysis of the bone matrix, inhibiting the enzyme reduces bone resorption.
Several new selective estrogen receptor modulators are also under investigation. “I don't think anyone has found the magic SERM that is as potent as estrogen on the skeleton, but without the problematic side effects,” said Dr. McClung.
Strontium ranelate is an interesting compound being investigated in Europe. The orally administered strontium salt is taken up in bone much the same way as is calcium; however, it is denser than calcium. It has been shown to reduce the risk of vertebral and nonvertebral fracture in older women with osteoporosis. It is available in several counties, but there are no immediate plans to market the drug in the United States.
New anabolic or bone-forming agents are also being studied. Parathyroid hormone 1–84 has been shown to increase bone formation and to reduce the risk of vertebral fractures in women with osteoporosis. The drug is under consideration by the Food and Drug Administration.
In animal studies, an antibody that binds sclerostin, an inhibitor of osteoblast activity, normalized bone mass and the deterioration of bone structure that occurred after estrogen deficiency.
“The availability of new agents will provide important new options for both clinicians and our patients,” said Dr. McClung. “Importantly, we may find new combinations of antiresorptive and anabolic agents that provide additive effects and, perhaps, even the cure for osteoporosis.”