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(CCR 2015) A number of new osteoporosis treatments are on the near horizon, drawing on a new understanding of bone biology, as described by a speaker at the Clinical Congress of Rheumatology.
A number of new osteoporosis treatments are on the near horizon, said John Bilezikian MD, Professor of Medicine at College of Physicians and Surgeons of Columbia University.
Current osteoporosis therapies, including estrogen, alendronate, risedronate, zoledronic acid, and denosumab, reduce fracture risk, but “none provide complete fracture protection. Adverse events are hyped, but some are true,” Bilezikian said at the Congress of Clinical Rheumatology 2015 in Destin FL.
“Cost is a consideration in some cases,” he added. “It seems reasonable to attempt to translate new insights from bone biology, skeletal dynamics, and anabolic and catabolic pathways into new therapies for osteoporosis.”
One way to target the osteoclast and prevent initiation of bone remodeling is through inhibition of cathepsin K. In a phase II randomized, double-blind trial, the cathepsin K inhibitor odancatib showed continuous increases in bone density of the lumbar spine and femoral neck. It also allowed some bone formation to continue, so perhaps osteoclast signaling to osteoblasts is maintained during odanacatib exposure, he said.
Three-year, phase III data on more than 16,000 subjects show that odancatib led to a 54% risk reduction (RR) of new, worsening morpholometric vertebral fractures, a 47% RR in clinical hip fractures, a 23% RR in non-vertebral fractures, and a 72% RR in clinical vertebral fractures. This “very impressive clinical data,” he said, has not yet been submitted to the FDA for review. The drug’s manufacturer, Merck, is reviewing safety data.
“What bisphosphonates and other antiresorptives don’t do is reconstruct the skeleton,” Bilezikian said.
“Maybe we can cure the disease by reconstructing the microarchitectural deterioration signature in osteoporosis.”
The new osteoanabolic abaloparatide has been compared to teriparatide in clinical trials.
In a phase II trial, abaloparatide led to larger changes in bone mineral density (BMD) over 12 months at the lumbar spine and total hip. In an international phase III double-blind trial with teriparatide as a positive control (presented previously at the Endocrine Society 2015 meeting), bone turnover markers were higher with teriparatide, but “abaloparatide seemed to give a greater osteoanabolic effect in comparison to the eventual bone remodeling effect,” he said.
Also, abaloparatide appears to reduce non-vertebral fractures very quickly and all clinical fractures are remarkably lower than with teriparatide. Abaloparatide may have more profound effects on cortical bone, he said, adding that it shows no other safety signals and possibly causes less hypercalcemia than teriperatide.
Combination therapy with an antiresorptive and osteoanabolic agent may be another avenue. “The rationale is clear, but the results show raloxifene and estrogen have a possible small benefit, alendronate a reduced benefit, risedronate a possible hip BMD benefit in men, and zoledronic acid early benefit primarily,” he said.
A combination of denosumab and teriparatide may be more promising. “Data on densiometry and microstructure of bone argue this might be a useful approach. But combination therapy is more expensive, not approved, and potentially has more side effects,” said Bilezikian, who noted that he has no osteoporosis patients on this combination therapy.
Two anti-sclerostin antibodies are being tested in osteoporosis, romosozumab and blosozumab. These drugs are “powerfully anabolic but have little effect on osteoclasts,” he said. There is evidence of bone modeling in humans.
Phase I and II studies of romosozumab show early, marked effects of sclerostin inhibition, but transient increase in markers of bone formation; modest, persistent reduction in bone resorption; and substantial increases in BMD. Phase III studies are underway.
Blosozumab shows similar effects in phase II studies with “impressive increases in bone formation,” he said.
Five years from now, Bilezikian predicted, “we will have the same drugs now available plus abateriparatide, 2 anti-sclerotin molecules, and a new class of cathepsin K inhibitors. The field is moving rapidly in a positive direction. The challenges will be how to prove efficacy, what instruments will be the best to demonstrate improved bone strength, what bone qualities are we going to focus on. Will these new approaches be safe, will they be specific to bone, and will they be affordable?”
Dr. Bilezikian has relationships with Radius Health, the developer of abaloparatide, Amgen, which is developing romosozumab, and Merck, which has sought FDA approval for oda