CHICAGO—During the ACR’s 2014 State-of-the-Art Clinical Symposium, Beatrice Edwards, MD, MPH, associate professor and geriatrician in the Department of General Internal Medicine at the M.D. Anderson Cancer Center at the University of Texas, said rheumatologists have reason to be optimistic about the prospects of a new treatment for osteoporosis.
Odanacatib
Bisphosphonates inhibit the production of osteoclasts, thus interrupting the normal cycle of bone resorption and formation.
“We’ve all heard the concerns with bisphosphonates, and the sporadic adverse events have really raised fear in the community,” Dr. Edwards said. One recent study found as many as 20% of patients discontinue their treatment with bisphosphonates.
According to Dr. Edwards, a new drug may soon offer an alternative to bisphosphonates. Odanacatib is a cathepsin-K inhibitor, a mechanism of action that reduces bone resorption without hindering bone formation, which is a primary problem with bisphosphonates.
“Cathepsin-K inhibitors only work on the enzyme and won’t affect the number or viability of osteoclasts,” Dr. Edwards said.
High-resolution quantitative computed tomography imaging of primates given odanacatib show improvements in the biomechanical strength of bone, Dr. Edwards said.
The Evidence
In a three-year, randomized controlled trial, the bone mineral density of the lumbar spine was up nearly 7%,1 “which is greater than what we tend to see in bisphosphonates, so it’s a very robust agent,” Dr. Edwards said.
For the hip, the density increase was almost 4%.
“At all sites studied, this is an agent that will produce an increase in bone density,” Dr. Edwards said.
Dr. Edwards said one concern with bone-resorption medications is that they might linger in the body long after patients stop using them. But that does not appear to be a problem with odanacatib. Graphs over time bear this out, she said.
“You see the bone-resorption markers are down [when use of the drug begins],” she said. “And there’s a discontinuation at 24 months. You see the bone-resorption markers shoot up. What this is telling us is that the drug doesn’t stay in bone very long.”
This is a sharp contrast from bisphosphonates, she noted.
“If you were to do this on bisphosphonates and you treated people for two years and you monitored their bone resorption markers, you would find that they persist low even after discontinuing the drug,” she said.
Before approval [of odanacatib] by the FDA, investigators will probably have to show that the drug prevents vertebral fractures, which has not yet been demonstrated.
“We are concerned with the drugs persisting in the skeleton,” she said. But with odanacatib, it appears that the metabolism of the bone returns to where it was originally. “This is a very welcome finding. … When you stop it, within two months, you’re starting to see an increase in bone resorption.”
One measure of bone strength is cortical thickness, and this increased with use of odanacatib as well, Dr. Edwards said.
The results over five years, shown in a Phase 2 trial of postmenopausal women, were even more impressive.2 At the lumbar spine, there was an increase of 11.9% in bone mineral density. In the case of total hip, it was about 6%.
“It’s very substantial; it’s not something that you’re going to miss,” she said.
Another plus was the patients’ response rate. “Most of the patients responded; there was not a large number of nonresponders,” Dr. Edwards said. “We tend to see about 4–5% of patients not responding to therapy. Here that was not an issue.”
The number of adverse events and discontinuations due to adverse events has been about the same as those on placebo.
The Promise
“So we have a drug that is an antiresorptive, that does not impair bone formation, but definitely shows effectiveness in inhibiting bone resorption,” Dr. Edwards said. “It increases bone mass. It increases volumetric bone mass. It increases biomechanical strength of the bone. It increases cortical thickness, all of which are elements that contribute to bone strength. So it seems fairly favorable.”
Before it can gain FDA approval, the investigators will have to show the drug prevents vertebral fractures, which has not yet been demonstrated, she said.
Romosozumab
Another promising osteoporosis agent, Dr. Edwards said, is the monoclonal antibody romosozumab that targets sclerostin, a protein in osteocytes whose main function is to inhibit bone formation.
A one-year study has shown increases in volumetric bone density at the spine and hip in patients on romosozumab. Like odanacatib, this drug has not yet been shown to prevent fractures, which will be a requirement before gaining FDA approval, Dr. Edwards said.
“It is very welcome to have a second anabolic agent,” Dr. Edwards said, “although this one will likely only be used for a year at a time [because] it loses some efficacy after 12 months. It opens up a new generation of drugs that we can consider for our patients.”
Thomas R. Collins is a freelance medical writer based in Florida.
References
- Eisman JA, Bone HG, Hosking DJ, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three-year continued therapy and resolution of effect. J Bone Miner Res. 2011;26(2):242–251.
- Langdahl B, Binkley N, Bone H, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: Five years of continued therapy in a phase 2 study. J Bone Miner Res. 2012;27(11):2251–2258.
